RESEARCH GROUPS

Breast cancer is the most common cancer in the female population worldwide including Thailand. Though several lines of management (surgery, radiation, chemotherapy, targeted therapy) have been well developed in the past decades, many breast cancer patients suffer from cancer relapse or resistance. Our group is interested in developing novel therapeutic approaches targeting tumor microenvironments mainly cancer-associated fibroblasts and tumor infiltrating immune cells. We are also interested in establishing breast cancer immunotherapy using dendritic cell-based tumor-specific T cells, neoantigen-specific T cells, and Chimeric Antigen Receptor (CAR)-engineered T-cell (CAR T cells). The ultimate goal is to offer cutting-edge treatment options to Thai breast cancer patients.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the leading cause of tumor-related mortality worldwide. The global incidence of this cancer is increasing in almost all countries, with the highest rates occurring in East Asia. According to the Nation Cancer Institute of Thailand, HCC represents the most common malignancy in males and the second most common in females. Key risk factors for HCC have been identified, including hepatitis B (HBV) or hepatitis C (HCV) viral infection, exposure to toxins (alcohol and aflatoxin), metabolic syndrome, and immune-related syndrome. Drivers of HCC prevalence vary depending on the socioeconomics of individual nations. In Thailand, the leading risk factor is HBV, followed by HCV. Overall, HCC is associated with a public health crisis. Current systemic therapeutics are limited with a high recurrence rate; therefore, new therapies are critically needed. Our research sets out to develop novel immunotherapeutic approaches for the treatment of HCC. Two cellular immunotherapy strategies have been developed, namely dendritic cell-based immunotherapy and adoptive immunotherapy using Chimeric Antigen Receptor (CAR)-engineered T-cells.  In the former approach, healthy volunteer or patient-derived peripheral blood mononuclear cells (PBMCs) are used to isolate monocytes, which in turn are induced to become mature dendritic cells (DCs). These cells are pulsed with relevant tumor-associated antigens (TAAs) during the maturation phase of culture. This enables the activation of autologous lymphocytes to become effector cells, as a result of major histocompatibility complex (MHC)-dependent antigen presentation upon co-culture with mature DCs. Recently generated data supports the promise of this approach, with the demonstration of in vitro tumor cell killing activity. The second area of research is to engineer T-cells to express CARs on their cell surface, thereby re-targeting their specificity against cancer cells in an MHC-independent manner. These studies will pave the way for the first human evaluation in Phase I clinical trial to improve quality of life and increase the probability of cure in HCC patients. Finally, effective immunotherapy such as this may also have a beneficial impact on treating other cancers prevalent in the Thai population.

Hematologic cancers or blood cancers occur when abnormal blood cells start growing out of control, consequently interrupting normal blood cells’ functions that fight off infection and produce new blood cells. The three main types of blood cancer are leukemia, lymphoma, and myeloma. Currently, chimeric antigen receptor (CAR) T-cell therapy is a remarkable therapeutic advance in blood cancers. Autologous CAR T therapy targeting CD19 antigen has achieved US Food and Drug Administration (FDA) approval since 2017. There are four CD19 targeted CAR T-cell products approved for treatments of relapsed/refractory acute lymphoblastic leukemia (r/r ALL), diffuse large B-cell lymphoma (DLBCL), relapsed or refractory large B-cell lymphomas, and mantle cell lymphoma. Despite the successes achieved to date, there are significant challenges associated with CAR T-cell therapy, such as variations in efficacy of CAR T products from different academic medical centers, high cost of CAR T products, low persistence of CAR T in patients, and resistance to CAR T treatments. Thus, substantial research efforts are underway to develop new targets and approaches for effective therapy. Previous CD19-specific CAR T contained murine single-chain variable fragment (scFv) that may induce human anti-mouse antibody responses, limiting CAR T survival and functions. Our team is thus interested in developing fully human CD19-specific CAR T for overcoming unwarranted immune responses. Our team aims to establish a safe and effective adoptive cell therapy for hematologic cancers.  Several approaches were proposed, including adoptive T cell therapy derived from cancer antigen- or peptide-pulsed dendritic cell primed T cells, CAR T cell therapy targeting ALL, lymphoma, and multiple myeloma, and engineered T cells secreting engager molecules or immune checkpoint inhibitors. We hope that adoptive cell therapy will treat blood cancer patients in Thailand and Southeast Asia in the near future.

Retinoblastoma (RB) is the most common intraocular malignancy in children. The incidence rate is 3.4% of all pediatric malignancies, and it tends to increase each year. Approximately 32-33 new cases were diagnosed each year in Thailand. The limitations and risks associated with RB's currently available treatments highlight the need for new, safer, and more effective therapeutic options. Recent gene therapy advances have demonstrated the clinical efficacy of chimeric antigen receptors (CAR)-engineered T cells, which can redirect T cells to target-specific tumor antigens via an MHC-independent antigen recognition process. The CAR gene therapy strategy demonstrated clinical success in the treatment of both CD19-positive B-cell leukemia and lymphoma. CAR T therapy is used as a "living drug" for cancer treatment. Although the promising outcome of using CAR T therapy was reported, this product's price is exclusively high. Our team thus aims to develop effective and safe engineered T cell therapy at affordable prices for Thai cancer patients. We had already produced the in-house CAR T products and tested cytotoxicity against various tumor cells in the laboratory. Our generation of CAR is designed to incorporate various intracellular costimulatory signaling domains that can specifically bind cancer antigens and effectively kill the tumors. Together with our international collaborator, Prof. Lung-Ji Chang, who had experience in several centers of CAR T clinical trials in China and other countries in Asia. We had demonstrated that CAR T targeting disialoganglioside 2 (GD2) could effectively eradicate RB tumor cells in vitro; however, the tumor evaded CAR T recognition and limited its function. Further investigation revealed the immune evasion mechanisms of RB required to be explored, and the modified CAR T cells are still needed. Our team is interested in developing super functional CAR T by targeting immune checkpoint molecules or combined with chemotherapy drugs and chemical compounds that prevent RB tumor immune escape. We also focused on other tumor-associated antigens for RB and other childhood cancers, for instance, neuroblastoma. We hope that our CAR T living drugs will be used in the clinic for Thai patients with cancers in the near future.