Kurzgesagt – In a Nutshell 

Sources – The Woman Who Cured Her Own Cancer

We are indebted to Dr. Beata Halassy (University of Zagreb, Croatia) for her support, insights and critical feedback in producing this video.

We also thank the following experts for their feedback and corrections:

– Dr. Dirk Nettelbeck

German Cancer Research Center (DKFZ), Heidelberg, Germany

– Prof. Dr. med. Ulrich M. Lauer

University of Tübingen, Germany

Disclaimer: This script is based on the published study about Dr. Beata Halassy’s case (DOI: 10.3390/vaccines12090958), personal communication between Dr. Halassy and our editorial team, as well as broader research on oncolytic viruses and expert input. In some cases, we include scientifically grounded inferences about likely cellular mechanisms based on general knowledge of oncolytic virotherapy, even if these were not directly measured in Dr. Halassy’s case. Dr. Halassy – an expert virologist herself – reviewed and approved the final version of this script.

– It had been a few years since Beata had been diagnosed with breast cancer - a pretty bad one. After a surgery to remove as much of the cancer as possible she went through four cycles of a pretty harsh dose of chemotherapy. The goal was to eliminate every last cancer cell that was still hiding in her body. And the chemo did its job – all rapidly dividing cells in Beata's body died en mass – the cells of her immune system, hair and mucosa and digestive system died in droves. We’ll spare you the details, but it was not fun. Beata was sure that if this harsh treatment would not destroy the cancer completely, then nothing would. Unfortunately at least one cell survived. After two years it came back again and was removed again. And again it came back, stronger, bigger and now even more dangerous than before. A hard dark mass that had begun invading Beata's muscles and skin, getting ready to spread all over her body. Stage 3b.

#Forčić D, Mršić K, Perić-Balja M, Kurtović T, Ramić S, Silovski T, Pedišić I, Milas I, Halassy B. An Unconventional Case Study of Neoadjuvant Oncolytic Virotherapy for Recurrent Breast Cancer. Vaccines. 2024

https://www.mdpi.com/2076-393X/12/9/958 

Quote: “The patient was a 50-year-old woman with a history of local recurrence of triple-negative breast cancer (TNBC), as specified in the Supplementary Materials. The tumour was first diagnosed in 2016 with several foci of invasive ductal cancer and was treated by mastectomy followed by adjuvant chemotherapy. In 2018, a small TNBC local recurrence below the suture from the previous mastectomy was surgically removed. However, a small seroma (<1 cm) remained at the site of excision, which was periodically monitored. Phase contrast magnetic resonance imaging (MRI) in 2020 showed that the structure so far described as “seroma” had progressed to a 2 cm diameter solid tumour. It appeared as a hard, palpable, bright red and inflamed nodule with a thin skin above it. Different imaging techniques described it as a circled plate at the base (chest wall side), with a bulging hill at the skin side. MRI, PET-CT scan, and two independent ultrasound estimations all gave matching tumour volume estimations of 2.47 ± 0.06 cm3. MRI showed that the tumour had invaded into the pectoral muscle, which was supported by the PET-CT. Skin infiltration was identified on all three of the diagnostic imaging methods. The PET-CT scan showed no evidence of metastatic disease or local spread to regional lymph nodes.”

#Forčić D, Mršić K, Perić-Balja M, Kurtović T, Ramić S, Silovski T, Pedišić I, Milas I, Halassy B. An Unconventional Case Study of Neoadjuvant Oncolytic Virotherapy for Recurrent Breast Cancer. Vaccines. 2024 [Supplemental Material]

https://www.mdpi.com/article/10.3390/vaccines12090958/s1 

Quote: “First diagnosis

The tumour was first diagnosed in 2016 after sudden (overnight) swelling of the whole breast, which was treated surgically (mastectomy) followed by adjuvant chemotherapy with doxorubicin and cyclophosphamide (4 cycles with 60 and 600 mg/m2, respectively). Histopathological analysis of excised breast revealed several foci of invasive ductal cancer (largest 0.7 cm) negative for oestrogen receptors, progesterone receptors and HER2 (ER 0, PR 0, HER2 0), while the 80% of the tumour mass contained in situ cancer of the same triple negative phenotype. The tumour was of histological grade III with lymphovascular (LVI) and perineural (PNI) invasion, with proliferation index Ki67 55%, and was negative for androgen receptor, CK 5/6, and CK 14.

First recurrence

In 2018 a small local recurrence at the site of the previous surgery (below the suture) was detected and surgically removed (TNBC, grade III, 0.4 cm, ER 0, PR 0, HER2 0, LVI and PNI negative, Ki67 23%). No adjuvant therapy was administered per the wish of the patient. However, a small seroma (<1 cm) remained at the site of excision and this was periodically monitored.

Second recurrence

Phase contrast magnetic resonance imaging (MRI) in August 2020 (as part of a regular monitoring protocol) showed that the structure so far described as “seroma” had progressed to become a 2 cm diameter solid tumour (in January 2020 the size of “seroma” was estimated to 1.2 cm by ultrasound and mammography). [...] At baseline the recurrent tumour was described as a hard, palpable nodule on the chest wall, at the site of previous mastectomy, bellow the surgical suture from the previous operations. The tumour was further described as being bright red, inflamed, and with a thin skin above it. Different imaging techniques described it as a circled plate at the base (chest wall side), with a bulging hill at the skin side. MRI, PET-CT scan, and two independent ultrasound estimations all gave matching tumour volume estimations of 2.47 ± 0.06 cm3. MRI showed that the tumour had invaded into the pectoral muscle and this was supported by the PET-CT. Skin infiltration was identified on all three of the diagnostic imaging methods. Under ultrasound, the tumour appeared as a hypoechoic and spiculated mass. PET-CT scan showed no evidence for metastatic disease or local spread to regional lymph nodes.”

We also received these insights into her treatment journey from Dr. Halassy herself (March 2026):

Quote: “I had only one round of chemotherapy during the initial diagnosis of my illness. After the surgery, I received four cycles of standard chemotherapy with doxorubicin and cyclophosphamide. The goal was to eliminate any cancer cells that might have remained after the operation. The chemotherapy did exactly what it is designed to do—it destroyed rapidly dividing cells. As a result, my hair fell out, my white blood cell count dropped significantly, and my mucosal tissues became very thin and prone to bleeding. [...] At the time, I told my doctor that if this treatment didn’t manage to destroy those few remaining cancer cells, then nothing would. Unfortunately, two years later, we discovered that the treatment had not eliminated the cancer. I decided I will not take chemotherapy any more. The second time, we only excised the recurrent tumor at the site of the previous surgery. I chose not to undergo chemotherapy again, as I had not yet fully recovered from the previous treatment. When it arrived for the third time, in less that two years, again at the site of the previous surgery, it was in its biggest form, started to spread in the surrounding tissue. It was staged 3b.”

#Cancer Research UK – Stage 3 breast cancer. Retrieved May 2026

https://www.cancerresearchuk.org/about-cancer/breast-cancer/stages-grades/stage-3

Quote: “Stage 3B means the cancer has spread to the skin of the breast or the chest wall. The chest wall means the structures surrounding and protecting the lungs, such as the ribs, muscles, skin or connective tissues. The cancer has made the skin break down (an ulcer) or caused swelling. The cancer may have spread to up to 9 lymph nodes in the armpit or to the lymph nodes near the breastbone.”

– If it was allowed to succeed, her chances of survival were very slim. 

“If it was allowed to succeed” refers to a scenario where the cancer would start to metastasize, i.e. spread into distant tissues. Dr. Halassy was initially diagnosed with triple-negative breast cancer (TNBC).  The median survival of metastatic TNBC is roughly 8-13 months. 

Later during her treatment, her tumour had changed to type “HER2 3+.” The median survival of metastatic HER2 3+ breast cancer is roughly 40-55 months (3-4 years).

#Kesireddy M, Elsayed L, Shostrom VK, Agarwal P, Asif S, Yellala A, Krishnamurthy J. Overall Survival and Prognostic Factors in Metastatic Triple-Negative Breast Cancer: A National Cancer Database Analysis. Cancers. 2024

https://www.mdpi.com/2072-6694/16/10/1791

Quote: “Metastatic triple-negative breast cancer is an aggressive cancer with an average survival of 8 to 13 months.”

#Leone J, Moges R, Leone J et al. Factors Associated With Short- and Long-Term Survival in Metastatic HER2-Positive Breast Cancer. Clinical Breast Cancer, 2025

https://www.clinical-breast-cancer.com/article/S1526-8209(25)00002-3/abstract 

Quote: “Overall, 5576 patients were included. Median follow up was 48 months (interquartile range 25-73 months), and median OS was 41 months. The proportion alive at 2, 5, and 8 years was 63.3% (95% confidence interval [CI] 62.0%-64.7%), 37.8% (95% CI, 36.2%-39.4%), and 26.8% (95% CI, 24.8%-28.9%), respectively. Factors associated with short-term OS were older age; Black race; nonductal nonlobular; brain, liver, or lung metastases; estrogen/progesterone receptor (ER/PR)-negative disease, and lower income (all P < .04). Number of metastatic organ sites was not significant. Factors associated with long-term OS were younger age, White race, fewer metastatic organ sites, ER/PR-positive disease, and higher income (all P < .02). Specific organ sites were not significant.”

#Kesireddy M, Masih D, Shostrom VK, Yellala A, Asif S, Krishnamurthy J. Overall Survival and Prognostic Factors in De Novo Metastatic Human Epidermal Growth Factor Receptor (HER)-2-Positive Breast Cancer: A National Cancer Database Analysis. Cancers. 2025

https://www.mdpi.com/2072-6694/17/11/1823 

Quote: “Results: Among 5376 women with metastatic HER2-positive breast cancer from 2010 to 2020, the median OS was 55.95 months (95% CI 53.55-NE). Multivariate analysis identified age, Charlson–Deyo comorbidity score, histology, HER2 IHC expression, hormone receptor status, the number of metastatic sites, metastasis location, first-line chemotherapy, anti-HER2 therapy, hormone-blocking therapy, surgery at primary/non-primary sites, and palliative treatment as significant factors affecting OS. Race and radiation receipt were not significant.”

– This is where Beata decided to take care of this cancer herself, with the support of her colleagues –  because they actually had a unique mix of expertise and resources. Her plan was as simple as it was daring: They would breed viruses that they were deeply familiar with from her lab and inject them directly into her cancer.

#Forčić D, Mršić K, Perić-Balja M, Kurtović T, Ramić S, Silovski T, Pedišić I, Milas I, Halassy B. An Unconventional Case Study of Neoadjuvant Oncolytic Virotherapy for Recurrent Breast Cancer. Vaccines. 2024

https://www.mdpi.com/2076-393X/12/9/958 

Quote: “The patient, who is also an expert virologist, anticipating that the recurrent tumour would be of TNBC phenotype for which therapies of only limited efficacies exist, informed her oncologists that she was going to treat this tumour by the i.t. administration of viruses similar to oncolytic viruses (that were in clinical development for BC) before undergoing any other treatment. Her oncologists agreed to monitor the progress of the treatment, primarily with the aim of discontinuing the injections and intervening with conventional therapy in the event of adverse effects or tumour progression (which has not occurred). OVT started immediately after all necessary baseline diagnostic tests had been run, including core needle biopsy sampling of the tumour.”

#Forčić D, Mršić K, Perić-Balja M, Kurtović T, Ramić S, Silovski T, Pedišić I, Milas I, Halassy B. An Unconventional Case Study of Neoadjuvant Oncolytic Virotherapy for Recurrent Breast Cancer. Vaccines. 2024 [Supplemental Material]

https://www.mdpi.com/article/10.3390/vaccines12090958/s1 

Quote: “The patient, who is also a virologist (1-7) and anticipating that the recurrent tumour would be of TNBC phenotype for which no specific and effective therapy exists, informed her oncologists that she was going to try to treat this tumour by the i.t. administration of viruses similar to the oncolytic viruses (OVs) that are in clinical development for breast cancer, before trying any other

treatment. Her oncologists accepted to monitor the progress of the treatment, mainly with the aim to stop the injections and intervene with conventional therapy if there were untoward effects or if the tumour progressed. The oncolytic virotherapy (OVT) started immediately after all necessary baseline diagnostic tests had been run, including FDG PET-CT scan and core needle biopsy sampling of the tumour.”

– Like many medical advances this one was discovered by accident. In the early 20th century baffled doctors observed that the tumors of some cancer patients shrank when they got virus infections like influenza or measles.

#Kelly E, Russell S. History of Oncolytic Viruses: Genesis to Genetic Engineering. Molecular Therapy. 2007

linkinghub.elsevier.com/retrieve/pii/S1525-0016(16)31331-4

Quote: “Since the turn of the nineteenth century, when their existence was first recognized, viruses have attracted considerable interest as possible agents of tumor destruction. Early case reports emphasized regression of cancers during naturally acquired virus infections, providing the basis for clinical trials where body fluids containing human or animal viruses were used to transmit infections to cancer patients. Most often the viruses were arrested by the host immune system and failed to impact tumor growth, but sometimes, in immunosuppressed patients, infection persisted and tumors regressed, although morbidity as a result of the infection of normal tissues was unacceptable. With the advent of rodent models and new methods for virus propagation, there were numerous attempts through the 1950s and 1960s to force the evolution of viruses with greater tumor specificity, but success was limited and many researchers abandoned the field. Technology employing reverse genetics later brought about a renewal of interest in virotherapy that allowed the generation of more potent, tumor-specific oncolytics. Here, examination of early oncolytic virotherapy before genetic engineering serves to highlight tremendous advances, yet also hints at ways to penetrate host immune defenses, a significant remaining challenge in modern virotherapy research.”

– When regular cells are infected with a virus they fight back hard and without compromise: First they slow down, calming their internal machinery so the virus has a harder time taking them over and making copies of itself. 

Host cells infected by a virus can selectively rewire metabolic pathways – often via so-called interferons – to starve viruses of critical nutrients and generate antiviral metabolites. Some of this requires a downregulation of cell-internal machinery, for example with the aim of stopping to produce metabolites that the virus needs for replication in the infected cell.

#Yang Liu et al. N6-methyladenosine RNA modification–mediated cellular metabolism rewiring inhibits viral replication. Science (2019)

https://www.science.org/doi/10.1126/science.aax4468 

Quote: “Host cell metabolism can be modulated by viral infection, affecting viral survival or clearance. Yet the cellular metabolism rewiring mediated by the N6-methyladenosine (m6A) modification in interactions between virus and host remains largely unknown. Here we report that in response to viral infection, host cells impair the enzymatic activity of the RNA m6A demethylase ALKBH5. This behavior increases the m6A methylation on α-ketoglutarate dehydrogenase (OGDH) messenger RNA (mRNA) to reduce its mRNA stability and protein expression. Reduced OGDH decreases the production of the metabolite itaconate that is required for viral replication. With reduced OGDH and itaconate production in vivo, Alkbh5-deficient mice display innate immune response–independent resistance to viral exposure. Our findings reveal that m6A RNA modification–mediated down-regulation of the OGDH-itaconate pathway reprograms cellular metabolism to inhibit viral replication, proposing potential targets for controlling viral infection.”

#Bhattacharjee, P., Wang, D., Anderson, D. et al. The immune response to RNA suppresses nucleic acid synthesis by limiting ribose 5-phosphate. EMBO J (2024).

https://link.springer.com/article/10.1038/s44318-024-00100-w 

Quote: “During infection, viruses hijack the host cell metabolism to promote their replication by altering the breakdown of glucose (Abrantes et al, 2012; Landini, 1984; Vastag et al, 2011; Xie et al, 2017), with metabolic analysis identifying anabolic processes are boosted through increased PPP activity (Chen et al, 2011; Delgado et al, 2012; Guo et al, 2019; Liu et al, 2015; Shi et al, 2016; Wang et al, 2016b; Yau et al, 2021). We identify that PKR counters this by selectively limiting a pentose precursor molecule that is required by viruses to replicate their genome. The findings identify a previously unknown immune-mediated metabolic adaptation to limit the replicative capacity of viruses during infection that has the potential to treat infectious pathogenesis.”

#Sengupta P, Chattopadhyay S. Interferons in Viral Infections. Viruses. 2024

https://pmc.ncbi.nlm.nih.gov/articles/PMC10974426/ 

Quote: “Interferons (IFNs) are cytokines that inhibit viral replication in host cells by triggering innate immune responses through the transcriptional induction of various IFN-stimulated genes (ISGs) [1,2]. Innate immunity is the first line of defense triggered a virus entering the body. The initiation of the innate immune response is facilitated by recognizing the nucleic acids (RNA or DNA genomes and mRNA) formed during viral replication [3]. These viral nucleic acids are recognized by cellular sensor proteins known as pattern recognition receptors (PRRs), recruited during viral infection. For instance, RNA viruses are recognized by endosomal transmembrane toll-like receptors (TLR3, TLR7, and TLR8) and by cytoplasmic RIG-I-like receptors (RLRs). Meanwhile, DNA viruses are recognized by endosomal TLR9 and several cytoplasmic DNA sensors, such as cyclic GMP-AMP synthase (cGAS) [4,5,6]. TLRs are preferentially expressed in myeloid cells, such as plasmacytoid dendritic cells and macrophages, while RLRs and DNA sensors are expressed in epithelial cells and fibroblasts. Activated PRRs, in turn, trigger downstream signaling cascades that activate transcription factors such as interferon regulatory factors (IRFs) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Activating these transcription factors leads to the induction of type-I IFNs and other proinflammatory cytokines [7]. Type-I IFN binds to the dimeric type-I IFN receptor, IFNAR, which activates the JAK-STAT signaling pathway to induce interferon-stimulated genes (ISGs). Thus, the cross-talk between IFN signaling and the pathways regulating the apoptotic and inflammatory responses elicits an antiviral state in the cell [8].

As mentioned above, this interferon signaling is exhibited primarily by two types of transcription factors: IRFs and NF-κB. There are nine IRF members in mammalian cells, of which five IRFs (IRF1, IRF3, IRF5, IRF7, and IRF8) are positive regulators of type-I IFN [9]. IRF3 and IRF7 are key to IFN production in most immune cells. Abnormal production of IFNs is associated with various diseases that can damage cellular development and homeostasis. Thus, in the maintenance of homeostasis, fine-grained regulation of IFN production is controlled by a balance between activation (e.g., protein phosphorylation and ubiquitination) and deactivation (e.g., protein dephosphorylation and deubiquitination) of IRFs [9,10,11]. Another transcription factor that regulates IFN production is NF-κB, a master regulator of controlling cell proliferation, apoptosis, and viral infection. It is involved in canonical (elicited by diverse stimuli, such as PAMPs) and non-canonical (elicited by a narrow set of stimuli, such as lymphotoxin receptor ligands, CD40, RANK, and the viral latent membrane protein 1 (LMP1) of Epstein–Barr virus (EBV)) signaling cascades according to phosphorylation and polyubiquitination [12].

Type-I IFN signaling causes the rapid induction of antiviral genes known as ISGs. There are more than 300 ISGs, such as IFITs, PKR, MxA, OAS, viperin, ISG15, and TDRD7, that function as antiviral genes [13,14]. Many of these ISGs function as viral restriction factors by directly interfering with specific stages of virus replication. Some of them regulate the cellular proteins required for viral replication [1,15,16,17] (Figure 1).”

#Thyrsted J, Holm CK. Virus-induced metabolic reprogramming and innate sensing hereof by the infected host. Curr Opin Biotechnol. 2021

https://www.sciencedirect.com/science/article/abs/pii/S0958166920301531?via%3Dihub 

Quote: “As outlined above, viruses are highly dependent on their ability to manipulate host metabolism. It therefore seems reasonable to assume that the targeted host has developed mechanisms to either counter this and even take advantage of pathogenic viruses’ dependency on distinct metabolites. Indeed, a few anti-viral host factors have already been identified, which function by depleting the host cell of selected metabolites vital to the virus. One example hereof is the IFN-stimulated gene (ISG) sterile alpha motif and histidine-aspartate domain containing protein 1 (SAMHD1). SAMHD1 functions as a dNTP hydrolase and potently regulates the cellular dNTP pool through degradation of dNTPs into deoxynucleotides and inorganic triphosphates [40]. Through this mode of action, SAMHD1 depletes essential building blocks for DNA synthesis needed for viral replication. Accordingly, SAMHD1 functions as an important restriction factor and can effectively inhibit infection with several viruses including HIV-1, SIV and HSV-1 [41–43]. In further support of the importance of SAMHD1, several viruses have developed strategies to counter its effects. Examples hereof are viruses of the beta and gamma herpesviruses where the conserved viral protein kinase BGLF4 phosphorylates SAMHD1 to inhibit its dNTPase activities [44]. HIV and SIV also target SAMHD1 but instead of inactivation through phosphorylation, SAMHD1 is targeted for proteasomal degradation by the viral protein Vpx [42]. A second example of the host targeting its own metabolism to prevent viral replication is the interferon mediated depletion of the amino acid Tryptophan. Tryptophan is an important building block for protein synthesis and for generation of several biomolecules [45]. The degradation of tryptophan is initiated by indoleamine-2,3-dioxygenase (IDO1), which was identified as an anti-viral ISG effective in restricting HIV-1 and HIV-2 replication [46]. Forced expression of IDO1 decreases viral yield by more than 100-fold — an effect which is completely reversed by the addition of excess tryptophan to the growth medium thus supporting that the anti-viral effect of IDO1 is driven by tryptophan depletion. Subsequently, IDO1 is demonstrated to effectively restrict other viruses as well including HSV2 [47], HBV [48], Vaccinia virus [49] and Parainfluenza virus (PIV3) [50]. Finally, the induction of itaconate by ZIKV through IRG1 described above [10], was accompanied by a clear IRG1-dependent shift in cellular metabolism which included reduced succinate dehydrogenase (SDH) activity. This is in line with previous work demonstrating that itaconate inhibits SDH activity and suggests that SDH itself could be a possible sensor of itaconate [37]. This shift in metabolism could be part of the anti-viral effect of IRG1 in this case and thus serves as an example of how viruses induce metabolic changes in the host, which are then sensed and responded to by the host.”

– Then they scream for the immune system to send anti-virus killers – which usually means that they will be killed themselves.

#Bonhomme D, Poirier EZ. Early signaling pathways in virus-infected cells. Curr Opin Virol. 2024

https://www.sciencedirect.com/science/article/pii/S1879625724000257

Quote: “Virus infection activates specific pattern recognition receptors and immune signal transduction, resulting in pro-inflammatory cytokine production and activation of innate immunity. We describe here the molecular organization of early signaling pathways downstream of viral recognition, including conformational changes, post-translational modifications, formation of oligomers, and generation of small-molecule second messengers. Such molecular organization allows tight regulation of immune signal transduction, characterized by swift but transient responses, nonlinearity, and signal amplification. Pathologies of early immune signaling caused by genomic mutations illustrate the fine regulation of the immune transduction cascade.”

Natural killer cells activated to eliminate infected cells:

#Letafati, A., Ardekani, O.S., Naderisemiromi, M. et al. Unraveling the dynamic mechanisms of natural killer cells in viral infections: insights and implications. Virol J 21, 18 (2024).

https://link.springer.com/article/10.1186/s12985-024-02287-0 

Quote: “Viral infections continue to pose an enduring challenge to human health, giving rise to a wide spectrum of illnesses that vary in their severity and can even result in fatal outcomes. Indeed, recent assessments have underscored the noteworthy influence of viral infections on the overall burden of cancer across the globe, accounting for roughly 10% of the total cancer burden worldwide. The outcome of an infection heavily relies on the intricate interaction between viruses and the host immune system. Natural killer (NK) cells, among the various cellular elements of the immune system, have been recognized as crucial participants in the protection against viral infections. These remarkable innate immune cells possess the unique ability to directly recognize and eliminate infected cells, making them crucial in the early control and containment of viral pathogens [1, 2]. 

NK cells, classified as innate lymphocytes, play a pivotal role as an initial defense mechanism against both tumors and viral infections. The increased susceptibility to viral diseases observed in people with congenital NK cell deficiency emphasizes the importance of NK cells in the immune response against viruses [3]. Humans have two major subsets of NK cells (CD56brightCD16low/− and CD56dimCD16+), which have different functions in immunity. CD56bright cells play a more immunomodulatory role and can generate significant quantities of cytokines. These cells possess limited capacity to eliminate targeted cells while CD56dim cells serve as cytotoxic effectors and it has the ability to cause lysis in target cells [4]. NK cells are finely tuned to recognize and react to viral infections through a complex interplay of activating and inhibitory receptors. These receptors allow NK cells to differentiate between healthy cells and those infected by viruses. The activation status and subsequent response of NK cells depend on the interplay between activating and inhibitory signals [5, 6]. When NK cells are activated, they deploy various mechanisms to eliminate cells infected by viruses. One of their main methods involves directly eliminating targeted cells by releasing cytotoxic granules that contain perforin and granzymes. Perforin creates pores in the target cell membrane, allowing granzymes to enter and initiate the process of apoptosis. Additionally, NK cells have the capability to initiate the death of target cells by interacting with death receptors through the Fas ligand (FasL) or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) [7, 8]. Apart from their cytotoxic effects, NK cells play a significant role in the antiviral defense by releasing a diverse array of proinflammatory cytokines that possess antiviral properties [9]. Moreover, NK cells can induce apoptosis by binding to antibodies that have opsonized infected cells, using the CD16 receptor. This mechanism, referred to as antibody-dependent cellular cytotoxicity (ADCC) [10]. These effector functions collectively contribute to the elimination of infected cells and limit viral spread.”

– And if they can, they push their self-destruct button and take the virus with them.

#Jorgensen, I., Rayamajhi, M. & Miao, E. Programmed cell death as a defence against infection. Nat Rev Immunol 17, 151–164 (2017).

https://www.nature.com/articles/nri.2016.147

Quote: “Programmed cell death (PCD) is a well-studied cellular mechanism that plays a critical role in immune responses, developmental processes, and the maintenance of tissue homeostasis. However, viruses have developed diverse strategies to bypass or manipulate the host apoptotic machinery to enhance their replication and survival. As a result, the interaction between PCD pathways and viruses has garnered increased interest, leading to many studies being published in recent years. This study aims to provide an overview of the current understanding of PCD pathways and their significance in viral infections. We will discuss various forms of cell death pathways, including apoptosis, autophagy, necroptosis, and pyroptosis, as well as their corresponding molecular mechanisms. In addition, we will show how viruses manipulate host PCD pathways to prevent or delay cell death or facilitate viral replication. This study emphasizes the importance of investigating the mechanisms by which viruses control the host’s PCD machinery to gain insight into the evolutionary dynamics of host-pathogen interactions and to develop new approaches for predicting and managing viral threats. Overall, we aimed to highlight new research areas in PCD and viruses, including introduction of new targets for the development of new antiviral drugs to modulate the cellular apoptotic machinery and novel inhibitors of host cell death pathways.”

– Cancer cells are unable to use any of these defenses, exactly because of the corruption that makes them cancer. 

Cancer cells are typically less able to defend themselves against viral attacks, i.e. they are more susceptible to them. However, this depends on the kind of virus, and the kind of tumour, so it is not a hard rule. For treatment of cancer with viruses, viruses are specifically selected for their ability to kill cancer cells better than they kill non-cancer cells. They can also be engineered to be even more specific to cancer cells.

#Appleton E, Chiocca EA, Ungerechts G, Melcher A, Vile R. Oncolytic viruses as anticancer agents: clinical progress and remaining challenges. Lancet. 2025

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(25)01206-1/abstract

Quote: “Tumour cells are commonly inherently vulnerable to viral infection in comparison to normal tissue, through mechanisms including interferon signalling defects, tumour-intrinsic immunosuppression, and resistance to apoptosis.”

#Matveeva OV, Chumakov PM. Defects in interferon pathways as potential biomarkers of sensitivity to oncolytic viruses. Rev Med Virol. 2018

https://onlinelibrary.wiley.com/doi/10.1002/rmv.2008 

Quote: “Increased sensitivity of cancer cells to viruses is a prerequisite for the success of oncolytic virotherapy. One of the major causes of such a phenotype is the disruption of innate antiviral defenses associated with dysfunction of type 1 interferons (IFNs) that permits unlimited replication of viruses in cancer cells. Defects in IFN pathways help cancer progression by providing additional advantages to tumor cells. However, while these defects promote the survival and accelerated proliferation of malignant cells, they facilitate viral replication and thus enhance the efficiency of viral oncolysis. This review describes a broad spectrum of defects in genes that participate in IFN induction and IFN response pathways. Expression levels and/or functional activities of these genes are frequently low or absent in cancer cells, making them sensitive to virus infection. Therefore, certain specific defects in IFN signaling cascades might serve as potential biomarkers to help in identifying individual cancer patients who are likely to benefit from oncolytic virotherapy.”

#Kim, M., Williamson, C., Prudhomme, J. et al. The viral tropism of two distinct oncolytic viruses, reovirus and myxoma virus, is modulated by cellular tumor suppressor gene status. Oncogene 29, 3990–3996 (2010).

https://www.nature.com/articles/onc2010137 

Quote: “Replication-competent oncolytic viruses hold great potential for the clinical treatment of many cancers. Importantly, many oncolytic virus candidates, such as reovirus and myxoma virus, preferentially infect cancer cells bearing abnormal cellular signaling pathways. Reovirus and myxoma virus are highly responsive to activated Ras and Akt signaling pathways, respectively, for their specificity for viral oncolysis. However, considering the complexity of cancer cell populations, it is possible that other tumor-specific signaling pathways may also contribute to viral discrimination between normal versus cancer cells. Because carcinogenesis is a multistep process involving the accumulation of both oncogene activations and the inactivation of tumor suppressor genes, we speculated that not only oncogenes but also tumor suppressor genes may have an important role in determining the tropism of these viruses for cancer cells. It has been previously shown that many cellular tumor suppressor genes, such as p53, ATM and Rb, are important for maintaining genomic stability; dysfunction of these tumor suppressors may disrupt intact cellular antiviral activity due to the accumulation of genomic instability or due to interference with apoptotic signaling. Therefore, we speculated that cells with dysfunctional tumor suppressors may display enhanced susceptibility to challenge with these oncolytic viruses, as previously seen with adenovirus. We report here that both reovirus and myxoma virus preferentially infect cancer cells bearing dysfunctional or deleted p53, ATM and Rb tumor suppressor genes compared to cells retaining normal counterparts of these genes. Thus, oncolysis by these viruses may be influenced by both oncogenic activation and tumor suppressor status.”

#Hanahan D. Hallmarks of cancer—Then and now, and beyond. Cell, 2026

https://www.cell.com/cell/fulltext/S0092-8674(25)01498-9

Quote: “A qualitatively distinct anti-proliferative cancer hallmark involves circumventing protective mechanisms that serve to eliminate aberrant or damaged cells—including cancer cells—via the induction of regulated pathways of cell suicide collectively termed “programmed cell death.”

– They are unhinged and hyperactive, eating and reproducing feverishly, unable to slow down.

Cancer cells generally proliferate faster and more persistently than most normal human cells. This phenomenon constitutes 2 of the “hallmarks of cancer” – “sustaining proliferative signaling (cancer cells constantly instruct themselves to grow and divide) and “evading growth suppressors” (cells ignore signals that would normally stop cell division).

#Hanahan D. Hallmarks of cancer—Then and now, and beyond. Cell, 2026

https://www.cell.com/cell/fulltext/S0092-8674(25)01498-9 

Quote: “As a fundamentally expansive disease, sustaining proliferative signaling of cancer cells is an obvious hallmark capability, one that is deeply embedded in our knowledge base about cancer. A majority of cancers contain activating mutations or chromosomal rearrangements in genes—dubbed oncogenes—that serve to chronically sustain otherwise transitory cell proliferation via triggering and stimulating progression through the cell division cycle. [...] The second hallmark capability is intuitively complementary to the first, given that the carefully orchestrated proliferation of normal cells during development and homeostasis is controlled not only by transitory proliferative signals but also by negative feedback loops and other mechanisms that activate genes encoding proteins that suppress cell proliferation. Both cell-intrinsic and -extrinsic mechanisms of growth suppression have been described, and these are variably inactivated or attenuated in fully developed cancers.”

– Cancer cells also can’t really call the immune system to help them out because it is trying really hard to kill them. 

One of the “hallmarks of cancer” is that cancer cells try to evade detection – and destruction – by the immune system. They do this by e.g. suppressing the immune system or avoiding to trigger the immune system response.

#Hanahan D. Hallmarks of cancer—Then and now, and beyond. Cell, 2026

https://www.cell.com/cell/fulltext/S0092-8674(25)01498-9 

Quote: “Evading immune destruction

It is now integral to our conceptualization that cancers almost invariably avoid attack and immune destruction by acquiring the hallmark capability to suppress the adaptive and certain components of the innate immune systems that recognize and would otherwise react against neoplastic abnormalities.”

#Tufail, M., Jiang, CH. & Li, N. Immune evasion in cancer: mechanisms and cutting-edge therapeutic approaches. Sig Transduct Target Ther 10, 227 (2025).

https://www.nature.com/articles/s41392-025-02280-1 

Quote: “Immune evasion represents a significant challenge in oncology. It allows tumors to evade immune surveillance and destruction, thereby complicating therapeutic interventions and contributing to suboptimal patient outcomes. This review addresses the critical need to understand how cancers evade immune surveillance. It aims to provide a comprehensive overview of strategies of tumors to escape immune detection by examining tumor-induced immune suppression, immune checkpoint regulation, and genetic and epigenetic influences. Moreover, it explores the dynamic role of the tumor microenvironment (TME) in fostering immune resistance and highlights the impact of metabolic reprogramming on immune suppression. Additionally, this review focuses on how tumor heterogeneity influences immune evasion and discusses the limitations of current immunotherapies.”

– Successful cancers actually build a protective zone around them that hides them from immune cells or even kills them. 

The tumour microenvironment (TME) is the local environment surrounding a tumour, made up of cancer cells, immune cells, and signaling molecules. It also has special chemical properties. Tumours actively shape this environment to support their growth, for example by suppressing immune responses and limiting immune cell access and replication. In many cases, the TME can also impair immune cell function or induce their exhaustion or death, helping the cancer evade immune surveillance.

#Tufail, M., Jiang, CH. & Li, N. Immune evasion in cancer: mechanisms and cutting-edge therapeutic approaches. Sig Transduct Target Ther 10, 227 (2025).

https://www.nature.com/articles/s41392-025-02280-1

Quote: “TME modulation

The TME is a complex ecosystem of cancer cells, stromal cells, immune cells, and signaling molecules.107 This microenvironment plays a crucial role in tumor development, metastasis, and immune evasion (Fig. 1).108 The TME is not merely a passive setting for tumor growth; instead, it actively shapes the immune response through various mechanisms that collectively promote immune suppression and allow tumor cells to avoid immune surveillance.108”

#Hanahan D. Hallmarks of cancer—Then and now, and beyond. Cell, 2026

https://www.cell.com/cell/fulltext/S0092-8674(25)01498-9

Quote: “While the limitations posed by the exhaustion pathway are implicit to T cell biology, the overarching importance of evading immune destruction is substantiated by the multi-faceted immunosuppressive mechanisms operative in the TME, as well as its capability to systemically impair T cell development in the lymphoid organs. Virtually every cell type in the TME has the demonstrable capability to suppress the recruitment and/or activity of CD8 and/or CD4 T cells, albeit to varying extents in different tumor types and at different stages of multistep tumorigenesis and subsequent tumor progression. While it is not surprising that developing cancer cells—in the context of their neo-Darwinian adaptation—elaborate immunosuppressive functions, so too can endothelial cells and pericytes of the tumor vasculature, CAFs, innate immune inflammatory cells (substates of macrophages, neutrophils, and NK cells), and innervation, along with regulatory T and B cells (Treg and Breg). Moreover, the physical microenvironment can suppress T cell and NK cell-mediated immune responses in the forms of hypoxia, extracellular matrix composition, and interstitial pressure, along with the chemical milieu in the extracellular space, involving metabolic insufficiencies for T cell activity (amino acids, lipids, and sugars), in addition to the immunoregulatory factors (cytokines and chemokines, exosomes, etc.) produced by the various cell types populating the TME.”

#Augustin RC, Delgoffe GM, Najjar YG. Characteristics of the Tumor Microenvironment That Influence Immune Cell Functions: Hypoxia, Oxidative Stress, Metabolic Alterations. Cancers. 2020

https://www.mdpi.com/2072-6694/12/12/3802 

Quote: “Even with sufficient TME infiltration, immune cells face a harsh metabolic environment that can significantly impair effector function. These tumor-mediated metabolic perturbations include hypoxia, oxidative stress, and metabolites of cellular energetics. Primarily through HIF-1-dependent processes, hypoxia invokes an immunosuppressive phenotype via altered molecular markers, immune cell trafficking, and angiogenesis. Additionally, oxidative stress can promote lipid peroxidation, ER stress, and Treg dysfunction, all associated with immune dysregulation. Finally, the metabolic byproducts of lipids, amino acids, glucose, and cellular energetics are associated with immunosuppression and ICI resistance.”

#Labani-Motlagh A, Ashja-Mahdavi M and Loskog A (2020) The Tumor Microenvironment: A Milieu Hindering and Obstructing Antitumor Immune Responses.

https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.00940/full

Quote: “

Figure 1. An overview of tumor microenvironment. In the immunosuppressive TME, malignant cells debilitate the antitumor immune responses through secretion of offensive and detrimental molecules, collaboration with cancer-associated stromal cells, and exploit immune scape mechanisms to outwit the immune cells. Tumor cells alter their milieu by lowering pH and glucose but high production of VEGF, non-classical HLA class I, death ligands such as FasL and TRAIL, anti-inflammatory cytokines, and metabolites such as IDO, ROS, RNS, ONOO−, and NO. These molecules can not only inhibit the immune cells but also elicit the stroma cells and facilitate tumor development. The cancer-associated stroma cells favor tumor cells by suppressing the immune responses and even induce each other. Tregs are capable to inhibit effector immune cells, eosinophils, basophils, and mast cells. Mast cells themselves induce MDSCs by releasing histamine. Tregs also stimulate tDC via IL-10 and impose M1-TAM polarization into M2-type. In turn, M2-TAMs eliminate effector cells via non-classical HLA class I, arginase I, IL-10, TGF-β, and PD-L1. In addition, MDSCs hinder effector cells by releasing arginase I, and metabolites such as IDO, ROS, ONOO−, and iNOS. TANs are other players that eliminate CD8+ T cells. The condition becomes more complicated with CAFs that promote angiogenesis, tumor growth, and invasion.”

– And lastly, their self-destruct button is broken.

The ability to resist programmed cell death is one of the hallmarks of cancer cells.

#Hanahan D. Hallmarks of cancer—Then and now, and beyond. Cell, 2026

https://www.cell.com/cell/fulltext/S0092-8674(25)01498-9

Quote: “A qualitatively distinct anti-proliferative cancer hallmark involves circumventing protective mechanisms that serve to eliminate aberrant or damaged cells—including cancer cells—via the induction of regulated pathways of cell suicide collectively termed “programmed cell death.”

– But much worse, once a virus starts killing, all of the ensuing death, virus- and tumor particles attract the immune system which then happily joins the massacre.

Viral replication and virus‑induced cell death cause the release of so-called DAMPs (damage-associated molecular patterns), PAMPS (pathogen-associated molecular patterns), and bits of tumour, which all attract and activate the immune system.

#Tian H, Liu Q, Yu X, Cao Y, Huang X. Damage-associated molecular patterns in viral infection: potential therapeutic targets. Crit Rev Microbiol. 2025

https://pubmed.ncbi.nlm.nih.gov/39091137/ 

Quote: “Frequent viral infections leading to infectious disease outbreaks have become a significant global health concern. Fully elucidating the molecular mechanisms of the immune response against viral infections is crucial for epidemic prevention and control. The innate immune response, the host's primary defense against viral infection, plays a pivotal role and has become a breakthrough in research mechanisms. A component of the innate immune system, damage-associated molecular patterns (DAMPs) are involved in inducing inflammatory responses to viral infections. Numerous DAMPs are released from virally infected cells, activating downstream signaling pathways via internal and external receptors on immune cells. This activation triggers immune responses and helps regulate viral host invasion. This review examines the immune regulatory mechanisms of various DAMPs, such as the S100 protein family, high mobility group box 1 (HMGB1), and heat shock proteins, in various viral infections to provide a theoretical basis for designing novel antiviral drugs.”

#Workenhe ST, Mossman KL. Rewiring cancer cell death to enhance oncolytic viro-immunotherapy. Oncoimmunology. 2013

https://pmc.ncbi.nlm.nih.gov/articles/PMC3912054/ 

Quote: “The anticancer activity of OVs is mediated by their ability to directly kill malignant cells, to interfere with the tumor vasculature, and to activate the immune system against cancer. The replication of OVs leads to the lysis of neoplastic cells coupled to the release of pathogen-associated molecular patterns (PAMPs) such as viral proteins and nucleic acids. PAMPs attract immune cells to neoplastic lesions, and these cells can take up tumor-associated antigens (TAAs) released along with the cytopathic effects for priming anticancer immune responses.”

#Zhang, Y., Li, Y., Chen, K. et al. Oncolytic virotherapy reverses the immunosuppressive tumor microenvironment and its potential in combination with immunotherapy. Cancer Cell (2021).

https://link.springer.com/article/10.1186/s12935-021-01972-2 

Quote: “(2) Anti-tumor immunity: Followed by OV-induced immunogenic cell lysis, pathogen-associated molecular pattern molecules (PAMPs), damage-associated molecular pattern molecules (DAMPs), and tumor-associated antigens (TAAs) are released, triggering rapid but unspecific innate immune responses. These reactions enhance tumor and viral antigen presentation by DCs, leading to subsequent T cell priming and activation, and ultimately creating an immunostimulatory microenvironment [72]. By taking advantage of this immune-potentiating ability, enhanced anti-tumor efficacy of OVs is achieved.”

– Cancer is also very much not cooperative in its own destruction and often very hard to reach, especially if it has already spread throughout the body. 

When cancer spreads from the primary tumour to other sites of the body (metastasis), it becomes generally much harder to treat. Treatment with oncolytic viruses also suffers from this problem, because the viruses have to either be injected at numerous locations, and/or they have to travel through the blood stream to distant tissues, where they risk getting eradicated by the immune system before they can attack the cancer.

#Shi, X., Wang, X., Yao, W. et al. Mechanism insights and therapeutic intervention of tumor metastasis: latest developments and perspectives. Sig Transduct Target Ther (2024).

https://www.nature.com/articles/s41392-024-01885-2

Quote: “Metastasis remains a pivotal characteristic of cancer and is the primary contributor to cancer-associated mortality. … While primary tumors might be amenable to curative interventions like local surgery or radiation therapy, metastasis exhibits a systemic disposition. Its management necessitates an amalgamation of chemotherapy, targeted therapies, and immunotherapy, among others.”

#Xu L, Sun H, Lemoine NR, Xuan Y and Wang P (2024) Oncolytic vaccinia virus and cancer immunotherapy. Front. Immunol.

https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1324744/full 

Quote: “Intratumor administration is one of the most important limiting factors. The presence of preexisting antiviral neutralizing antibodies or their development during viral therapy render repeat systemic treatments of OVs ineffective, limiting the application in some cancer types with metastases or unable to be administrated in situ. For instance, T-VEC is only approved in patient without visceral metastases. The development of novel and more potent oncolytic viruses is urgently needed.”

#Yan, Z., Zhang, Z., Chen, Y. et al. Enhancing cancer therapy: the integration of oncolytic virus therapy with diverse treatments. Cancer Cell Int (2024).

https://link.springer.com/article/10.1186/s12935-024-03424-z 

Quote: “Effective delivery remains a major hurdle, as systemic administration often leads to rapid clearance by the immune system, and intratumoral injection is not feasible for all tumor types, especially those that are inaccessible or metastatic [69,70,71,72].”

– And in the end, you need to kill every last cell to really slay it. 

Cancer can grow back from a small number of cancer cells that survived a treatment. Since those cells often hide in tissues distant from the primary tumour, viruses have a hard time reaching there since they risk getting cleared by the immune system before they can attack the cancer cells.

#Damen, M.P.F., van Rheenen, J. and Scheele, C.L.G.J. (2021), Targeting dormant tumor cells to prevent cancer recurrence. FEBS J

https://febs.onlinelibrary.wiley.com/doi/10.1111/febs.15626 

Quote: “Over the years, developments in oncology led to significantly improved clinical outcome for cancer patients. However, cancer recurrence after initial treatment response still poses a major challenge, as it often involves more aggressive, metastatic disease. The presence of dormant cancer cells is associated with recurrence, metastasis, and poor clinical outcome, suggesting that these cells may play a crucial role in the process of disease relapse.”

#Phan, T.G., Croucher, P.I. The dormant cancer cell life cycle. Nat Rev Cancer 20 (2020).

https://www.nature.com/articles/s41568-020-0263-0 

Quote: “The success of targeted therapies and immunotherapies has created optimism that cancers may be curable. However, not all patients respond, drug resistance is common and many patients relapse owing to dormant cancer cells. These rare and elusive cells can disseminate early and hide in specialized niches in distant organs before being reactivated to cause disease relapse after successful treatment of the primary tumour.”

#Yan, Z., Zhang, Z., Chen, Y. et al. Enhancing cancer therapy: the integration of oncolytic virus therapy with diverse treatments. Cancer Cell Int (2024).

https://link.springer.com/article/10.1186/s12935-024-03424-z 

Quote: “Effective delivery remains a major hurdle, as systemic administration often leads to rapid clearance by the immune system, and intratumoral injection is not feasible for all tumor types, especially those that are inaccessible or metastatic [69,70,71,72].”

– Cancer is also a living, evolving entity and doesn’t look exactly the same in two people. So it is extremely difficult to find virotherapies that work in many different patients. 

Oncolytic virotherapy doesn’t act on a static target: tumors evolve under the viral pressure. This can for example lead to the emergence of virus-resistant cells within the tumour, limiting the effectiveness of the viral therapy.

#Larrieux, A., Sanjuán, R. Murine colon cancer derived cells exhibit heterogeneous resistance profiles against an oncolytic virus. Sci Rep (2024).

https://www.nature.com/articles/s41598-024-78313-6 

Quote: “Oncolytic viruses are promising biotherapies that exploit cellular vulnerabilities to selectively infect and replicate within tumor cells, while exempting healthy cells from the infectious process1,2,3. An extensive body of experimental evidence, conducted using both natural and engineered oncolytic viruses, such as vesicular stomatitis virus (VSV), adenovirus, herpes simplex virus, and Newcastle disease virus, among others, supports the efficacy of this therapeutic approach4. However, as other cancer therapies, oncolytic virotherapies encounter resistance challenges, including antibody and cellular responses5, interferon (IFN)-mediated resistance6,7, epigenetic modifications8,9, inactivation of cell death mechanisms, insensitivity to growth suppressor signals, and spatial barriers10,11, among many others12. For instance, many oncolytic viruses are particularly sensitive to interferon (IFN)-mediated cellular antiviral responses, and their efficacy is thus dependent on the degree of disruption of IFN signaling shown by target cells13. Unfortunately, a significant percentage of tumor cells retain intact IFN signaling, as well as constitutive expression of IFN-stimulated genes (ISGs) and resistance gene signatures14,15,16,17. Therefore, the emergence of immune-based cellular resistance in populations initially susceptible to infection represents a barrier to the development of oncolytic viruses and determines their efficacy10,16,17,18.”

#Bhatt DK, Janzen T, Daemen T, Weissing FJ. Modelling the spatial dynamics of oncolytic virotherapy in the presence of virus-resistant tumour cells. PLoS Comput Biol. 2022

https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1010076 

Quote: “Potential explanations could be technical limitations related to virus delivery and treatment, variability in cancer types, generation of weak anti-tumour immunity, individual differences among patients, and occurrence of infection-resistant cancer cells [4,8–10]. Here we focus on the role of resistance, as it remains to be a relatively unexplored area of research [11].

The presence of resistant cancer cells in the tumour tissue may restrict the efficient spread of the virus and thereby undermine its oncolytic potential. The therapeutic efficacy of a virus does therefore not only depend on the properties of the virus but also on the density and spatial configuration of resistant tumour cells, as these factors are crucial for the spatial dynamics of viral spread in the tumour. To unravel the causes of therapeutic failure it is therefore paramount to map the spatial interactions between virus, infection-sensitive cancer cells, and virus-resistant cancer cells, and to investigate the implications of these interactions for tumour eradication.

[...] Resistance to virotherapy is a relatively unexplored area. Still, diverse mechanisms have been identified in the literature (reviewed in Bhatt et al. 2021) [11], including interferon-mediated resistance, epigenetic modifications, hypoxia-mediated inhibition, APOBEC-mediated resistance, virus-entry barriers, and spatiotemporal restrictions to viral spread.”

Cancer treatment with viruses is also notorious for working great in some people but not in others. The reasons for this are complex, but they typically include tumour heterogeneity (the virus can kill some cells but not others), physical barriers (in some patients, not enough viruses can reach enough tumour cells), immune system clearance of the virus, and/or an especially immune-suppressive tumour environment that not even a viral infection can overcome. All these anti-viral-therapy factors vary in their strength from patient to patient.

#Yan, Z., Zhang, Z., Chen, Y. et al. Enhancing cancer therapy: the integration of oncolytic virus therapy with diverse treatments. Cancer Cell Int (2024).

https://link.springer.com/article/10.1186/s12935-024-03424-z 

Quote: “Despite the significant promise and advancements of oncolytic virotherapy, several challenges and obstacles persist in its clinical application. Effective delivery remains a major hurdle, as systemic administration often leads to rapid clearance by the immune system, and intratumoral injection is not feasible for all tumor types, especially those that are inaccessible or metastatic [69,70,71,72]. The heterogeneous and often immunosuppressive tumor microenvironment can further inhibit the spread and replication of OVs [73]. Additionally, pre-existing immunity to common viruses can neutralize OVs before they reach the tumor cells, and the induced immune responses can limit viral replication and spread. Tumors may also develop resistance mechanisms, reducing the efficacy of oncolytic virotherapy over time.”

#Xiao, D., Zhang, H., Liu, Y. et al. Oncolytic viruses: advanced strategies in cancer therapy. Sig Transduct Target Ther (2026).

https://www.nature.com/articles/s41392-025-02343-3 

Quote: “Despite the substantial antitumor activity observed in numerous preclinical and clinical studies, indicating its great potential as a novel immunotherapy approach, the efficacy of OVs as monotherapies remains limited, akin to many conventional cancer treatments.11 This limitation is attributed primarily to resistance mechanisms driven by tumor heterogeneity, complex genetic mutations, and the intricate composition of the TME. These factors pose significant challenges for single-agent therapies, including OVs, in achieving optimal antitumor effects independently.314”

– On top of all that, cancer is typically treated with chemotherapy first – often with incredible results and great survival rates. 

Chemotherapy is generally effective at shrinking tumors, often improving survival, and in a few cancers can be curative. But its impact can be constrained by resistance and toxicity, so chemotherapy is nowadays more often used as part of combination strategies rather than a stand‑alone cure. It is also important to note that chemotherapy is many different drugs used in different ways, depending on the patient, the type of cancer and other factors. So the average effectiveness strongly varies depending on all these factors.

#Anand U, Dey A, Chandel AKS, Sanyal R, Mishra A, Pandey DK, De Falco V, Upadhyay A, Kandimalla R, Chaudhary A, Dhanjal JK, Dewanjee S, Vallamkondu J, Pérez de la Lastra JM. Cancer chemotherapy and beyond: Current status, drug candidates, associated risks and progress in targeted therapeutics. Genes Dis. 2022

https://www.sciencedirect.com/science/article/pii/S2352304222000472

Quote: “Cancer is an abnormal state of cells where they undergo uncontrolled proliferation and produce aggressive malignancies that causes millions of deaths every year. With the new understanding of the molecular mechanism(s) of disease progression, our knowledge about the disease is snowballing, leading to the evolution of many new therapeutic regimes and their successive trials. In the past few decades, various combinations of therapies have been proposed and are presently employed in the treatment of diverse cancers. Targeted drug therapy, immunotherapy, and personalized medicines are now largely being employed, which were not common a few years back. The field of cancer discoveries and therapeutics are evolving fast as cancer type-specific biomarkers are progressively being identified and several types of cancers are nowadays undergoing systematic therapies, extending patients' disease-free survival thereafter. Although growing evidence shows that a systematic and targeted approach could be the future of cancer medicine, chemotherapy remains a largely opted therapeutic option despite its known side effects on the patient's physical and psychological health. Chemotherapeutic agents/pharmaceuticals served a great purpose over the past few decades and have remained the frontline choice for advanced-stage malignancies where surgery and/or radiation therapy cannot be prescribed due to specific reasons. The present report succinctly reviews the existing and contemporary advancements in chemotherapy and assesses the status of the enrolled drugs/pharmaceuticals; it also comprehensively discusses the emerging role of specific/targeted therapeutic strategies that are presently being employed to achieve better clinical success/survival rate in cancer patients.”

#Anand U, Dey A, Chandel AKS, Sanyal R, Mishra A, Pandey DK, De Falco V, Upadhyay A, Kandimalla R, Chaudhary A, Dhanjal JK, Dewanjee S, Vallamkondu J, Pérez de la Lastra JM. Cancer chemotherapy and beyond: Current status, drug candidates, associated risks and progress in targeted therapeutics. Genes Dis. 2022 Mar 18;10(4):1367-1401. doi: 10.1016/j.gendis.2022.02.007. Erratum in: Genes Dis. 2024

https://pmc.ncbi.nlm.nih.gov/articles/PMC10310991/ 

Quote: “Revised clinical strategies further underlined that combination therapy could emerge as a promising therapeutic approach to treat diverse cancers in the future. Combination strategies comprise an obvious overlap of the chemotherapeutic regimes with the targeted drug delivery, personalized medicine, and immunotherapy. It may not only improve the efficacy of enrolled treatment but can also elicit the responsiveness of certain tumors towards their effective therapeutic targeting in the clinic. Among these, personalized combination therapies that target individual tumor types based on their molecular signatures may offer a great promise. With acquiring more personalized insights in the chemotherapeutic treatments, a greater emphasis will be on individual regimes that could meet a high clinical success.277 Therefore, chemotherapy beyond its conventional clinical efficacy offers to improve the clinical outcome in combination therapies. Translation of these combined approaches in the clinics is yet to see a complete success and thus warrants more clinical investigations.”

– But one of its most brutal side effects is that it can severely weaken your immune system. 

Chemotherapy is many different drugs used in different ways, depending on the patient, the type of cancer and other factors. It can strongly suppress some components of the immune system and this is considered a “classic” side-effect of chemotherapy. However, modern chemotherapy has made much progress, so that those side-effects can often be less intense than they used to be.

#Crawford, J., Herndon, D., Gmitter, K., & Weiss, J. (2024). The impact of myelosuppression on quality of life of patients treated with chemotherapy. Future Oncology, 20(21), 1515–1530.

https://www.tandfonline.com/doi/full/10.2217/fon-2023-0513 

Quote: “Chemotherapy can cause side effects by killing blood-forming cells in the bone marrow. This is known as myelosuppression and leads to neutropenia (decreased neutrophils [white blood cells]), anemia (decreased red blood cells) and thrombocytopenia (decreased platelets). Neutropenia can increase the risk of getting an infection, and severe cases might result in patients being hospitalized. Both neutropenia and anemia can cause fatigue, which is often reported by patients as being the most draining symptom of chemotherapy. Thrombocytopenia increases the risk of bleeding and can cause patients with cancer to become even more scared and anxious. Myelosuppression due to chemotherapy is usually managed with delays or reductions in the amount of chemotherapy that patients receive, but this may worsen the disease. Other treatments, known as supportive care interventions, include growth factors, which stimulate the production of blood cells and red blood cell or platelet transfusions. However, having these treatments in addition to chemotherapy can be a burden to patients, and they can cause side effects such as bone pain and blood clots. A treatment called trilaciclib is approved by the US Food and Drug Administration for patients receiving certain types of chemotherapy for advanced small-cell lung cancer. Trilaciclib has been shown to reduce neutropenia, anemia and thrombocytopenia in these patients and improve their quality of life. Other drugs are also being assessed in clinical trials for preventing or treating myelosuppression in patients with different cancer types. In the future, these drugs may improve quality of life for patients on chemotherapy.”

#Sharma, A., Jasrotia, S. & Kumar, A. Effects of Chemotherapy on the Immune System: Implications for Cancer Treatment and Patient Outcomes. Naunyn-Schmiedeberg's Arch Pharmacol 397, 2551–2566 (2024).

https://link.springer.com/article/10.1007/s00210-023-02781-2 

Quote: “Chemotherapy is a cornerstone of cancer treatment, but it can also induce immune suppression, which can have significant implications for patient outcomes. This review paper aims to give a general overview of how chemotherapy affects the immune system and how it affects cancer treatment. Chemotherapy can directly affect immune cells, leading to cytotoxic effects, cell differentiation and function alterations, and cell communication and signaling pathways disruptions. Such immune suppression can weaken the anti-tumor immune response and increase the risk of immune-related toxicities. Understanding the mechanisms of chemotherapy-induced immune suppression is crucial for optimizing treatment strategies. Strategies to mitigate immune suppression include immunomodulatory agents as adjuvants to chemotherapy, combination therapies to enhance immune function, and supportive care measures of the immune system. Additionally, identifying potential biomarkers to predict immune suppression and guide treatment decisions holds promise for personalized cancer medicine. Future directions in this field involve further elucidating underlying mechanisms, exploring novel combination therapies, and developing targeted interventions to minimize immune suppression. By understanding and addressing chemotherapy-induced immune suppression, we can optimize cancer treatment strategies, enhance the anti-tumor immune response, and improve patient outcomes.”

– And without your immune system at its A game, virotherapy can’t work properly because it is doing most of the slaughter.

Immune suppression from chemotherapy is a double-edged sword for oncolytic virotherapy: it can help viral replication by dampening the antiviral immune system, but it can also impair the very antitumor immunity the viruses are supposed to unleash.

#Ma R, Li Z, Chiocca EA, Caligiuri MA, Yu J. The emerging field of oncolytic virus-based cancer immunotherapy. Trends Cancer. 2023 

https://pmc.ncbi.nlm.nih.gov/articles/PMC9877109/ 

Quote: “Additionally, OVs can be used as adjuvants for chemotherapy, particularly for in the setting of drug-resistant tumors. Although chemotherapy can enhance OV therapy by preventing OV elimination due to antiviral immunity, it may also diminish OV therapeutic efficacy. For example, low-dose CPA removed immunosuppressive cells (e.g., Treg cells) to improve vaccine-induced adaptive antitumor immune responses while promoting the antiviral immune response to clear the virus early [97]. However, high-dose CPA enhanced viral oncolytic capacity by widespread immunosuppression of innate and adaptive antiviral immune responses, but also completely abrogated antitumor immune responses [100]. Temozolomide, a current standard of care for GBM, adversely affected oHSV immunovirotherapy [101]. These results illustrate that the clinic’s combination of chemotherapy and OV therapy should be carefully considered.”

– So she developed a plan – she would take her chances, forgo another round of chemo and keep her immune system ready to fight. 

#Forčić D, Mršić K, Perić-Balja M, Kurtović T, Ramić S, Silovski T, Pedišić I, Milas I, Halassy B. An Unconventional Case Study of Neoadjuvant Oncolytic Virotherapy for Recurrent Breast Cancer. Vaccines. 2024

https://www.mdpi.com/2076-393X/12/9/958 

Quote: “The patient, who is also an expert virologist, anticipating that the recurrent tumour would be of TNBC phenotype for which therapies of only limited efficacies exist, informed her oncologists that she was going to treat this tumour by the i.t. administration of viruses similar to oncolytic viruses (that were in clinical development for BC) before undergoing any other treatment. Her oncologists agreed to monitor the progress of the treatment, primarily with the aim of discontinuing the injections and intervening with conventional therapy in the event of adverse effects or tumour progression (which has not occurred). OVT started immediately after all necessary baseline diagnostic tests had been run, including core needle biopsy sampling of the tumour. Histopathological analysis subsequently indicated that the tumour had evolved from TNBC to HER2 3+.”

#Forčić D, Mršić K, Perić-Balja M, Kurtović T, Ramić S, Silovski T, Pedišić I, Milas I, Halassy B. An Unconventional Case Study of Neoadjuvant Oncolytic Virotherapy for Recurrent Breast Cancer. Vaccines. 2024 [Supplemental Material]

https://www.mdpi.com/article/10.3390/vaccines12090958/s1 

Quote: “The patient, who is also a virologist (1-7) and anticipating that the recurrent tumour would be of TNBC phenotype for which no specific and effective therapy exists, informed her oncologists that she was going to try to treat this tumour by the i.t. administration of viruses similar to the oncolytic viruses (OVs) that are in clinical development for breast cancer, before trying any other treatment. Her oncologists accepted to monitor the progress of the treatment, mainly with the aim to stop the injections and intervene with conventional therapy if there were untoward effects or if the tumour progressed. The oncolytic virotherapy (OVT) started immediately after all necessary baseline diagnostic tests had been run, including FDG PET-CT scan and core needle biopsy sampling of the tumour.”

We also received these insights into her treatment journey from Dr. Halassy herself (March 2026):

Quote: “I had only one round of chemotherapy during the initial diagnosis of my illness. After the surgery, I received four cycles of standard chemotherapy with doxorubicin and cyclophosphamide. The goal was to eliminate any cancer cells that might have remained after the operation. The chemotherapy did exactly what it is designed to do—it destroyed rapidly dividing cells. As a result, my hair fell out, my white blood cell count dropped significantly, and my mucosal tissues became very thin and prone to bleeding. [...] At the time, I told my doctor that if this treatment didn’t manage to destroy those few remaining cancer cells, then nothing would. Unfortunately, two years later, we discovered that the treatment had not eliminated the cancer. I decided I will not take chemotherapy any more. The second time, we only excised the recurrent tumor at the site of the previous surgery. I chose not to undergo chemotherapy again, as I had not yet fully recovered from the previous treatment. When it arrived for the third time, in less that two years, again at the site of the previous surgery, it was in its biggest form, started to spread in the surrounding tissue. It was staged 3b.”

– In labs viruses are usually produced by injecting them into cell cultures, letting them multiply and then purifying the mix. Creating a liquid with mostly viruses but also some cell debris and garbage. 

While this is in principle how viruses are typically produced in research laboratories, the details vary a lot depending on the virus, the cell line, the exact experiment or purpose of the viruses, and the laboratory. Below we cite the exact protocol that was used to produce the viruses for Dr. Beata Halassy’s treatment.

#Forčić D, Mršić K, Perić-Balja M, Kurtović T, Ramić S, Silovski T, Pedišić I, Milas I, Halassy B. An Unconventional Case Study of Neoadjuvant Oncolytic Virotherapy for Recurrent Breast Cancer. Vaccines. 2024

https://www.mdpi.com/2076-393X/12/9/958 

Quote: “The Edmonston-Zagreb measles vaccine strain (Institute of Immunology Inc., Zagreb, Croatia) [32] and vesicular stomatitis virus Indiana strain (ATCC) were used for laboratory-grade production of viruses for OVT. Viruses were freshly prepared immediately before application and i.t. administered, multifocally, in a total volume of 1–2 mL (details in Figure 1B and Supplementary Materials).”

#Forčić D, Mršić K, Perić-Balja M, Kurtović T, Ramić S, Silovski T, Pedišić I, Milas I, Halassy B. An Unconventional Case Study of Neoadjuvant Oncolytic Virotherapy for Recurrent Breast Cancer. Vaccines. 2024 [Supplemental Material]

https://www.mdpi.com/article/10.3390/vaccines12090958/s1 

Quote: “Edmonston Zagreb measles vaccine strain (Institute of Immunology Inc., Zagreb, Croatia) (8-9) and vesicular stomatitis virus Indiana strain (ATCC) were used for laboratory-grade production of viruses for OVT. The genome sequence of Edmonston Zagreb MeV has been determined and deposited in GenBank under accession numbers AY486084. Working banks of Vero and MRC-5 cells, that originate from Vero (WHO) (ECACC 88020401) and MRC-5 pd19 (ECACC 05072101), respectively, were provided by the Institute of Immunology Inc. The registered production process of pediatric measles vaccine (Institute of Immunology Inc.) was scaled down for laboratory-grade production of both viruses for this study. MeV was propagated in MRC-5 or Vero cell culture (as indicated in Figure 1B). Infections were performed by Edmonston Zagreb vaccine strain working seed (EZ D242/99, Institute of Immunology Inc.) at a cell density of 75,000 cells/cm2 when MRC-5 or 100,000 cells/cm2 when Vero cells were used with a MOI of 0.01 in MEM + 10% FBS. After 24 hours of cultivation at 36 °C, the medium was replaced with MEM without FBS, and cultivated at 32 °C, 5% CO2 until the appearance of cytopathic changes. Supernatant of such cell culture was collected, clarified by centrifugation (10 min, 1400 g) and sterilized by 0.45 μm filtration (Millipore). VSV was propagated in Vero cell culture. Infections were performed by Laboratory VSV working seed at a cell density of 100,000 cells/cm2, with a MOI of 0.5 in MEM +10% FBS. After 4 hours of cultivation at 37 °C, the medium was replaced with MEM without FBS and cultivated for 24 hours at 37 °C, 5% CO2, until the appearance of cytopathic changes. Virus suspensions were collected from the cell culture supernatant after centrifugation (10 min, 1400 g) and were sterilized by 0.45 μm filtration (Millipore). Freshly prepared virus suspension was used for each OVT application and time between the virus harvest and administration was never longer than one hour.”

– This is good enough for most lab experiments, but would never be allowed to be used in humans. Anything that goes into our bodies has to be clinical grade, way more pure to be as safe as possible.

"Clinical grade" in virus preparation for therapy (such as oncolytic viruses or viral vectors for gene therapy) refers to material manufactured to comply with strict regulatory guidelines. These guidelines can differ by country/ region and also depend on the viruses’ intended purpose. The goal is to ensure that the prepared virus is safe, pure, potent, and consistent for use in humans such as e.g. in the context of clinical trials or commercial use. Purity is not just important for safety, but also to ensure that the “other” materials present don’t affect the results of an experiment in a clinical trial.

The viruses used in Dr. Beata Halassy’s treatment were less pure than required for the “clinical grade” standard. Her priority was of course to save her own life, and she did not have access to “clinical grade” viruses. It is very laborious and expensive to produce those. Clinical-grade reagents are typically mass-produced by pharmaceutical companies. Some scientists have criticized that the requirements of clinical-grade reagents are too restrictive, and that they therefore slow down progress.

#Forčić D, Mršić K, Perić-Balja M, Kurtović T, Ramić S, Silovski T, Pedišić I, Milas I, Halassy B. An Unconventional Case Study of Neoadjuvant Oncolytic Virotherapy for Recurrent Breast Cancer. Vaccines. 2024

https://www.mdpi.com/2076-393X/12/9/958 

Quote: “It is important to emphasize that virus preparations were of research grade and of complex biological composition, considering that purification of viruses from host–cell components was not performed. These impurities could also affect the overall outcome of the described protocol. Two cell lines, MRC-5 and Vero, both regulatory acceptable and widely in use for the upstream processing of human viral vaccines [20], were used for the laboratory-grade virus production. MeV was first grown in the MRC-5 cell line, but later we switched to Vero cells because higher titres were achieved, except for the preparation administered on day 19, when MRC-5 was used due to the temporarily unavailable Vero cells.”

#Fernandes, Rita & Göbel, Sven & Reiter, Manfred & Bryan, Alexander & Altomonte, Jennifer & Genzel, Y. & Peixoto, Cristina. (2024). Streamlining the purification of a clinical-grade oncolytic virus for therapeutic applications. Separation and Purification Technology. 354. 128769.

https://www.sciencedirect.com/science/article/pii/S1383586624025085

Quote: “As OVs are categorized as gene therapy medical products by the European Medicine Agency (EMA), production and final downstream processing (DSP) must comply with specific guidelines [14,15]. To achieve a therapeutic effect and effective delivery to tumor sites, final dose inputs of rVSV-NDV in the range of 10⁹–10¹¹ virions/injection are required, imposing high virus concentration to achieve small-volume doses with the quality desirable. Host cell protein (HCP) and host cell DNA (hcDNA) should not exceed 100 ng/mL and 10 ng per dose, respectively [16]. Lastly, the ratio of noninfectious to infectious particles, while not exactly defined, should be minimal for the final product, and high oncolytic potency in the target cell must be maintained. These quality attributes require a delicate interplay between upstream and downstream process development steps to maintain virus activity and yield, while removing an adequate level of impurities. Particularly for fusogenic OVs, such as rVSV-NDV, usage of adherent cell culture systems only results in very low virus titers (~10⁶ TCID50/mL) due to the rapid formation of large multinucleated syncytia, before sufficient titers can be reached [5].”

– So her next big question was which virus to inject. The main thing she was looking for was a virus that specifically attacked the cell types the cancer emerged from. Ideally it should not cause a serious disease, because surviving cancer doesn’t help if you then die of ebola. And this virus had to have been clinically tested in humans before.

So for her first virus Beata and her colleagues chose… measles. 

#Forčić D, Mršić K, Perić-Balja M, Kurtović T, Ramić S, Silovski T, Pedišić I, Milas I, Halassy B. An Unconventional Case Study of Neoadjuvant Oncolytic Virotherapy for Recurrent Breast Cancer. Vaccines. 2024

https://www.mdpi.com/2076-393X/12/9/958 

Quote: “Given that the tumour was of epithelial origin, viruses that are known to successfully infect epithelial cells and have documented safety in humans were selected. The Edmonston-Zagreb measles vaccine strain is known for its safety in paediatric vaccines that have been in use for over 40 years [11,12]. Breast carcinomas express abundantly cell surface CD46 and nectin-4, both utilized as cell entry receptors by the vaccine strain of measles, particularly viruses of the Edmonston vaccine lineage [13,14]. Hence, the usage of the Edmonston-Zagreb vaccine strain was found appropriate. In addition, measles OVT has been clinically tested in patients with advanced stages of different types of BC (NCT01846091) [6].”

– Not the wild, dangerous type that killed about 100,000 people in 2024. 

#World Health Organization – Measles. Retrieved May 2026

https://www.who.int/news-room/fact-sheets/detail/measles 

Quote: “

• Measles is a highly contagious, serious airborne disease caused by a virus that can lead to severe complications and death.

• Measles vaccination averted nearly 59 million deaths between 2000 and 2024.

• Even though a safe and cost-effective vaccine is available, in 2024, there were an estimated 95 000 measles deaths globally, mostly among unvaccinated or under vaccinated children under the age of 5 years.

• The proportion of children receiving a first dose of measles vaccine was 84% in 2024, slightly below the 2019 level of 86%.”

– The weakened and pathetic version we have been using in the measles vaccines for over 40 years.

Several different types (“strains”) of the measles virus are used in vaccines. They all have in common that they are “live and attenuated”, meaning they are weakened, living forms of the virus to trigger a strong, lasting immune response. In Beata Halassy’s case, the “Edmonston-Zagreb” strain of measles vaccine virus was used. It has been in use for vaccination since the 1980s.

#Medecins Sans Frontieres – 2.1 Measles vaccine. Retrieved May 2026

https://medicalguidelines.msf.org/en/viewport/mme/english/2-1-measles-vaccine-32407628.html 

Quote: “The measles vaccine is a live, attenuated virus vaccine. [...] Most of the vaccines currently in use are derived from the Edmonston strain of the measles virus: Schwarz, Edmonston-Zagreb, AIK-C and Moraten. Vaccines derived from other strains are also available: CAM-70, TD-97, Leningrad-16 and Shanghai-191.

There is no significant difference (in terms of efficacy and adverse effects) between these vaccines, and all strains may be used interchangeably.”

#Forčić D, Mršić K, Perić-Balja M, Kurtović T, Ramić S, Silovski T, Pedišić I, Milas I, Halassy B. An Unconventional Case Study of Neoadjuvant Oncolytic Virotherapy for Recurrent Breast Cancer. Vaccines. 2024

https://www.mdpi.com/2076-393X/12/9/958 

Quote: “The Edmonston-Zagreb measles vaccine strain (Institute of Immunology Inc., Zagreb, Croatia) [32] and vesicular stomatitis virus Indiana strain (ATCC) were used for laboratory-grade production of viruses for OVT.”

#Forčić D, Mršić K, Perić-Balja M, Kurtović T, Ramić S, Silovski T, Pedišić I, Milas I, Halassy B. An Unconventional Case Study of Neoadjuvant Oncolytic Virotherapy for Recurrent Breast Cancer. Vaccines. 2024 [Supplemental Material]

https://www.mdpi.com/article/10.3390/vaccines12090958/s1 

Quote: “Edmonston Zagreb measles vaccine strain (Institute of Immunology Inc., Zagreb, Croatia) (8-9) and vesicular stomatitis virus Indiana strain (ATCC) were used for laboratory-grade production of viruses for OVT. The genome sequence of Edmonston Zagreb MeV has been determined and deposited in GenBank under accession numbers AY486084. Working banks of Vero and MRC-5 cells, that originate from Vero (WHO) (ECACC 88020401) and MRC-5 pd19 (ECACC 05072101), respectively, were provided by the Institute of Immunology Inc. The registered production process of pediatric measles vaccine (Institute of Immunology Inc.) was scaled down for laboratory-grade production of both viruses for this study. MeV was propagated in MRC-5 or Vero cell culture (as indicated in Figure 1B). Infections were performed by Edmonston Zagreb vaccine strain working seed (EZ D242/99, Institute of Immunology Inc.) at a cell density of 75,000 cells/cm2 when MRC-5 or 100,000 cells/cm2 when Vero cells were used with a MOI of 0.01 in MEM + 10% FBS. After 24 hours of cultivation at 36 °C, the medium was replaced with MEM without FBS, and cultivated at 32 °C, 5% CO2 until the appearance of cytopathic changes. Supernatant of such cell culture was collected, clarified by centrifugation (10 min, 1400 g) and sterilized by 0.45 μm filtration (Millipore).”

#Whittle H, Rowland M, Mann G et al. Immunisation Of 4-6 Month Old Gambian Infants With Edmonston-Zagreb Measles Vaccine. The Lancet (1984)

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(84)90873-0/fulltext 

Quote: “Five different vaccination schedules were used to immunise Gambian infants aged 4-6 months against measles with the attenuated Edmonston-Zagreb strain of virus, which has a history of passage in human diploid cells. Vaccine aerosol given either by mask in a dose of 3500 or 7000 plaque-forming units (PFU) or from a plastic bag at a dose of 7000 PFU raised haemagglutinininhibiting or plaque-inhibiting measles antibody 16-24 weeks after vaccination to a titre of 1 in 8 or greater in all but 3 of the 51 children so vaccinated. All 21 infants given 11 400 PFU of vaccine intradermally in two divided doses and the 21 given 39 000 PFU of the virus subcutaneously also had satisfactory levels of measles antibody 16 weeks after vaccination. None of the vaccinated children had clinical evidence of measles in the 12 to 17 months after vaccination. The Edmonston-Zagreb vaccine, given subcutaneously or by other routes at 4-6 months, may be useful in preventing measles in infants in African cities, where 15-30% of children have measles before they are 9 months old, which is the recommended age for immunisation with the chick-cell-adapted strains of measles virus.”

– Beata went to work and, together with her team, produced her first dose: A syringe filled with about 600,000 measles viruses. 

This corresponds to a logCCID50 value of 5.8, meaning 105.8 ≈ 6.3×105. Importantly, this is not an exact count of infectious virions, but rather a measure of “infectious dose units” defined by the measurement technique. It represents the amount of virus that, when diluted appropriately, would infect 50% of cell cultures at that concentration. This metric is used because raw particle counts are not very informative on their own, as many viral particles can be defective or otherwise noninfectious.

Of note: the doses used for virotherapy are orders of magnitude higher than the comparably tiny doses needed for vaccination.

#Forčić D, Mršić K, Perić-Balja M, Kurtović T, Ramić S, Silovski T, Pedišić I, Milas I, Halassy B. An Unconventional Case Study of Neoadjuvant Oncolytic Virotherapy for Recurrent Breast Cancer. Vaccines. 2024

https://www.mdpi.com/2076-393X/12/9/958

Quote: “Figure 1. [...] (B) Details on viruses used for each application; CCID50-cell culture infective dose 50.”

– The plan was to get an injection every few days, for the next few weeks and monitor closely what would happen to the cancer.

#Forčić D, Mršić K, Perić-Balja M, Kurtović T, Ramić S, Silovski T, Pedišić I, Milas I, Halassy B. An Unconventional Case Study of Neoadjuvant Oncolytic Virotherapy for Recurrent Breast Cancer. Vaccines. 2024

https://www.mdpi.com/2076-393X/12/9/958 

Quote: “OVT consisted of seven MeV applications in three- to four-day intervals over a period of three weeks, followed by three VSV applications separated by two and one week, prior to the surgical excision (Figure 1). Two months after the tumour excision, MeV was applied subcutaneously once around the surgical suture, as a preventive adjuvant treatment. Detailed step-by-step follow up of the OVT is provided in the Supplementary Materials.”

Figure 1. Oncolytic virotherapy (OVT) protocol and outcomes. (A) OVT time-course showing timepoints of each individual virus administration (blue arrows for MeV and green ones for VSV) in relation to outcomes monitored as changes in tumour size (red symbols) and virus-specific neutralizing antibody titers (NT) (blue and green circles for anti-MeV and anti-VSV NT, respectively). (B) Details on viruses used for each application; CCID50-cell culture infective dose 50.”

– But after the second dose of tens of thousands of viruses the tumor suddenly exploded, almost doubling in size, and became more spikey, aggressive looking. 

This corresponds to a logCCID50 value of 4.9 (second dose), meaning 104.9 ≈ 8 ×104. Importantly, this is not an exact count of infectious virions, but rather a measure of “infectious dose units” defined by the measurement technique. It represents the amount of virus that, when diluted appropriately, would infect 50% of cell cultures at that concentration. This metric is used because raw particle counts are not very informative on their own, as many viral particles can be defective or otherwise noninfectious.

With “almost doubling”, we are referring to tumour size going from 2.47 cm3 to 4.28 cm3.

#Forčić D, Mršić K, Perić-Balja M, Kurtović T, Ramić S, Silovski T, Pedišić I, Milas I, Halassy B. An Unconventional Case Study of Neoadjuvant Oncolytic Virotherapy for Recurrent Breast Cancer. Vaccines. 2024

https://www.mdpi.com/2076-393X/12/9/958

Quote: “Figure 1. Oncolytic virotherapy (OVT) protocol and outcomes. (A) OVT time-course showing timepoints of each individual virus administration (blue arrows for MeV and green ones for VSV) in relation to outcomes monitored as changes in tumour size (red symbols) and virus-specific neutralizing antibody titers (NT) (blue and green circles for anti-MeV and anti-VSV NT, respectively). (B) Details on viruses used for each application; CCID50-cell culture infective dose 50.

After only two months of therapy, in which a total of 7.89 log CCID50 of MeV and 9.07 log CCID50 of VSV was administered, the tumour was significantly reduced in size from a baseline volume of 2.47 ± 0.06 cm3 estimated by four independent imaging analyses to 0.91 cm3, which was the pathologic size of the excised tumour (Figure 1A). [...] Transient tumour swelling, already described in clinical trials assessing OVT for the treatment of hepatocellular carcinoma [9,10], was noticed at the beginning of the therapy, reaching a maximum volume of 4.28 cm3 on day 8. The repeated MRI performed two weeks after the first VSV administration again revealed a transient increase in size (2.17 cm3 on day 41), which might have occurred due to the infiltration and multiplication of the VSV-specific lymphocytes. Accordingly, lymph nodes enlarged in both axillae.

Figure 2. Imaging evidence of the effect of oncolytic virotherapy (OVT). (A) Changes in the ultrasound images of the treated tumour made at the same ultrasound system in the same position; representative images with tumour dimensions taken at the beginning and at the end of the therapy, and on day 8 when the worst clinical and ultrasound picture of the tumour size was noted.”

#Forčić D, Mršić K, Perić-Balja M, Kurtović T, Ramić S, Silovski T, Pedišić I, Milas I, Halassy B. An Unconventional Case Study of Neoadjuvant Oncolytic Virotherapy for Recurrent Breast Cancer. Vaccines. 2024 [Supplemental Material]

https://www.mdpi.com/article/10.3390/vaccines12090958/s1 

Quote: “One week after the first MeV administration (before the third dose) the tumour mass had enlarged and was tense, with extremely thin skin covering the mass and looking like it might break. Under ultra-

sound the mass appeared more hypoechoic and more spiculated compared to baseline, and was slightly larger.”

– After two more injections the tumor began to shrink and constrict. 

This refers to the first, strong swelling, observed around day 8 of the injections. There was also some transient, weaker swelling around days 40-43 of the injections.

#Forčić D, Mršić K, Perić-Balja M, Kurtović T, Ramić S, Silovski T, Pedišić I, Milas I, Halassy B. An Unconventional Case Study of Neoadjuvant Oncolytic Virotherapy for Recurrent Breast Cancer. Vaccines. 2024

https://www.mdpi.com/2076-393X/12/9/958

Quote: “Figure 1. Oncolytic virotherapy (OVT) protocol and outcomes. (A) OVT time-course showing timepoints of each individual virus administration (blue arrows for MeV and green ones for VSV) in relation to outcomes monitored as changes in tumour size (red symbols) and virus-specific neutralizing antibody titers (NT) (blue and green circles for anti-MeV and anti-VSV NT, respectively). (B) Details on viruses used for each application; CCID50-cell culture infective dose 50.”

#Forčić D, Mršić K, Perić-Balja M, Kurtović T, Ramić S, Silovski T, Pedišić I, Milas I, Halassy B. An Unconventional Case Study of Neoadjuvant Oncolytic Virotherapy for Recurrent Breast Cancer. Vaccines. 2024 [Supplemental Material]

https://www.mdpi.com/article/10.3390/vaccines12090958/s1 

Quote: “The first sign of improvement was observed on the day of 11 (4th MeV). The clinical picture was improved with less redness and less tension. Under ultra-sound the mass appeared less spiculated and better circumscribed. The majority of the mass was soft, and needle insertion and virus application were easier, no longer painful and not accompanied by bleeding from the injection site. It was the first time when 2 mL of suspension could be easily administered into the tumour. From that time until the last (7th) MeV administration on day 21, the mass was constantly shrinking by palpation and was less tense, with less overlying redness (it looked more like a healing bruise). Also, the mass was getting better circumscribed, less spiculated and less hypoechoic on ultrasound (Figure 2A) and i.t. virus administration was becoming steadily easier.”

– They had found the most amazing hunting grounds and they went to work, infecting, killing, multiplying. 

Oncolytic viruses infect and kill cancer cells basically the same way they kill any other human cell, with the difference that cancer cells are often more susceptible to them than non-cancer cells.

#Xiao, D., Zhang, H., Liu, Y. et al. Oncolytic viruses: advanced strategies in cancer therapy. Sig Transduct Target Ther (2026).

https://www.nature.com/articles/s41392-025-02343-3 

Quote: “The antitumor mechanism of OVs

Direct oncolytic activity

OVs selectively target and eliminate cancer cells while sparing healthy tissues. This tumor-specific targeting is driven by two main mechanisms: the recognition of tumor-specific surface receptors and the exploitation of unique vulnerabilities in the TME. Consequently, OVs preferentially infect and replicate in cancer cells, thereby disrupting their cellular functions and ultimately inducing cell death.190 Their ability to recognize and infect tumor cells is mediated by interactions with tumor-specific surface receptors and intracellular signaling pathways (Fig. 2).191 OVs interact with distinct receptors, which are often overexpressed on tumor cells but exhibit minimal expression on normal cells.92,192,193 For example, OAd utilizes receptors such as coxsackievirus and adenovirus receptors, integrins, and CD46 for cell entry,194 whereas MV employs CD46, and HSV-1 targets NECTIN or herpesvirus entry mediators.195 Other OVs, such as NDV and VV, lack specific attachment receptors and instead rely on endocytosis for cellular entry, thereby broadening their applicability to diverse tumor types.175,196 This receptor diversity highlights the adaptability of OVs in targeting heterogeneous tumor populations. By exploiting specific receptor‒ligand interactions, OVs achieve tumor selectivity while minimizing their cytotoxic effects on normal cells.

Fig. 2. Pathways, receptors, and mechanisms used by OVs to target cancer cells. OVs exploit tumor-specific vulnerabilities to selectively infect and lyse cancer cells. These viruses take advantage of overexpressed extracellular receptors, such as CAR, ICAM-1, DAF, CD155, CD46, and sialic acid-containing receptors, which are abundantly present on the surface of tumor cells. These receptors facilitate viral entry, allowing OVs to initiate infection and replicate within the tumor. Additionally, OVs exploit dysregulated intracellular signaling pathways, including Ras, PKR, p53, and E2F, which are frequently altered in cancer cells. These disruptions enhance viral replication and promote oncolysis by bypassing normal host defense mechanisms. Furthermore, defective antiviral responses in tumor cells, such as impaired IFN-γ signaling, further support viral replication, enabling OVs to efficiently propagate within the tumor microenvironment. By leveraging these tumor-specific characteristics, OVs preferentially target cancer cells while sparing healthy tissues, making them a promising strategy for targeted cancer therapy. CAR coxsackievirus-adenovirus receptor, DAF decay-accelerating factor, HSV herpes simplex virus, HVEM herpesvirus entry mediator, ICAM-1 intercellular adhesion molecule-1, LDLR low-density lipoprotein receptor, NDV Newcastle disease virus, VV vaccinia virus, VSV vesicular stomatitis virus, LSAMP limbic system associated membrane protein, E2F E2 transcription factor, PKR protein kinase R. Created with BioRender.com

Once inside tumor cells, OVs exploit dysregulated signaling pathways and altered metabolic states within the TME to replicate effectively.197 Tumor-specific features, such as hyperactive Ras signaling, hypoxic conditions, and uncontrolled proliferation, create a favorable environment for viral replication.198,199,200 For example, Ras signaling activation enhances nucleotide metabolism and upregulates transcription factors essential for viral gene expression, amplifying OV replication within tumor cells.201,202,203,204 Tumor hypoxia suppresses antiviral responses and enhances the replication of certain OVs adapted to low-oxygen environments. This tumor-specific targeting capability minimizes off-target effects, optimizing the therapeutic index while enhancing the safety and efficacy of OVs in cancer therapy. OVs subsequently hijack the host cell’s biological machinery to facilitate their replication. This interference disrupts essential cellular processes, including protein and nucleic acid synthesis, leading to the dysfunction of critical organelles such as the nucleus, mitochondria, and ER. The resulting cellular stress induces apoptosis or necrosis. For example, recombinant NDV R2B-GFP induces a loss of mitochondrial membrane permeability in 4T1 and B16-F10 cells, triggering apoptosis and amplifying its therapeutic effect.205 After replication, OVs release newly formed viral progeny from lysed tumor cells. These progeny infect neighboring cancer cells, initiating a self-sustaining cycle of infection and oncolysis.206,207 Capsid proteins contribute to cellular destruction by disrupting membrane integrity, increasing viral release and spread.208 This cycle continues until tumor cells are depleted or immune clearance mechanisms are activated, making OVs highly effective tools for reducing the tumor burden.

The TME plays a key role in enhancing OV replication and activity. Owing to impaired antiviral defenses, tumor cells are unable to mount effective immune responses against viral infections. In normal cells, viral infections activate innate immune pathways, including type I IFN signaling, which involves Janus kinase (JAK), signal transducer and activator of transcription (STAT), and interferon regulatory factors (IRFs).209,210 These pathways promote antiviral gene expression, induce apoptosis in infected cells, and trigger proinflammatory cytokine production to limit viral spread. However, tumor cells often downregulate key components of these pathways, such as retinoic acid-inducible gene I (RIG-I), IRF3, and IRF7, increasing their susceptibility to OV infection.1 Once cancer cells undergo lysis and die, OVs are released, spreading viral replication to adjacent cells.”

– Until this moment the cancer had been protected by a chemical defense zone around itself, hiding from the immune system. No anti-cancer cell could cross it. But the measles massacre shattered the protection.

Here we are referring to the tumour microenvironment (TME). The TME is the local environment surrounding a tumour, made up of cancer cells, immune cells, and signaling molecules. It also has special chemical properties. Tumours actively shape this environment to support their growth, for example by suppressing immune responses and limiting immune cell access and replication. In many cases, the TME can also impair immune cell function or induce their exhaustion or death, helping the cancer evade immune surveillance.

#Tufail, M., Jiang, CH. & Li, N. Immune evasion in cancer: mechanisms and cutting-edge therapeutic approaches. Sig Transduct Target Ther 10, 227 (2025).

https://www.nature.com/articles/s41392-025-02280-1

Quote: “TME modulation

The TME is a complex ecosystem of cancer cells, stromal cells, immune cells, and signaling molecules.107 This microenvironment plays a crucial role in tumor development, metastasis, and immune evasion (Fig. 1).108 The TME is not merely a passive setting for tumor growth; instead, it actively shapes the immune response through various mechanisms that collectively promote immune suppression and allow tumor cells to avoid immune surveillance.108”

#Hanahan D. Hallmarks of cancer—Then and now, and beyond. Cell, 2026

https://www.cell.com/cell/fulltext/S0092-8674(25)01498-9

Quote: “While the limitations posed by the exhaustion pathway are implicit to T cell biology, the overarching importance of evading immune destruction is substantiated by the multi-faceted immunosuppressive mechanisms operative in the TME, as well as its capability to systemically impair T cell development in the lymphoid organs. Virtually every cell type in the TME has the demonstrable capability to suppress the recruitment and/or activity of CD8 and/or CD4 T cells, albeit to varying extents in different tumor types and at different stages of multistep tumorigenesis and subsequent tumor progression. While it is not surprising that developing cancer cells—in the context of their neo-Darwinian adaptation—elaborate immunosuppressive functions, so too can endothelial cells and pericytes of the tumor vasculature, CAFs, innate immune inflammatory cells (substates of macrophages, neutrophils, and NK cells), and innervation, along with regulatory T and B cells (Treg and Breg). Moreover, the physical microenvironment can suppress T cell and NK cell-mediated immune responses in the forms of hypoxia, extracellular matrix composition, and interstitial pressure, along with the chemical milieu in the extracellular space, involving metabolic insufficiencies for T cell activity (amino acids, lipids, and sugars), in addition to the immunoregulatory factors (cytokines and chemokines, exosomes, etc.) produced by the various cell types populating the TME.”

#Augustin RC, Delgoffe GM, Najjar YG. Characteristics of the Tumor Microenvironment That Influence Immune Cell Functions: Hypoxia, Oxidative Stress, Metabolic Alterations. Cancers. 2020

https://www.mdpi.com/2072-6694/12/12/3802 

Quote: “Even with sufficient TME infiltration, immune cells face a harsh metabolic environment that can significantly impair effector function. These tumor-mediated metabolic perturbations include hypoxia, oxidative stress, and metabolites of cellular energetics. Primarily through HIF-1-dependent processes, hypoxia invokes an immunosuppressive phenotype via altered molecular markers, immune cell trafficking, and angiogenesis. Additionally, oxidative stress can promote lipid peroxidation, ER stress, and Treg dysfunction, all associated with immune dysregulation. Finally, the metabolic byproducts of lipids, amino acids, glucose, and cellular energetics are associated with immunosuppression and ICI resistance.”

#Labani-Motlagh A, Ashja-Mahdavi M and Loskog A (2020) The Tumor Microenvironment: A Milieu Hindering and Obstructing Antitumor Immune Responses. Front. Immunol. 11:940.

https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.00940/full

Quote: “

Figure 1. An overview of tumor microenvironment. In the immunosuppressive TME, malignant cells debilitate the antitumor immune responses through secretion of offensive and detrimental molecules, collaboration with cancer-associated stromal cells, and exploit immune scape mechanisms to outwit the immune cells. Tumor cells alter their milieu by lowering pH and glucose but high production of VEGF, non-classical HLA class I, death ligands such as FasL and TRAIL, anti-inflammatory cytokines, and metabolites such as IDO, ROS, RNS, ONOO−, and NO. These molecules can not only inhibit the immune cells but also elicit the stroma cells and facilitate tumor development. The cancer-associated stroma cells favor tumor cells by suppressing the immune responses and even induce each other. Tregs are capable to inhibit effector immune cells, eosinophils, basophils, and mast cells. Mast cells themselves induce MDSCs by releasing histamine. Tregs also stimulate tDC via IL-10 and impose M1-TAM polarization into M2-type. In turn, M2-TAMs eliminate effector cells via non-classical HLA class I, arginase I, IL-10, TGF-β, and PD-L1. In addition, MDSCs hinder effector cells by releasing arginase I, and metabolites such as IDO, ROS, ONOO−, and iNOS. TANs are other players that eliminate CD8+ T cells. The condition becomes more complicated with CAFs that promote angiogenesis, tumor growth, and invasion.”

Viruses infecting and physically destroying cancer cells disrupts this environment and allows the influx of anti-tumor immune cells.

#Zhang, Y., Li, Y., Chen, K. et al. Oncolytic virotherapy reverses the immunosuppressive tumor microenvironment and its potential in combination with immunotherapy. Cancer Cell Int 21, 262 (2021).

https://link.springer.com/article/10.1186/s12935-021-01972-2 

Quote: “OVs reverse immunosuppression by modulating TME components

Generally, the multifaceted roles of OVs in tumors are performed through several mechanisms [71] as is shown in Fig. 2. (1) Direct oncolysis: In the context of viral infection, OVs selectively infect and replicate in tumor cells, leading to lysis of tumor cells and subsequent release of viral progeny and tumor cell components. (2) Anti-tumor immunity: Followed by OV-induced immunogenic cell lysis, pathogen-associated molecular pattern molecules (PAMPs), damage-associated molecular pattern molecules (DAMPs), and tumor-associated antigens (TAAs) are released, triggering rapid but unspecific innate immune responses. These reactions enhance tumor and viral antigen presentation by DCs, leading to subsequent T cell priming and activation, and ultimately creating an immunostimulatory microenvironment [72]. By taking advantage of this immune-potentiating ability, enhanced anti-tumor efficacy of OVs is achieved. (3) Vascular pruning: Studies have shown that OVs act as an anti-angiogenic agent by directly targeting tumor-associated ECs and proangiogenic factors through stimulating host immune cells to produce anti-angiogenic factors to reshape the tumor vasculature [4]. (4) Stroma degradation: OVs attract neutrophils that are a potent ECM modifier to decompose the ECM [73]. Additionally, stroma-decomposing agents have been integrated into OV genomes to alleviate fibrotic reactions and facilitate drug spreading and immune cell infiltration within tumors.

Mechanism of oncolytic viruses (OVs) targeting the TME. (i) Direct oncolysis: immunogenic cell death (ICD) induced by OVs leads to the release of numerous molecules, including pathogen-associated molecular pattern molecules (PAMPs), damage-associated molecular pattern molecules (DAMPs), and tumor-associated antigens (TAAs), which enhance activation of antigen presenting cells (APCs) such as dendritic cells (DCs). Simultaneously, infected tumor cells also produce various inflammatory cytokines such as type I interferon (IFN) and chemokines. (ii) Anti-tumor immunity: Inflammatory cytokines and chemokines are produced under OV infection, leading to the recruitment of innate immune cells such as neutrophils and natural killer (NK) cells. Antigen-loaded DCs after OV infection trigger T cell priming and degraded extracellular matrix (ECM) by OVs enhances intratumoral infiltration of T cells. The proinflammatory microenvironment created by OVs includes M2-to-M1 transition of tumor-associated macrophages (TAMs), decreased level of regulatory-T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), and upregulated major histocompatibility complex-I (MHC-I) on tumor cells, which facilitate T cells to overcome immune suppression and complete the final recognition and killing step. Further immunostimulatory effect of OVs was achieved by synergizing with immune checkpoint blockade (ICB) therapy. (iii) Vascular pruning: OVs exert anti-angiogenic effects through direct lysis of tumor-associated endothelial cells (ECs) and reducing the level of vascular endothelial growth factor (VEGF), preventing the immunosuppressive effect from those angiogenic components. (iv) Stroma degradation: various ECM-degrading agents expressed by engineered OVs induce stroma degradation. Concurrently, OV-induced CAF lysis also inhibits excessive ECM production. Alleviated stroma fibrosis subsequently promotes the infiltration of T cells.”

– There is nothing that makes your immune system more aggressive than evidence of cells being killed. Death is always an emergency. And with that much death and virus parts leaking into healthy tissue Beata’s immune system suddenly jolted awake in shock. Not only was there an enormous virus infection that somehow had been able to fester … no there was something else.... A hidden archenemy, suddenly ripped from the shadows and without protection.

Beata’s immune system chose violence. Like angry angels of death, millions of immune cells invaded the tumor furiously fighting and killing viruses and cancer. 

While some evidence suggests that it was the case, technically there is no definitive proof in the original study on Dr. Beata Halassy’s case that anti-tumour immunity was responsible for the eradication of her tumour. However, it is widely established in the medical literature that anti-cancer virotherapy causes both anti-virus and anti-tumour immune responses.

#Forčić D, Mršić K, Perić-Balja M, Kurtović T, Ramić S, Silovski T, Pedišić I, Milas I, Halassy B. An Unconventional Case Study of Neoadjuvant Oncolytic Virotherapy for Recurrent Breast Cancer. Vaccines. 2024

https://www.mdpi.com/2076-393X/12/9/958 

Quote: “CD8-positive T cell and B cell co-localization observed in excised tumours has already been documented and considered as a positive prognostic factor in epithelial ovarian cancers [24,25]. CTLs have been considered the central effectors for optimal elimination of tumour cells [26,27]. The pivotal role of B lymphocytes in anti-tumour immune responses has only begun to be appreciated [28,29]. Since the increase in CD8-positive T cells and CD20-positive B cells was the consequence of applied OVT (Figure 2C), we could speculate that the activated adaptive immune response was directed dominantly toward viral antigens on tumour cells. It is possible that B-cells served as alternative antigen-presenting cells in the tumour environment, sustaining the survival and proliferation of tumour-infiltrating T cells, as already speculated [25,30].”

#Zhang, Y., Li, Y., Chen, K. et al. Oncolytic virotherapy reverses the immunosuppressive tumor microenvironment and its potential in combination with immunotherapy. Cancer Cell Int 21, 262 (2021).

https://link.springer.com/article/10.1186/s12935-021-01972-2 

Quote: “(2) Anti-tumor immunity: Followed by OV-induced immunogenic cell lysis, pathogen-associated molecular pattern molecules (PAMPs), damage-associated molecular pattern molecules (DAMPs), and tumor-associated antigens (TAAs) are released, triggering rapid but unspecific innate immune responses. These reactions enhance tumor and viral antigen presentation by DCs, leading to subsequent T cell priming and activation, and ultimately creating an immunostimulatory microenvironment [72]. By taking advantage of this immune-potentiating ability, enhanced anti-tumor efficacy of OVs is achieved.”

#Tian H, Liu Q, Yu X, Cao Y, Huang X. Damage-associated molecular patterns in viral infection: potential therapeutic targets. Crit Rev Microbiol. 2025

https://pubmed.ncbi.nlm.nih.gov/39091137/ 

Quote: “Frequent viral infections leading to infectious disease outbreaks have become a significant global health concern. Fully elucidating the molecular mechanisms of the immune response against viral infections is crucial for epidemic prevention and control. The innate immune response, the host's primary defense against viral infection, plays a pivotal role and has become a breakthrough in research mechanisms. A component of the innate immune system, damage-associated molecular patterns (DAMPs) are involved in inducing inflammatory responses to viral infections. Numerous DAMPs are released from virally infected cells, activating downstream signaling pathways via internal and external receptors on immune cells. This activation triggers immune responses and helps regulate viral host invasion. This review examines the immune regulatory mechanisms of various DAMPs, such as the S100 protein family, high mobility group box 1 (HMGB1), and heat shock proteins, in various viral infections to provide a theoretical basis for designing novel antiviral drugs.”

#Workenhe ST, Mossman KL. Rewiring cancer cell death to enhance oncolytic viro-immunotherapy. Oncoimmunology. 2013

https://pmc.ncbi.nlm.nih.gov/articles/PMC3912054/ 

Quote: “The anticancer activity of OVs is mediated by their ability to directly kill malignant cells, to interfere with the tumor vasculature, and to activate the immune system against cancer. The replication of OVs leads to the lysis of neoplastic cells coupled to the release of pathogen-associated molecular patterns (PAMPs) such as viral proteins and nucleic acids. PAMPs attract immune cells to neoplastic lesions, and these cells can take up tumor-associated antigens (TAAs) released along with the cytopathic effects for priming anticancer immune responses.”

– This sudden influx of cells is what caused Beata’s tumour to swell so explosively. 

The swelling of a tumor in response to cancer therapy, which could be mistakenly interpreted as the cancer “growing”, is called “pseudoprogression”. It is a common phenomenon in cancer therapy. Even though the treatment is effectively killing cancer cells, tumors often initially appear to grow or new lesions emerge. This is due to immune cell infiltration and resulting inflammation. It is distinguished from true progression by subsequent shrinkage (as ended up being the case for Dr. Beata Halassy).

#Guo S, Miao H, Cui D, Wang S, Ning Li N. Pseudoprogressions in oncolytic therapy: alerts and regulations needed. Clin Oncol J. 2025;6(1):1–2.

https://clinicaloncologyjournal.com/article/1000297/pseudoprogressions-in-oncolytic-therapy-alerts-and-regulations-needed 

Quote: “Pseudoprogression (PsP) refers to either visually observed or imaging-detected tumor enlargement followed by regression after cancer therapies. Characterized by robust localized immune infiltration, PsP is most commonly seen in immunotherapies, with an occurrence rate of around 10% [1]. However, there was limited discussion of oncolytic therapy-related PsP. We argue that PsP is a commonly encountered phenomenon in oncolytic virotherapy, warranting increased attention during assessments in clinical applications and trials.”

#Sarzhevskiy V.O., Melnichenko V.I., Panshina I.V., Mochkin N.E., Bogatyrov V.S., Borshevetskaya M.M., Smirnova E.G., Bannikova A.E., Samoylova A.A., Mamedova A.A., Rukavitsin A.A., Vasilev S.S., Bronov O.I. The phenomenon of pseudoprogression in cancer immunotherapy: is everything so unambiguous? // Journal of Modern Oncology. 2021

https://modernonco.orscience.ru/1815-1434/article/view/88627 

Quote: “When evaluating the effect of therapy for malignant neoplasms with inhibitors of CTLA-4, PD-1 and PD-L1, the phenomenon of pseudoprogression may occur. Pseudoprogression is an increase in the volume of tumor tissue due to immunocompetent cells (lymphocytes, macrophages) mobilized into the tumor focus under the action of immunotherapy. As the antitumor effect of lymphocytes and macrophages is realized, the tumor decreases or disappears over time. Pseudoprogression occurs with varying frequency in various types of cancer.”

– Viruses killed defenseless cancer cells, virus hunter cells gobbled up viruses and cancer killers exploded cancer cells left and right, while cancer cells still fought back and deactivated immune cells where they could. 

Viruses killing cancer cells:

#Xiao, D., Zhang, H., Liu, Y. et al. Oncolytic viruses: advanced strategies in cancer therapy. Sig Transduct Target Ther (2026).

https://www.nature.com/articles/s41392-025-02343-3 

Quote: “The antitumor mechanism of OVs

Direct oncolytic activity

OVs selectively target and eliminate cancer cells while sparing healthy tissues. This tumor-specific targeting is driven by two main mechanisms: the recognition of tumor-specific surface receptors and the exploitation of unique vulnerabilities in the TME. Consequently, OVs preferentially infect and replicate in cancer cells, thereby disrupting their cellular functions and ultimately inducing cell death.190 Their ability to recognize and infect tumor cells is mediated by interactions with tumor-specific surface receptors and intracellular signaling pathways (Fig. 2).191 OVs interact with distinct receptors, which are often overexpressed on tumor cells but exhibit minimal expression on normal cells.92,192,193 For example, OAd utilizes receptors such as coxsackievirus and adenovirus receptors, integrins, and CD46 for cell entry,194 whereas MV employs CD46, and HSV-1 targets NECTIN or herpesvirus entry mediators.195 Other OVs, such as NDV and VV, lack specific attachment receptors and instead rely on endocytosis for cellular entry, thereby broadening their applicability to diverse tumor types.175,196 This receptor diversity highlights the adaptability of OVs in targeting heterogeneous tumor populations. By exploiting specific receptor‒ligand interactions, OVs achieve tumor selectivity while minimizing their cytotoxic effects on normal cells.

Fig. 2. Pathways, receptors, and mechanisms used by OVs to target cancer cells. OVs exploit tumor-specific vulnerabilities to selectively infect and lyse cancer cells. These viruses take advantage of overexpressed extracellular receptors, such as CAR, ICAM-1, DAF, CD155, CD46, and sialic acid-containing receptors, which are abundantly present on the surface of tumor cells. These receptors facilitate viral entry, allowing OVs to initiate infection and replicate within the tumor. Additionally, OVs exploit dysregulated intracellular signaling pathways, including Ras, PKR, p53, and E2F, which are frequently altered in cancer cells. These disruptions enhance viral replication and promote oncolysis by bypassing normal host defense mechanisms. Furthermore, defective antiviral responses in tumor cells, such as impaired IFN-γ signaling, further support viral replication, enabling OVs to efficiently propagate within the tumor microenvironment. By leveraging these tumor-specific characteristics, OVs preferentially target cancer cells while sparing healthy tissues, making them a promising strategy for targeted cancer therapy. CAR coxsackievirus-adenovirus receptor, DAF decay-accelerating factor, HSV herpes simplex virus, HVEM herpesvirus entry mediator, ICAM-1 intercellular adhesion molecule-1, LDLR low-density lipoprotein receptor, NDV Newcastle disease virus, VV vaccinia virus, VSV vesicular stomatitis virus, LSAMP limbic system associated membrane protein, E2F E2 transcription factor, PKR protein kinase R. Created with BioRender.com

Once inside tumor cells, OVs exploit dysregulated signaling pathways and altered metabolic states within the TME to replicate effectively.197 Tumor-specific features, such as hyperactive Ras signaling, hypoxic conditions, and uncontrolled proliferation, create a favorable environment for viral replication.198,199,200 For example, Ras signaling activation enhances nucleotide metabolism and upregulates transcription factors essential for viral gene expression, amplifying OV replication within tumor cells.201,202,203,204 Tumor hypoxia suppresses antiviral responses and enhances the replication of certain OVs adapted to low-oxygen environments. This tumor-specific targeting capability minimizes off-target effects, optimizing the therapeutic index while enhancing the safety and efficacy of OVs in cancer therapy. OVs subsequently hijack the host cell’s biological machinery to facilitate their replication. This interference disrupts essential cellular processes, including protein and nucleic acid synthesis, leading to the dysfunction of critical organelles such as the nucleus, mitochondria, and ER. The resulting cellular stress induces apoptosis or necrosis. For example, recombinant NDV R2B-GFP induces a loss of mitochondrial membrane permeability in 4T1 and B16-F10 cells, triggering apoptosis and amplifying its therapeutic effect.205 After replication, OVs release newly formed viral progeny from lysed tumor cells. These progeny infect neighboring cancer cells, initiating a self-sustaining cycle of infection and oncolysis.206,207 Capsid proteins contribute to cellular destruction by disrupting membrane integrity, increasing viral release and spread.208 This cycle continues until tumor cells are depleted or immune clearance mechanisms are activated, making OVs highly effective tools for reducing the tumor burden.”

Immune cells killing viruses:

#Marelli G, Howells A, Lemoine NR, Wang Y. Oncolytic Viral Therapy and the Immune System: A Double-Edged Sword Against Cancer. Front Immunol. 2018

https://pmc.ncbi.nlm.nih.gov/articles/PMC5932159/ 

Quote: “Anti-viral immunity occurs as the immune system responds to the presence of virus in tumor cells within the body. This attracts various types of immune cell to the site of infection including innate cells (e.g., NK cells) and adaptive cells (e.g., CTL). These immune cells will lead to the destruction of infected cells (i.e., tumor cells) which augments the direct lysis of tumor cells by viral infection itself. This effect can be improved by arming viruses with immune modulatory proteins like cytokines which aid in the attraction of immune components to the tumor site (11).”

Immune cells killing cancer cells:

#Xiao, D., Zhang, H., Liu, Y. et al. Oncolytic viruses: advanced strategies in cancer therapy. Sig Transduct Target Ther (2026).

https://www.nature.com/articles/s41392-025-02343-3 

Quote: “OVs play a crucial role in activating the host’s innate immune system, which triggers an adaptive immune response that targets tumors.1 Various OVs, including OAd, HSV, coxsackievirus, VV, and NDV, induce ICD to varying degrees. The ICD is essential for triggering antitumor immune responses and promoting immune memory.222,223,224,225,226 ICD, a cornerstone of the antitumor immune response induced by OVs,227 encompasses several forms of cell death, including apoptosis, necrosis, ferroptosis, autophagic cell death, and pyroptosis.228,229,230 During ICD, tumor cells release TAAs and tumor-associated neoantigens (TANs), both of which are crucial for activating adaptive immunity.231,232,233”

OV-induced antitumor immunity transitions from “cold” to “hot” tumors. OVs infect tumor cells, leading to cell lysis and the release of TAAs, viral antigens, DAMPs and PAMPs into the TME. This process activates the immune system, stimulating the release of cytokines and chemokines that recruit immune cells, including dendritic cells, macrophages, natural killer cells, and T cells, into the TME. Initially, the TME is “cold”, with minimal immune infiltration and a limited antitumor response. OVs help transform the TME into a “hot” environment characterized by increased infiltration of immune cells, including cytotoxic T cells, M1 macrophages, and natural killer cells. This shift enhances tumor cell recognition and eradication, promoting antitumor immunity. TAAs tumor-associated antigens, DAMPs damage-associated molecular patterns, PAMPs pathogen-associated molecular patterns, TME tumor microenvironment. Created with BioRender.com”

Cancer cells deactivating immune cells:

#Zhang, Y., Li, Y., Chen, K. et al. Oncolytic virotherapy reverses the immunosuppressive tumor microenvironment and its potential in combination with immunotherapy. Cancer Cell Int 21, 262 (2021).

https://link.springer.com/article/10.1186/s12935-021-01972-2 

Quote: “The TME consists of cellular and non-cellular components. The cellular components include neoplastic cells, cancer-associated fibroblasts (CAFs), endothelial cells (ECs), innate immune cells [e.g., neutrophils, dendritic cells (DCs), and natural killer (NK) cells], adaptive immune cells (e.g., T and B cells), and immunosuppressive cells [e.g. myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and regulatory T cells (Tregs)]. The non-cellular components include the extracellular matrix (ECM), tumor vasculature, and secretory molecules (e.g. cytokines, chemokines, growth factors, and proteases) [6]. Notably, the majority of TME components contribute to the immunosuppressive microenvironment in various manners, as is shown in Fig. 1.

Fig. 1. Components of tumor microenvironment (TME) contribute to the immunosuppression in various manners. Tumor cells downregulate expression of major histocompatibility complex-I (MHC-I) and antigens to avoid antigen presentation and T cell recognition, and express immune checkpoint proteins such as programmed cell-death ligand 1 (PD-L1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) to inactivate infiltrated T cells. Additionally, tumor cells recruit various immunosuppressive cells [e.g. myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and regulatory-T cells (Tregs)] by expressing immunosuppressive molecules [e.g. interleukin (IL)-10, chemokine ligand (CCL)-5, granulocyte–macrophage colony-stimulating factor (GM-CSF), indoleamine-2,3-dioxygenase (IDO) and tumor growth factor-β (TGF-β)]. Tumor cells, immunosuppressive cells and various immunoregulatory molecules [e.g. reactive oxygen species (ROS), arginase-1 (Arg-1), CCL-22, IL-10, and PD-L1] construct an immunosuppressive network in the TME. The activities of dendritic cells (DCs), T cells, natural killer (NK) cells, and other immune cells are therefore repressed severely. Moreover, classical stromal components contribute to immunosuppression. Continuous release of tumor-derived vascular endothelial growth factor (VEGF) leads to the formation of dysfunctional blood vessels with loose endothelial cell (EC)-EC connections and poor pericyte coverage, which exacerbates hypoxia and acidosis in the TME, thereby impairing the functionality of immune cells. Activated cancer associated fibroblasts (CAFs) lead to excessive extracellular matrix (ECM) deposition, which results in dense and tenacious fibrotic tissue surrounding the tumor mass and an elevated interstitial fluid pressure (IFP). These formidable physical barriers severely hinder immune infiltration and drug perfusion.

The sophisticated interactions of tumor cells, tumor stroma, and the host immune system construct a highly immunosuppressive TME as a tumor develops. Malignant tumor cells escape from host immunosurveillance by various mechanisms that include downregulating major histocompatibility complex (MHC)-I to escape T cell recognition, expressing immunoinhibitory surface proteins such as programmed cell death protein ligand-1 (PD-L1) to inactivate cytotoxic T cells (CTLs), and secreting immunosuppressive cytokines [e.g. transforming growth factor-β (TGF-β), granulocyte–macrophage colony-stimulating factor (GM-CSF), and interleukin (IL)-10], chemokines [e.g. chemoattractant cytokine ligand (CCL) 20 and CCL17], indoleamine-2,3-dioxygenase, and other secretory factors, thereby inhibiting T cell proliferation, inducing recruitment of immunosuppressive cells such as Tregs and MDSCs, and promoting phenotype conversion of macrophages from anti-tumor M1 to pro-tumor M2-like TAMs [7, 8]. Recruited immunosuppressive cells impair host immunosurveillance through various mechanisms. TAMs promote immunosuppression by producing IL-10 and TGF-β, and recruit Tregs by producing CCL22 [9, 10]. In terms of MDSCs, arginase-1 expressed by MDSCs degrades L-arginine required for T cell proliferation, and T cell receptor signaling is downregulated by MDSCs, which contributes further to T cell inactivation. MDSCs also recruit Tregs by secreting chemokines such as CCL3, CCL4, and CCL5 [11]. Tregs exert a wide range of immunosuppressive effects by secreting immunosuppressive cytokines or acting in a contact-dependent manner, such as inhibiting antigen presentation of DCs, halting early expansion of T cells, downregulating proinflammatory IL-12 signaling by expressing a competitive receptor [12], repressing the expression of T cell-associated cytokines (e.g. IFN-γ, TNF-α, and IL-2), and inhibiting B cells, NK cells, and other immune cells [13, 14]. Collectively, densely distributed negative immune cells and anergic T cells have been recognized as common features of the immunosuppressive TME, which indicate a poor prognosis [15].”

– Every few days fresh injections followed, saturating Beata’s cancer with at least 80 million viruses in total, keeping the massacre going.

The total amount of administered measles virus corresponds to a logCCID50 value of 7.89, meaning 107.89 ≈ 8 × 106. Importantly, this is not an exact count of infectious virions, but rather a measure of “infectious dose units” defined by the measurement technique. It represents the amount of virus that, when diluted appropriately, would infect 50% of cell cultures at that concentration. This metric is used because raw particle counts are not very informative on their own, as many viral particles can be defective or otherwise noninfectious.

#Forčić D, Mršić K, Perić-Balja M, Kurtović T, Ramić S, Silovski T, Pedišić I, Milas I, Halassy B. An Unconventional Case Study of Neoadjuvant Oncolytic Virotherapy for Recurrent Breast Cancer. Vaccines. 2024

https://www.mdpi.com/2076-393X/12/9/958

“Figure 1. [...] (B) Details on viruses used for each application; CCID50-cell culture infective dose 50.”

– There was one problem though: the immune system was too good at its job – soon Beata would be totally immune against measles and likely eradicate the virus, which might end the therapy before it finished. 

Of note: even when the viruses are eradicated by the immune system during anti-cancer virotherapy, they can still help eliminate the tumor by activating long-lasting anti-tumor immune responses.

From Dr. Dirk Nettelbeck (German Cancer Research Center) we received the following relevant insight:

Quote: "What has been widely shown in mouse models and patients is that during virotherapy, tumor antigen-specific T cell responses are activated. These work systemically and independent of a continuing anti-viral immune response. So the believe is that oncolytic viruses have to powerfully infect tumor cells and effectively set-off anti-tumor immunity. BTW, the latter works systemically and thus in lesions that have never seen a virus."

#Forčić D, Mršić K, Perić-Balja M, Kurtović T, Ramić S, Silovski T, Pedišić I, Milas I, Halassy B. An Unconventional Case Study of Neoadjuvant Oncolytic Virotherapy for Recurrent Breast Cancer. Vaccines. 2024

https://www.mdpi.com/2076-393X/12/9/958 

Quote: “Further, we anticipated the rapid induction of a virus-specific antibody response, which has also been proven experimentally. Although current knowledge [10] does not imply that anti-viral neutralizing antibodies prevent intratumoural efficacy of OVT, to minimize such a possibility, we exploited a sequential virotherapy strategy in which treatment was initiated using MeV and was switched later to another virus – VSV, after three weeks of therapy. The sequential usage of two different viruses has already been suggested and demonstrated in preclinical models [21,22,23].”

Regarding the decision to switch from the measles vaccine virus to a different virus, Dr. Beata Halassy provided us the following insights (March 2025):

Quote: “Knowing that after ca 3 weeks the immune response to foreign antigen is at its maximum, we expected this also to happen with antivirus antibodies. So, although current literature does not imply that anti-virus antibody could affect viruses applied directly into the tumour, to avoid even theoretical possibility that it happens, we switched to another, unrelated virus. VSV was chosen because we were skilled to work with, it also infects epithelial cells (breast cancer cells are of epithelial origin), and is not pathogenic to humans.”

– So after a few weeks Beata started injecting a second virus: VSV, a pretty harmless relative of rabies that causes mild flu symptoms in the extremely rare cases a human catches it. 

#Forčić D, Mršić K, Perić-Balja M, Kurtović T, Ramić S, Silovski T, Pedišić I, Milas I, Halassy B. An Unconventional Case Study of Neoadjuvant Oncolytic Virotherapy for Recurrent Breast Cancer. Vaccines. 2024

https://www.mdpi.com/2076-393X/12/9/958 

Quote: “OVT consisted of seven MeV applications in three- to four-day intervals over a period of three weeks, followed by three VSV applications separated by two and one week, prior to the surgical excision (Figure 1).

Figure 1. Oncolytic virotherapy (OVT) protocol and outcomes. (A) OVT time-course showing timepoints of each individual virus administration (blue arrows for MeV and green ones for VSV) in relation to outcomes monitored as changes in tumour size (red symbols) and virus-specific neutralizing antibody titers (NT) (blue and green circles for anti-MeV and anti-VSV NT, respectively). (B) Details on viruses used for each application; CCID50-cell culture infective dose 50.

[...] VSV is an animal pathogen, but is almost non-pathogenic for humans, causing flu-like symptoms in the worst case [15]. It was shown to confer protection against re-challenge in a murine model of BC [16]. Wild-type VSV is considered to be potentially neurotoxic to humans [17], based on the strong neurotoxicity observed in mice after intranasal administration, and especially intrathecal and intracerebellar application [18]. Wild-type VSV also induced neurotoxicity in non-human primates, but only after direct intrathecal inoculation [19]. Its neurotoxicity has so far not been demonstrated in any animal species after administration by any other route, especially not s.c. Wild-type VSV did not cause any signs of neurological symptoms after intratumoural application in the case presented here. However, despite this, it is essential to be cautious and to further conduct neurotoxicity tests in future safety studies of the VSV-based preparations, especially if developed for the treatment of brain tumours. The strains of MeV and VSV that were used in the current study had not been genetically engineered to improve their oncolytic properties, but were nevertheless effective when administered according to the schedule and protocol described herein.”

#Forčić D, Mršić K, Perić-Balja M, Kurtović T, Ramić S, Silovski T, Pedišić I, Milas I, Halassy B. An Unconventional Case Study of Neoadjuvant Oncolytic Virotherapy for Recurrent Breast Cancer. Vaccines. 2024 [Supplemental Material]

https://www.mdpi.com/article/10.3390/vaccines12090958/s1 

Quote: "Three days after the 7th MeV application, VSV therapy was initiated. The tumour was not dense any more, the needle was easily inserted, and a higher volume of virus suspension was easily administered, in comparison to the first MeV inoculation. Two mL of VSV suspension were distributed at multiple intratumoural foci. A few hours later, the tumour was obviously swollen and the skin was very red. Twelve hours after the administration, the patient developed rigors that lasted for 2 hours and became febrile to 40 °C. The high fever persisted for approximately 24 hours despite ibuprofen therapy and resolved slowly during the second day post virus administration. This was the moment when the tumour was of the highest softness (like a sponge) during the whole OVT period. Because of the strong side reaction to the first dose of VSV, additional dosing was temporarily suspended and a phase-contrast MRI was performed two weeks later. While the repeated MRI did not at this time point show substantial reduction in the size of the mass, there was no longer any visible infiltration of the underlying pectoral muscle. An increased number of enlarged lymph nodes was observed in both axillae compared to the baseline MRI. The patient was then referred to a surgeon who noted that the tumour mass was now freely mobile over the underlying muscle and could be easily removed by surgery. Prior to the planned date of surgery, the VSV administration was continued in one-week intervals. In the second administration, only 1 mL was applied as a precautionary measure to reduce potential systemic side effects, but this time, there was no febrile reaction, nor was there any adverse reaction after the last administration of 1.1 mL of VSV given a week later. At that time, the tumour had a more cystic appearance by ultrasound scan. In total, three doses of VSV were administered, separated by two and one weeks, respectively, within the total period of 24 days. The cumulative dose of administered VSV was 109.1 CCID50, and volumes and infective virus quantities in separated doses are listed in Figure 1B."

– Within a day after the first VSV injection, Beata fell ill with a fever and chills. But amazingly these would remain her only side effects during the entire experiment.

#Forčić D, Mršić K, Perić-Balja M, Kurtović T, Ramić S, Silovski T, Pedišić I, Milas I, Halassy B. An Unconventional Case Study of Neoadjuvant Oncolytic Virotherapy for Recurrent Breast Cancer. Vaccines. 2024

https://www.mdpi.com/2076-393X/12/9/958 

Quote: “The patient did not experience any serious side effects during the course of OVT. The needle insertion and suspension administration were tolerably painful at the beginning. The only systemic side effect was experienced after the first application of VSV, manifested as fever and rigors with onset twelve hours after VSV administration, with complete resolution over the next three days.”

#Forčić D, Mršić K, Perić-Balja M, Kurtović T, Ramić S, Silovski T, Pedišić I, Milas I, Halassy B. An Unconventional Case Study of Neoadjuvant Oncolytic Virotherapy for Recurrent Breast Cancer. Vaccines. 2024 [Supplemental Material]

https://www.mdpi.com/article/10.3390/vaccines12090958/s1 

Quote: “Two mL of VSV suspension were distributed at multiple intratumoural foci. A few hours later, the tumour was obviously swollen and the skin was very red. Twelve hours after the administration, the patient developed rigors that lasted for 2 hours and became febrile to 40 °C. The high fever persisted for approximately 24 hours despite ibuprofen therapy and resolved slowly during the second day post virus administration.”

Oncolytic virotherapy is generally considered very safe. Severe side-effects can happen – it is cancer therapy after all – but they are very rare. 

#Lau P, Liang L, Chen X, Zhang J, Liu H. Comparative safety and efficacy of oncolytic virotherapy for the treatment of individuals with malignancies: a systematic review, meta-analysis, and Bayesian network meta-analysis. EClinicalMedicine. 2025

https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(25)00294-9/fulltext 

Quote: “Of 1976 studies screened, 186 clinical trials with 6979 participants met the inclusion criteria. The most common adverse events associated with oncolytic virotherapy were fatigue (1.98%, 1.71–2.28), pyrexia (2.16%, 1.69–2.69), fever (3.32%, 2.64–4.07), and chills (1.65%, 1.39–1.82), with neutropenia (1.07%, 0.67–1.55) and lymphocytopenia (0.71%, 0.51–0.94) being the predominant severe adverse events. While oncolytic virus monotherapy (OV vs immunotherapy, DCR 2.45, 95% CI 1.60–3.76) and combination regimens (OV plus chemotherapy vs OV, DCR 8.53, 95% CI, 1.97–37.03) enhanced therapeutic efficacy, they presented higher toxicity risks compared to conventional treatments (OV vs immunotherapy, all-grade AE 2.07, 95% CI 1.75–2.44). Notably, combination therapies involving chemotherapy (OV plus chemotherapy vs chemotherapy, all-grade AE 1.10, 95% CI 1.02–1.18) or radiotherapy (OV plus radiotherapy vs radiotherapy, all-grade AE 1.53, 95% CI 1.27–1.84) significantly increase adverse event risks. Conversely, oncolytic virotherapy combined with immunotherapy showed a more favorable safety profile (OV plus immunotherapy vs OV plus chemotherapy, severe AE 0.32, 95% CrI 0.15–0.66) and clinical benefits (OV plus immunotherapy vs OV plus chemotherapy, DCR 0.08, 95% CrI 0.02–0.33). Efficacy varied significantly across treatment strategies (adjusted p = 0.040), virus classifications (adjusted p = 0.0027), administration routes (adjusted p = 0.0080), and patient age groups (adjusted p = 0.00080).

Interpretation

This analysis provides robust evidence on the tolerability and efficacy of oncolytic virotherapy in cancer treatment. Oncolytic virotherapy demonstrates significant potential as both monotherapy and in combination regimens, offering a favorable balance of efficacy and safety. Virotherapy paired with immunotherapy exhibits a more favorable safety profile, particularly in regimens involving Reoviridae- or Poxviridae-based strategies. The therapeutic efficacy of oncolytic virotherapy varies notably by multiple factors.”

#Xiao, D., Zhang, H., Liu, Y. et al. Oncolytic viruses: advanced strategies in cancer therapy. Sig Transduct Target Ther (2026).

https://www.nature.com/articles/s41392-025-02343-3 

Quote: “Safety concerns

Although OVs generally have an acceptable safety profile, their use as live replicating organisms necessitates special precautions, including the risks of viral shedding and unintentional transmission to healthcare workers, close contacts, and the environment. To minimize these risks, comprehensive safety guidelines for the storage, handling, and administration of OVs must be established, along with protocols for managing accidental spills, overdosing, and disinfecting areas that may come into contact with the virus.445,446,447 Additionally, specific measures must be developed to address the potential for viral exposure and accidental transmission through needles, wounds, or contaminated materials.448 The safe use of OVs also depends on educating healthcare professionals and providing patients with guidance on managing injection sites.

Viral shedding, a well-documented phenomenon in OVT, presents another safety concern. Although viral shedding has been observed, no conclusive evidence supports active virus transmission to contacts. For example, 8.4% of family members in contact with T-VEC patients reported experiencing cold sore symptoms. However, these symptoms are mild, unconfirmed as OV infections, and do not pose significant clinical concerns. The results suggest that although viral shedding occurs, the risk of transmission remains minimal when appropriate safety measures are followed.315,435 Furthermore, special safety precautions may be needed when specific viruses are used in immunocompromised patients. Genetic modifications in OVs, especially those containing recombinant DNA elements, raise concerns about possible recombination with wild-type viruses, increasing the complexity of their safety profile.

Viral shedding during OV treatment has been documented in several clinical trials, primarily in blood, serum, and urine.449 Other fluids and tissues, such as saliva, oral swabs, cerebrospinal fluid, peritoneal lavage fluid, and injection sites, have also shown evidence of viral shedding.450 Infectious viruses shed during treatment can disseminate throughout the patient’s body and to individuals most likely to come into contact with these fluids, particularly family members and healthcare workers. Although the shed viruses observed in studies were highly attenuated and limited, posing minimal harm, the doses of OVs used in cancer treatments are generally too low to cause significant shedding. To minimize environmental viral shedding further, healthcare provider exposure should be strictly controlled during OV administration. Continuous monitoring of safety protocols and OV behavior in the body is crucial to ensure the safety and efficacy of these therapeutic agents.”

– Her immune system was freshly offended and once again hurled itself into the tumor with new found anger. 

#Xiao, D., Zhang, H., Liu, Y. et al. Oncolytic viruses: advanced strategies in cancer therapy. Sig Transduct Target Ther (2026).

https://www.nature.com/articles/s41392-025-02343-3 

Quote: “OVs play a crucial role in activating the host’s innate immune system, which triggers an adaptive immune response that targets tumors.1 Various OVs, including OAd, HSV, coxsackievirus, VV, and NDV, induce ICD to varying degrees. The ICD is essential for triggering antitumor immune responses and promoting immune memory.222,223,224,225,226 ICD, a cornerstone of the antitumor immune response induced by OVs,227 encompasses several forms of cell death, including apoptosis, necrosis, ferroptosis, autophagic cell death, and pyroptosis.228,229,230 During ICD, tumor cells release TAAs and tumor-associated neoantigens (TANs), both of which are crucial for activating adaptive immunity.231,232,233"

OV-induced antitumor immunity transitions from “cold” to “hot” tumors. OVs infect tumor cells, leading to cell lysis and the release of TAAs, viral antigens, DAMPs and PAMPs into the TME. This process activates the immune system, stimulating the release of cytokines and chemokines that recruit immune cells, including dendritic cells, macrophages, natural killer cells, and T cells, into the TME. Initially, the TME is “cold”, with minimal immune infiltration and a limited antitumor response. OVs help transform the TME into a “hot” environment characterized by increased infiltration of immune cells, including cytotoxic T cells, M1 macrophages, and natural killer cells. This shift enhances tumor cell recognition and eradication, promoting antitumor immunity. TAAs tumor-associated antigens, DAMPs damage-associated molecular patterns, PAMPs pathogen-associated molecular patterns, TME tumor microenvironment. Created with BioRender.com.”

– After two months of injections the tumor was only a shadow of its former self – 63% smaller, it had turned soft and lost its density.

#Forčić D, Mršić K, Perić-Balja M, Kurtović T, Ramić S, Silovski T, Pedišić I, Milas I, Halassy B. An Unconventional Case Study of Neoadjuvant Oncolytic Virotherapy for Recurrent Breast Cancer. Vaccines. 2024

https://www.mdpi.com/2076-393X/12/9/958 

Quote: “After only two months of therapy, in which a total of 7.89 log CCID50 of MeV and 9.07 log CCID50 of VSV was administered, the tumour was significantly reduced in size from a baseline volume of 2.47 ± 0.06 cm3 estimated by four independent imaging analyses to 0.91 cm3, which was the pathologic size of the excised tumour (Figure 1A). The tumour was converted from a hard, fixed nodule with overlying inflamed skin to a much smaller and softer mobile nodule without skin inflammation. At baseline, it was extremely difficult to insert the needle and to inoculate the virus suspension, whereas by the end of therapy, the tumour had softened considerably, enabling easier needle insertion and virus administration. Under ultrasound imaging, the tumour had become less hypoechoic, less spiculated, better circumscribed, and significantly flattened compared to the baseline (Figure 2A).”

– And critically: it had completely stopped any advances into the muscle and skin tissue. 

#Forčić D, Mršić K, Perić-Balja M, Kurtović T, Ramić S, Silovski T, Pedišić I, Milas I, Halassy B. An Unconventional Case Study of Neoadjuvant Oncolytic Virotherapy for Recurrent Breast Cancer. Vaccines. 2024

https://www.mdpi.com/2076-393X/12/9/958 

Quote: “Histopathological analysis of the finally excised tumour confirmed that it was confined to the subcutis, with no infiltration of either skin or pectoral muscle, in contrast to the baseline diagnosis.”

– Now surgeons removed the weakened tumor and examined it in the lab – half of its mass was immune cells angrily bashing cancer cells to death. 

#Forčić D, Mršić K, Perić-Balja M, Kurtović T, Ramić S, Silovski T, Pedišić I, Milas I, Halassy B. An Unconventional Case Study of Neoadjuvant Oncolytic Virotherapy for Recurrent Breast Cancer. Vaccines. 2024

https://www.mdpi.com/2076-393X/12/9/958 

Quote: “The tumour showed strong lymphocyte infiltration—45% (in relation to tumour mass) in comparison to baseline 10%, with some areas rich in lymphocytes and fibrous tissue but without discernible tumour cells (Figure 2B). Such a picture of abundant fibrosis is often seen after a complete pathological response to classical neoadjuvant chemotherapy. Immunohistochemical characterization of infiltrating lymphocytes showed that two subpopulations were dominantly increased within the tumour due to OVT: CD20-positive B cells (from 10% to 70%) and CD8-positive T cells (from 30% to 60%) indicating activation of an adaptive immune response (Figure 2C). Infiltration of macrophages (CD68-positive cells) was also increased. In addition, PD-L1 expression was detected after OVT in contrast to the PD-L1-negative phenotype before the treatment with viruses.”

– To be sure no survivors could grow back her doctors treated her with additional anti-cancer drugs for a year – but at the time of the making of this video it has been six years and her cancer has not returned. 

#Forčić D, Mršić K, Perić-Balja M, Kurtović T, Ramić S, Silovski T, Pedišić I, Milas I, Halassy B. An Unconventional Case Study of Neoadjuvant Oncolytic Virotherapy for Recurrent Breast Cancer. Vaccines. 2024

https://www.mdpi.com/2076-393X/12/9/958 

Quote: “The tumour was significantly shrunken in size, and was not infiltrating either muscle below or skin above in contrast to the baseline. Consequently, it was successfully excised. Due to the HER2 3+ phenotype of the excised tumour, the patient additionally completed adjuvant one-year trastuzumab therapy, in line with recommendations for the treatment of HER2 3+ breast cancers [31].”

In addition to the anti-cancer drug trastuzumab, Dr. Beata Halassy was also given a final injection of the measles vaccine virus two months after surgical removal of the tumor.

#Forčić D, Mršić K, Perić-Balja M, Kurtović T, Ramić S, Silovski T, Pedišić I, Milas I, Halassy B. An Unconventional Case Study of Neoadjuvant Oncolytic Virotherapy for Recurrent Breast Cancer. Vaccines. 2024 [Supplemental Material]

https://www.mdpi.com/article/10.3390/vaccines12090958/s1 

Quote: “Ten days after the last (the third) VSV application, the tumour was excised. Two months after the tumour excision, MeV was applied subcutaneously once around the surgical suture, as a preventive adjuvant treatment.”

As of March 2026, Dr. Beata Halassy has been in remission and her cancer has not returned.

Oncolytic virotherapy may also induce long-lasting anti-tumour immunity, which might prevent tumour relapse. However, the evidence for this so far is mostly based on animal models and a handful of patient cases. But even there, it is mostly indirect evidence, i.e. the patients did not have a recurrence of their cancer and they also still had some anti-tumour immune cells active in their body. But it is still unclear how much (if at all) those cells contributed to the lack of cancer recurrence.

#Chaurasiya S, Chen NG, Fong Y. Oncolytic viruses and immunity. Curr Opin Immunol. 2018

https://pmc.ncbi.nlm.nih.gov/articles/PMC9285655/ 

Quote: “Formation of protective antitumor immunity leading to rejection of subsequent tumor challenges [...] Induction of an anti-tumor memory response, which prevented tumor growth upon reinjection of tumor cells.”

#Kollmann CF, van Montfoort N, Cordelier P, Pol J, Olagnier D. Oncolytic virotherapy: Sparking durable anti-tumor immunity through microenvironment modulation. Semin Immunol. 2025

https://www.sciencedirect.com/science/article/pii/S1044532325000661 

Quote: “Oncolytic virotherapy (OVT) is a novel approach to cancer treatment that utilizes viruses to infect and destroy tumor cells selectively. Beyond direct oncolysis, OVT significantly reshapes the tumor microenvironment (TME), activating the adaptive immune system to generate robust and durable anti-tumor immunity. This review examines the diverse mechanisms by which OVT modulates the TME, including physical remodeling, alterations in cellular composition, and the induction of immunogenic cell death, which releases antigens and adjuvants that enhance immune activation. We also explore the synergistic effects of combining OVT with immune checkpoint inhibitors to counteract the immunosuppressive TME. Additionally, recent clinical studies are highlighted, demonstrating the transition of 'cold' tumors to 'hot' tumors and the establishment of systemic tumor control in patients treated with OVT. By enhancing TME immunogenicity, OVT emerges as a potent adjunct to anti-tumor immunotherapies, offering new opportunities to overcome resistance and achieve better therapeutic outcomes.”

– Beata’s decision to inject herself with viruses earned her much admiration and applause but also a ton of criticism from medical ethicists – mostly because the viruses and methods she used were not approved for use in humans. 

There are/were several ethical questions surrounding the Beata Halassy case. For example: Should scientists be allowed to experiment on themselves? Should scientific journals publish the results of such self-experimentation? Should cancer patients have easier or earlier access to experimental treatments? If yes, under which circumstances? Should Beata have sought ethical approval by an independent commission before treating herself? Did her doctors do anything wrong by helping her? 

Aside from these ethical questions, there were also concerns around the scientific usefulness of her case study, because the treatment happened outside of a clinical trial, with “impure” reagents, and because it was only administered to a single patient.

#Pueyo T. How to Beat Cancer with Viruses: An Interview with Beata Halassy. Uncharted Territories. 2024

https://unchartedterritories.tomaspueyo.com/p/how-to-beat-cancer-with-viruses-an

Quote: “TP: Your paper has become quite popular, with tens of thousands of reads. What do you think of that?

DBH: I’m very glad that so many people have been discussing the paper, but I think it’s for the wrong reasons. I think this case indicates that oncolytic virotherapy is very promising as a first line of treatment, but unfortunately most of the debate has been around ethics. 

TP: Why do you think the ethics have been so polemic?

DBH: The question of the ethics of self-experimentation had been consistently raised while we were trying to publish this article, specifically with the issue of trying to do this without an ethics board. As it was a case of self-experimentation, I did not consider it necessary to ask for anyone’s approval. In addition, all this was happening during the COVID-19 epidemic, when all medical efforts were involved in treating COVID-19 infected people. I do not think that anyone would have been able or interested in providing ethical approval for something so unconventional, at such an unconventional time. 

Given the hesitance to publish the paper, I searched the history of self-experimentation (a nice review is available by Hanley et al.) and the history of ethical principles in science generation, and learned that there is indeed nothing unethical or illegal in self-experimentation. 

TP: That was the main concern, but were there others to note?

DBH: The only big other concern was about the use of laboratory-grade viruses instead of clinical-grade. The difference is that clinical-grade is purer and better characterized, and the content is quantified and defined with more reliability, which means we’re very confident that it was the virus that shrunk the cancer, not something else inside of the lab-grade injection. 

Clinical grade is clearly better, but that wasn’t available to me. So the question becomes: Is laboratory-grade good enough to prove it was the virus that did the work?

I think it is, because otherwise, if we follow the argument that lab-grade is not good enough, most experiments in mice would never get published: They use lab-grade preparations too. 

The question is rather: How pure was our lab-grade virus? And that’s where it matters who our lab is. We have a huge amount of expertise in virus preparation characterization. We have been granted patents on virus purification; we have publications on virus preparations during COVID-19 time. I am very confident that these preparations were quite well characterized, particularly the quantity of infective virus.

I think in this type of paper, what matters is that we clearly disclose the entire process: How viruses were prepared, how they were characterized, what is the level of our expertise… That way, anyone reading the article will be fully informed, which is the point of a paper. 

TP: It took many attempts to get this published: 13 rejections in 2.5 years. Has this been your experience in the past?

DBH: I have never experienced such a level of paper rejection in my whole career with close to 80 publications published in international journals. 

We did expect it to be harder than other papers we had published for a couple of reasons. First, we aimed at even more prestigious journals than usual given the uniqueness and novelty of the case. Second, our team has lots of virology and immunotherapy expertise, but no oncological expertise. So we expected some pushback, but not at this level. 

In several journals, the paper was immediately rejected due to ethical concerns. We even received three positive reviews in one of the journals, and then a completely unexpected rejection by the academic editor.

From another perspective, this might have been for the best. This has allowed for time to pass. Now I’ve been cancer-free for 4 years, which is much stronger support for this approach.”

#Pugh J, Wilkinson D, Savulescu J. Self-censorship: should scientific journals decline to publish self-experimentation? J Med Ethics. 2025 https://jme.bmj.com/content/medethics/early/2025/09/09/jme-2025-110730.full.pdf 

Quote: “A virologist recently made headlines after successfully using an experimental form of oncolytic virotherapy to treat her own recurrent breast cancer. This case has come at a time when regulators are increasingly having to grapple with the proliferation of self-experimentation outside of accredited research institutions. There is, therefore, a pressing need to outline the key ethical dimensions of self-experimentation and to develop ethical guidance for journals that may be faced with decisions about whether to publish research involving self-experimentation. In this paper, we aim to provide such guidance. We argue that while self-experimentation is not always ethically problematic, neither is there an in-principle moral reason for exempting it from ethical evaluation. After summarising the details of the recent case report of self-experimentation and briefly placing it in historical context, we suggest that it is possible to navigate the ethical issues raised in cases of self-experimentation by returning to fundamental values in research ethics, focusing on the implications of self-experimentation for respect for autonomy, reasonable risk, and preventing harm to others. We apply these principles to the case report and explain why the publication of this report can be morally justified. We ultimately advocate for a case-by-case assessment of studies involving self-experimentation submitted for publication by ethical review boards and journal editors, and we propose a decision-making algorithm to help guide such decisions.”

#Borchers M. Erfolgreiche Brustkrebs-Selbsttherapie mit onkolytischen Viren wirft Fragen auf. ÄrzteZeitung. 2024 (German)

https://archive.is/20250122020545/https://www.aerztezeitung.de/Medizin/Fallbericht-zu-Selbstbehandlung-mit-onkolytischen-Viren-wirft-Fragen-auf-454739.html 

Quote: “Kontroverse Kasuistik

Erfolgreiche Brustkrebs-Selbsttherapie mit onkolytischen Viren wirft Fragen auf

Die vermeintliche Heilung eines Brustkrebsrezidivs durch eine Selbsttherapie mit onkolytischen Viren sorgte in Publikumsmedien für viel Wirbel. Die zugehörige Kasuistik wirft jedoch viele Fragen auf – nicht nur ethische.”

Translation: “Controversial case report

Successful self-treatment of breast cancer with oncolytic viruses raises questions

The alleged cure of a recurrent breast cancer through self-treatment with oncolytic viruses caused quite a stir in the popular media. However, the associated case report raises many questions—not only ethical ones.”

#Pugh J et al. Is it ever OK for scientists to experiment on themselves? Murdoch Children’s Research Institute. 2024

https://www.mcri.edu.au/news/insights-and-opinions/is-it-ever-ok-for-scientists-to-experiment-on-themselves

Quote: “It can be ethical for scientists to experiment on themselves. Such studies should at least sometimes be permitted, and certainly should be published so that others can learn from them. But it is a mistake to assume that self-experimentation only ever affects the individual involved. Halassy embarked on her self-experiment without any ethical oversight. Things ended well for her, but that won’t always be the case.”

– In this case, if you make medical trials easy, fast and cheap then there will be experiments that will seriously harm a few people – but on average you will make more progress, faster. Which will potentially save more lives in the end. 

If you make medical trials hard, very slow and expensive, on average you will harm fewer people and can be pretty confident that new therapies are pretty safe. 

Before they can conduct any medical studies on humans, in most countries scientists have to first adhere to rigorous ethical standards and have their planned research approved by an ethics review board. It typically involves quite a bit of paperwork and adherence to complex regulations, which means clinical trials take a lot of time and work before they can even get started. Additionally, clinical trial applications can get rejected if they don’t adhere to some of the rules, meaning sometimes certain things are not allowed to be tested (or only in a certain way).

It is an extremely complicated process, which also strongly differs by country and sometimes even between hospitals, universities or local/regional laws. 

Below we post some example sources for guidelines of ethical research in clinical trials.

• USA: Ethics in Clinical Research

• UK: Ethics and approvals – UKRI

• Germany: Ethik-Kommissionen 

– But you also hugely slow down medical progress and even completely prevent some new therapies. In today's world the slider is firmly on this side. 

Many promising therapeutic approaches don’t make it from the laboratory or animal experimentation stage into research in humans, due to ethical concerns or lack of adherence to medical/clinical regulations. This is also called the “valley of death”. Additionally, many new experimental therapies for cancer – especially those with a risk of serious side-effects – are first tested in patients with no other therapies available anymore (i.e. those at very advanced stages of disease). This increases the risk that the therapy shows no or little effect.

The reasons for this are manifold, but one part is the idea that it is more important that people don’t get harmed in clinical trials, than it is to make research as fast as possible/feasible. This is also backed by the medical concept of non-maleficence, which a lot of people in medicine feel guided by. 

There is also a real risk in harming the public’s trust in medical research when patients are harmed or die in clinical trials due to an experimental treatment. Below, we list some links describing the case of Jesse Gelsinger, who died from a novel gene therapy and whose case severely restricted research into these therapies for decades.

For these and other reasons, the “slider” of ethics in research has been firmly on the side of “safety first”, and not on the side of ”innovation first”. 

However, within the medical community there are researchers, physicians and patient advocacy groups who strive for lesser/looser medical regulations: they argue that regulations have become too strict and are actually preventing too many treatments from being tested properly and fairly, meaning the regulations potentially do more harm in this regard. There is also the role of financing: due to a lack of funding for (often very expensive) clinical trials, researchers often rely on collaborations with pharmaceutical companies, who shoulder the trial costs e.g. in exchange for the rights to produce the drug if the trial is successful. This can lead to situations where promising drugs or treatments struggle to find sponsors for trials if the drugs would e.g. not be profitable to produce, even if the trials were successful. However, there are also non-profit funding models for clinical trials with the aim to offset this incentive.

The whole topic is subject to intense scientific and political/regulatory debate.

#Traversing the valley of death. Nat Rev Bioeng 1, 875 (2023)

https://www.nature.com/articles/s44222-023-00146-1 

Quote: “Academic research plays a central role in the translational ecosystem, sitting on one end of the valley of death, that is, the gap between preclinical research and real-world clinical applications. Considering clinical need and applicability early in research and development, and knowing about regulatory and commercialization processes, may help academics push innovations across the valley.

The aim of bioengineering and biomedical research is to ultimately provide new treatments, diagnostics and prevention approaches that reach the patients. However, the huge strides made in the laboratory-scale development of biomedical innovations are not resulting in commensurate gains in new clinically translated solutions, and, even if they enter the market, patient access often remains limited, particularly in low-resource settings.”

#Spreafico A, Hansen AR, Abdul Razak AR, Bedard PL, Siu LL. The Future of Clinical Trial Design in Oncology. Cancer Discov. 2021

https://pmc.ncbi.nlm.nih.gov/articles/PMC8099154/ 

Quote: “After the establishment of safety and tolerability in early phase studies, initial efficacy evaluations of novel agents or combinations are typically conducted in patients with advanced metastatic disease. With some notable exceptions, such as molecularly agents that target oncogenic drivers (e.g. EGFR inhibitors in EGFR mutant non-small cell lung cancer) and anti-PD-1/L1 antibodies in inflamed tumors, most active new drugs produce only modest benefits in patients with recurrent and/or metastatic cancers. In order to achieve larger magnitude gains in survival, promising regimens must be tested in patients with curable malignancies who have undergone definitive treatment but are at high risk of relapse. Cancer interception is the active intervention of cancers at an early stage, offering an opportunity to eliminate molecular residual disease (MRD) before clinical relapse (13). MRD describes the state in which cancer-derived biomarkers are detectable, typically using highly sensitive and specific molecular assays in blood or other body fluids that are below the threshold of detection by conventional tests such as radiological imaging (14). Interception or “nip in the bud” clinical trials that evaluate adjuvant or maintenance treatment in MRD settings are challenging to conduct. These studies must not only identify patient subsets who would benefit from additional interventions with an acceptable therapeutic index, but they often require lengthy follow-up to observe sufficient events in time-based endpoints such as relapse-free survival. The choice of systemic agents being administered should be justified based on the biological rationale and their therapeutic index. For instance, as hyperprogression has been reported as a pattern of disease progression in some patients with immune checkpoint inhibitors and there is no clear-cut way to pre-identify such patients (15), thus the use of these agents in interception trials must be carefully considered and accompanied by close ctDNA monitoring.”

#The Medic Portal. Medical Ethics: Non-Maleficence. Retrieved May 2026

https://www.themedicportal.com/application-guide/medical-school-interview/medical-ethics/medical-ethics-non-maleficence/

Quote: “What Is Non-Maleficence?

Non-maleficence is a core principle of medical ethics stating that a physician has a duty to ‘do no harm’ to a patient. It directs a medical professional to consider the benefits of all procedures and weigh them against the potential risks and burdens on the patient.

The concept of non-maleficence is derived from the Latin phrase “primum non nocere” (“first, do no harm”). It can be applied to assessing the risks of medical procedures – or ensuring that all treatments and medical advice are administered by professionals with appropriate qualifications.”

#Sibbald B. Death but one unintended consequence of gene-therapy trial. CMAJ. 2001

https://pmc.ncbi.nlm.nih.gov/articles/PMC81135/

Quote: “Jesse Gelsinger wanted to help others overcome the same metabolic disorder he had, so he agreed to enter a gene-therapy trial. A short time later, the 18-year-old American became the first person to die because of participation in gene-therapy research.

His death would be but one of several unintended consequences: it also resulted in a lawsuit, a government investigation, the delay of some other clinical trials and the creation of a new regulatory process for gene-therapy trials in the US.”

#Wikipedia – Jesse Gelsinger. Retrieved May 2026

https://en.wikipedia.org/wiki/Jesse_Gelsinger

Quote: “Jesse Gelsinger (June 18, 1981 – September 17, 1999) was the first person publicly identified as having died in a clinical trial for gene therapy. Gelsinger suffered from ornithine transcarbamylase deficiency, an X-linked genetic disease of the liver, the symptoms of which include an inability to metabolize ammonia – a byproduct of protein breakdown. The disease is usually fatal at birth, but Gelsinger had a milder form of the disease, in which the ornithine transcarbamylase gene is mutated in only part of the patient's cells, a condition known as somatic mosaicism. As his deficiency was partial, Gelsinger managed to survive on a restricted diet and special medications.

Gelsinger joined a clinical trial run by the University of Pennsylvania that aimed at developing a treatment for infants born with the severe form of the disease. On September 13, 1999, Gelsinger was injected with an adenoviral vector carrying a corrected gene to test the safety of the procedure. He died four days later at the age of 18, on September 17, apparently having suffered a massive immune response triggered by the use of the viral vector to transport the gene into his cells, leading to multiple organ failure and brain death.[1]”

#Wells M, Cross C, Taylor K. Ethical Considerations for FDA Accelerated Approval. The Regulatory Review. 2024

https://www.theregreview.org/2024/12/07/ethical-considerations-for-fda-accelerated-approval/

Quote: “The U.S. Food and Drug Administration (FDA) recently granted accelerated approval of a treatment for adults with metastatic biliary tract cancer—a condition with less than a 5 percent five-year survival. Doctors explained that this approval addresses the unmet need for effective treatment for patients with this disease.

The process of getting FDA approval for a new drug takes, on average, 10 years and hundreds of millions of dollars. This extensive process risks leaving patients who suffer from severe or life-threatening conditions without access to treatment during this time.

For a drug to receive traditional FDA approval, developers must conduct studies that prove that the drug produces a clinical benefit—defined as a positive impact on the patient’s health—in patients with a certain condition. FDA then uses this data to determine whether the treatment’s clinical benefits outweigh its risks. If the benefits prevail, FDA grants the drug approval.

Recognizing that the length of the approval process may harm patients with untreatable conditions, FDA passed regulations that allow for accelerated approval of drugs that are likely to be effective in treating serious or life-threatening conditions. Rather than basing approval on clinical benefit, FDA evaluates whether a drug has a positive effect on a “surrogate endpoint.”

A surrogate endpoint is a medical indicator or sign that is reasonably likely to predict a clinical benefit. For example, a tumor shrinking in response to treatment is a surrogate endpoint that likely predicts the clinical benefit of increased survival rate or improved quality of life in cancer patients. Clinical trials that use surrogate endpoints more quickly produce results that can be used to seek accelerated approval.

Surrogate endpoints, however, are not always accurate predictors of a treatment’s effectiveness. To ensure that an accelerated drug actually produces a clinical benefit, FDA requires developers to conduct post-approval clinical trials that verify the benefit predicted by the surrogate endpoint. If trials confirm the clinical benefit, FDA grants the treatment traditional approval. Failure to conduct post-marketing studies diligently can result in FDA withdrawing its approval.

Accelerated approval has improved outcomes and treatment options for patients with severe medical conditions. For example, 59 cancer drugs received accelerated approval between 2013 and 2023. The process, however, has been heavily criticized.”

#Rubin M & Matthews K. The Impact of Right to Try Laws on Medical Access in the United States. Baker Institute for Public Policy. 2016

https://www.bakerinstitute.org/research/right-try-unproven-drugs 

Quote: “The U.S. Food and Drug Administration (FDA) has two major objectives: (1) “assuring the safety, efficacy, and security of human and veterinary drugs” and other medical interventions, and (2) “advancing public health by helping to speed product innovation.” These aims are addressed through research and clinical trials, a sometimes lengthy process designed to clearly assess the safety and efficacy of experimental interventions. However, these two charges can conflict at times as the public pressures the FDA for quick access to new treatments and interventions yet also expect approved treatments to be safe.

A major movement of patient advocates has worked since 2014 to hasten access to experimental interventions in the U.S. As a result, a number of state legislatures have passed “Right to Try” laws, which are designed to give terminally ill patients access to early investigational drugs before full FDA approval and before they are available under the FDA’s “expanded access” policy. Right to Try laws highlight a growing conflict between patients and the FDA, and arguably make the safety and efficacy of unproven drugs secondary to speedy access during the test phase.

In this paper, we review the background and purpose of the FDA, the clinical trials process, and the history of the FDA’s expanded access policy as well as the Right to Try movement and the collection of laws it has produced. Finally, we discuss how Right to Try laws impact the FDA and patients’ rights in the United States and recommend ways to promote faster access to safe treatments.” 

– So as a result, many novel cancer therapies are usually only given to people who have exhausted all other conventional therapies and whose cancer is very advanced. As a last resort of sorts. 

Many new cancer treatments are first tested in patients whose cancer is very hard to treat. This includes people with “refractory” cancer (which does not respond to treatment) or “relapsed” cancer (which comes back after treatment). These patients are often included in early clinical trials, where doctors are mainly studying whether a new treatment is safe and how it should be used. 

In some cases, patients can also receive experimental treatments through programs like “expanded access” or “compassionate use”, which are meant for people with serious illness and no other options left. 

#U.S. Food and Drug Administration – Expanded Access. Retrieved May 2026

https://www.fda.gov/news-events/public-health-focus/expanded-access

Quote: “Sometimes called “compassionate use”, expanded access is a potential pathway for a patient with a serious or immediately life-threatening disease or condition to gain access to an investigational medical product (drug, biologic, or medical device) for treatment outside of clinical trials when no comparable or satisfactory alternative therapy options are available. 

Expanded access may be appropriate when all the following apply:

• Patient has a serious or immediately life-threatening disease or condition.

• There is no comparable or satisfactory alternative therapy to diagnose, monitor, or treat the disease or condition.

• Patient enrollment in a clinical trial is not possible.

• Potential patient benefit justifies the potential risks of treatment.

• Providing the investigational medical product will not interfere with investigational trials that could support a medical product’s development or marketing approval for the treatment indication.

Investigational drugs, biologics or medical devices have not yet been approved or cleared by FDA and FDA has not found these products to be safe and effective for their specific use. Furthermore, the investigational medical product may, or may not, be effective in the treatment of the condition, and use of the product may cause unexpected serious side effects.”

#Federal Institute for Drugs and Medical Devices – "Compassionate Use" Programmes. Retrieved May 2026

https://www.bfarm.de/EN/Medicinal-products/Clinical-trials/Compassionate-Use/_node.html 

Quote: "(2) A marketing authorisation (Zulassung) shall not be required for medicinal products which: [...] 6. are made available free of charge under the conditions specified to in Article 83 of Regulation (EC) No. 726/2004 for administration to patients with a seriously debilitating disease or whose disease is life-threatening, and who cannot be treated satisfactorily with an authorised medicinal product; this applies equally to medicinal products which do not fall under the categories stipulated in Article 3 first or second paragraph of Council Regulation (EC) No. 726/2004; rules of procedure shall be specified in an ordinance pursuant to Section 80. [...]"

– At the time of making this video, over 100 studies are actively testing viruses against cancer in humans, but the vast majority are restricted to late-stage cancers. 

As of April 2026, a search on the ClinicalTrials.gov database yielded 101 results for the keywords “Cancer" & “oncolytic virus”, with the status of either “Not Yet Recruiting”, “Recruiting”, or “Active / Not Recruiting”.

https://clinicaltrials.gov/search?cond=Cancer&intr=oncolytic%20virus&aggFilters=status:not%20rec%20act&viewType=Card

– And this slows down progress – because it means that new therapies are tested in people whose body and immune systems are already severely weakened while their cancer is at the height of its strength.

#Lønning PE. Assessing Novel Therapies Based on Late-Stage Efficacy: A Dangerous Concept? Trends Cancer. 2021

https://www.cell.com/trends/cancer/fulltext/S2405-8033(20)30311-3

Quote: “Traditionally, the efficacy of novel cancer therapies has been confirmed in patients failing regular treatment before being tested in early disease. Improved understanding of the mechanisms guiding therapeutic efficacy may challenge this dogma, suggesting novel therapies to move into early evaluation based on biological rationales without late-stage efficacy evaluation.

Since the introduction of chemotherapeutics in the 1950s, the concept of implementing novel cancer therapies has been first to explore efficacy in late-stage disease in patients failing conventional treatment before moving into an early setting. The idea was logical; if a drug proved to have limited efficacy in advanced disease, it was not likely to become a treatment success in early disease.

While this strategy proved feasible at a time when the number of treatment regimens for each tumour type was limited, currently, multiple systemic treatment options are available for most types of cancer, offering several lines of therapy and extended survival for patients. However, increases in the number of standard regimens applied sequentially as well as extended tumour lifespan due to prolonged survival may both promote drug resistance. These factors challenge the convention that drug efficacy must be proven in late advanced disease following standard treatment before testing in the early setting.”

#Wu X, Chau YF, Bai H, Zhuang X, Wang J and Duan J (2023) Progress on neoadjuvant immunotherapy in resectable non-small cell lung cancer and potential biomarkers. Front. Oncol.

https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.1099304/full 

Quote: “The rationale for immune neoadjuvant therapy could be concluded as the following points (Figure 1): Firstly, the excellent efficacy of immunotherapy in locally advanced and metastatic NSCLC has been confirmed by several clinical trials, and both FDA and NMPA have approved several PD-1/PD-L1/CTLA-4 inhibitors alone or in combination for the first-line treatment of advanced driver-negative NSCLC; secondly, pre-operation patients are more likely to better tolerate full-dose systemic therapy with a better performance status(PS) score and fewer complications. Another reason to support immune neoadjuvant therapy is that preoperative patients harbor a relatively high tumor burden and high neoantigen loads, besides, the immune system remains intact so the application of immunotherapy at this time can maximize the strength and activate the immune system to kill tumor cells and obliterate distant micro-metastases (8). This will provide the basis for tumor shrinkage, down-staging, and more complete radical surgery, to obtain longer survival benefits.”

– To be crystal clear – virotherapy is not and won’t be the cure to cancer. Cancer is hundreds of different diseases and the best therapy depends on the type, location and how far it has spread. But in the best case virotherapy could be much less toxic and as effective or better than chemo – especially in combination with other therapies. Another weapon in our arsenal. 

The best therapy for a given cancer patient also depends on additional factors such as the patient's individual biology, their tumor’s biology, the size of the tumor, the stage at which the cancer was detected and more.

As of 2026, oncolytic virotherapy is considered a therapeutic option with high potential in combination with other treatments, such as radiation, surgery, chemotherapy and/or other anti-cancer drugs such as antibodies, immune checkpoint inhibitors etc.

A lot of research is also done with genetically engineered viruses to boost their cancer-killing and anti-tumour-immunity-activating effects.

#Zhou X, Hu S, Wang X. Recent advances in oncolytic virus combined immunotherapy in tumor treatment. Genes & Diseases, 2025, 12(6): 101599.

https://www.sciencedirect.com/science/article/pii/S2352304225000881

Quote: “Oncolytic viruses (OVs), a kind of emerging therapeutics for treating tumors, are characterized by high replication efficiency, superior killing effects, and few adverse reactions, which have shown great application prospects in preclinical tumor treatment trials. To overcome the limitations of OV monotherapy, recent studies have found that combination therapy with other anti-tumor therapeutics, especially with immunotherapy, yields promising outcomes in tumor eradication. Due to the advancements in genetic engineering, the combination of OVs with novel immunotherapy, including cellular immunotherapy, adoptive cellular immunotherapy, immune checkpoint inhibitors, cancer vaccines, cytokines, and bi- or tri-specific T cell engagers, has greatly improved clinical outcomes and quality of life of tumor patients. In this review, we systematically summarize the latest progress of OVs combined with immunotherapy in tumor treatment and highlight the future directions of the combination strategies, which will promote the clinical application of OVs in tumor therapy.”

#Wang Y, Zhu M, Chi H, Liu Y, Yu G. The combination therapy of oncolytic virotherapy. Front Pharmacol. 2024

https://pmc.ncbi.nlm.nih.gov/articles/PMC11079273/

Quote: “Introduction: Compared to other cancer immunotherapies, oncolytic viruses possess several advantages, including high killing efficiency, excellent targeting capabilities, minimal adverse reactions, and multiple pathways for tumor destruction. However, the efficacy of oncolytic viruses as a monotherapy often falls short of expectations. Consequently, combining oncolytic viruses with traditional treatments to achieve synergistic effects has emerged as a promising direction for the development of oncolytic virus therapies.

Methods: This article provides a comprehensive review of the current progress in preclinical and clinical trials exploring the combination therapies involving oncolytic viruses.

Results: Specifically, we discuss the combination of oncolytic viruses with immune checkpoint inhibitors, chemotherapy, targeted therapy, and cellular therapy.

Discussion: The aim of this review is to offer valuable insights and references for the further advancement of these combination strategies in clinical applications. Further research is necessary to refine the design of combination therapies and explore novel strategies to maximize the therapeutic benefits offered by oncolytic viruses.”

#Appleton E, Chiocca EA, Ungerechts G, Melcher A, Vile R. Oncolytic viruses as anticancer agents: clinical progress and remaining challenges. Lancet. 2025

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2825%2901206-1/abstract 

Quote: “Immunotherapy has transformed the treatment of cancer, yet many patients do not have response or lasting benefit. Strategies to overcome resistance remain of crucial importance. Oncolytic viruses offer a promising approach, with the unique ability to selectively replicate within (and to destroy) cancer cells, remodel the immunosuppressive tumour microenvironment, and stimulate antitumour immunity. Interest in the potential of oncolytic viruses has grown steadily over the past two decades, fuelled by advances in cancer immunology and viral engineering. However, clinical translation has not kept pace, and although a plethora of promising new constructs have entered clinical testing, several barriers continue to restrict widespread clinical implementation. This Therapeutics paper highlights key milestones in oncolytic virus clinical development, discusses the challenges that remain, and, through clinical reflection, considers how future research might be streamlined to achieve meaningful benefit for patients.”

#Rivera-Orellana, S., Bautista, J., Palacios-Zavala, D. et al. Oncolytic virotherapy and tumor microenvironment modulation. Clin Exp Med 25, 256 (2025)

https://link.springer.com/article/10.1007/s10238-025-01691-2 

Quote: “Oncolytic viruses (OVs) have emerged as a transformative approach in cancer therapy, offering tumor-specific lysis while sparing normal tissues. In addition to their direct cytolytic effects, OVs actively reshape the tumor microenvironment (TME) by enhancing immune infiltration, disrupting immunosuppressive signals, and promoting tumor antigen presentation. However, the complexity of the TME poses challenges, often necessitating combination therapies to improve OV efficacy and overcome tumor resistance. This review explores the evolution of oncolytic virotherapy, from the early use of naturally occurring viruses to the development of genetically engineered OVs. Among the most significant advancements, T-VEC, an FDA-approved herpesvirus, has been modified to express GM-CSF, enhancing immune activation in metastatic melanoma. Similarly, JX-594, a vaccinia virus, has been engineered for selective replication in tumor cells, demonstrating the potential of OVs to combine direct oncolysis with immune modulation. Other HSV-based OVs, such as HF10 and HSV1716, further highlight the ability of OVs to enhance immune cell infiltration and increase antigen presentation within the TME. Recent advances in tumor microenvironment remodeling have expanded OV therapeutic strategies. By converting immunologically “cold” tumors into “hot” tumors, OVs can overcome immune evasion through mechanisms such as enhanced antigen release, immune checkpoint inhibition, and metabolic reprogramming. To maximize therapeutic potential, researchers are developing genetically engineered OVs carrying immune-stimulatory transgenes, exploring synergistic combination therapies with immune checkpoint inhibitors, and utilizing nanoparticle-based delivery systems for improved precision. Additionally, novel OVs—including measles virus, Newcastle virus, Zika virus, and SARS-CoV-2—are being investigated for their unique ability to disrupt the TME and enhance anti-tumor immunity. Looking ahead, OV therapy will depend on optimizing TME-targeted strategies, improving viral delivery mechanisms, and identifying predictive biomarkers to personalize patient responses. Advances in viral engineering and immunomodulation hold the potential to revolutionize cancer treatment, offering more precise and effective therapeutic options. This review provides a comprehensive analysis of current progress in oncolytic virotherapy, emphasizing its potential to remodel the TME and improve clinical outcomes.”

#Lin, D., Shen, Y. & Liang, T. Oncolytic virotherapy: basic principles, recent advances and future directions. Sig Transduct Target Ther 8, 156 (2023).

https://www.nature.com/articles/s41392-023-01407-6 

Quote: “Oncolytic viruses (OVs) have attracted growing awareness in the twenty-first century, as they are generally considered to have direct oncolysis and cancer immune effects. With the progress in genetic engineering technology, OVs have been adopted as versatile platforms for developing novel antitumor strategies, used alone or in combination with other therapies. Recent studies have yielded eye-catching results that delineate the promising clinical outcomes that OVs would bring about in the future. In this review, we summarized the basic principles of OVs in terms of their classifications, as well as the recent advances in OV-modification strategies based on their characteristics, biofunctions, and cancer hallmarks. Candidate OVs are expected to be designed as “qualified soldiers” first by improving target fidelity and safety, and then equipped with “cold weapons” for a proper cytocidal effect, “hot weapons” capable of activating cancer immunotherapy, or “auxiliary weapons” by harnessing tactics such as anti-angiogenesis, reversed metabolic reprogramming and decomposing extracellular matrix around tumors. Combinations with other cancer therapeutic agents have also been elaborated to show encouraging antitumor effects. Robust results from clinical trials using OV as a treatment congruously suggested its significance in future application directions and challenges in developing OVs as novel weapons for tactical decisions in cancer treatment.”

– And in the process, she hoped to inspire more research on virotherapy as early options for patients – to save other lives like hers. 

#Pueyo T. How to Beat Cancer with Viruses: An Interview with Beata Halassy. Uncharted Territories. 2024

https://unchartedterritories.tomaspueyo.com/p/how-to-beat-cancer-with-viruses-an 

Quote: “Normally, when there’s a new potential treatment for cancer, the current approach is to start by testing it as a last resort: We first attempt what’s been tried and proven to work, like surgery, chemotherapy, biological therapy, or radiation. Only when those options fail do we explore experimental treatments, including oncolytic virotherapy. This means it’s initially used in patients with advanced or resistant cancers.

For most novel cancer treatments, this slows down progress because they’re facing the most challenging cases. But in the case of oncolytic virotherapy, this is especially bad, because we need to recruit the immune system to do a big chunk of the work, but by the time the cancer is advanced, the immune system is extremely weak due to both the cancer and the treatments against it.

The consequence is that oncolytic virotherapy looks like a much worse approach in many of these RCTs than it would probably be if we tested it as a first line of treatment rather than a last resort.

TP: So you think clinical trials with oncolytic virotherapy should be done earlier in the cancer process.

DBH: Yes, they will probably work much better than they do today, and maybe they don’t always work as well as other treatments, but they are certainly less destructive. So maybe we can use them as first line or treatment, or in combination with other treatments. 

This is why I cared so much about publishing my case. It may encourage the researchers already working on these drugs to target earlier stages of the cancer in clinical trials, as a neoadjuvant treatment [=pre-treatment before the main intervention] instead of conventional approaches like chemotherapy with/without immunotherapy. 

If we could get it as a first line of cancer treatment that is not toxic to the immune system and health of the patient, this would be an amazing achievement. It may also promote the development of combined treatments, with more than just one oncolytic virotherapy. It also opens the possibility that some already existing viral strains that have been safely used over the years for prophylactic vaccination against viral diseases could be used as oncolytics, if formulated and applied differently. In other words—some already approved products might be studied and developed for novel application. I hope that the article will stimulate investigations in all these directions, and that will finally provide novel, less toxic, and at least equally effective—if not better—therapies to cancer patients.”

– But she was also in a pretty unique position to try this experiment – and since she was doing it on herself, she didn’t need to go through the processes that would usually have slowed it down or forbidden it.

While cancer patients are typically involved in decision-making about their own treatments, they (and their doctors) often don’t have access to very new, experimental treatments unless very specific legal and ethical requirements are met.

#Pueyo T. How to Beat Cancer with Viruses: An Interview with Beata Halassy. Uncharted Territories. 2024

https://unchartedterritories.tomaspueyo.com/p/how-to-beat-cancer-with-viruses-an 

Quote: “TP: Why do you think the ethics have been so polemic?

DBH: The question of the ethics of self-experimentation had been consistently raised while we were trying to publish this article, specifically with the issue of trying to do this without an ethics board. As it was a case of self-experimentation, I did not consider it necessary to ask for anyone’s approval. In addition, all this was happening during the COVID-19 epidemic, when all medical efforts were involved in treating COVID-19 infected people. I do not think that anyone would have been able or interested in providing ethical approval for something so unconventional, at such an unconventional time.”

– In 2026, 6 years after Beata’s treatment, over a dozen studies are underway to test viruses as early-stage cancer therapies. 

As of April 2026, a search on the ClinicalTrials.gov database yielded 13 results for the keywords “Cancer" & “neoadjuvant” & “virus”, with the status of either “Not Yet Recruiting”, “Recruiting”, or “Active / Not Recruiting”.

https://clinicaltrials.gov/search?cond=Cancer&intr=virus&term=Neoadjuvant%20&aggFilters=status:not%20rec%20act&viewType=Card