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*updates ongoing
The overall goal of the Brainson Lab, located at the University of Kentucky's Markey Cancer Center, is to define precision therapy options for genotype- and subtype-specific lung cancer using ideas and techniques from stem cell biology and epigenetic research.
Non-small cell lung cancer (NSCLC) is a highly complex and severe disease, characterized by significant genetic, cellular, and epigenetic diversity. A typical human lung tumor has over 200 non-synonymous mutations and may include cells with markers from various lung lineages. The lineage connections and epigenetic distinctions between the two main subtypes of NSCLC, lung adenocarcinoma (LADC) and lung squamous cell carcinoma (LSCC), remain unclear.
Lung cancer is the leading cause of cancer-related death worldwide. Despite advances in many therapies, the 5-year overall survival rate for lung cancer patients in the U.S. remains at 23% and is among the lowest of all cancer types. Statistics are trending in a hopeful direction, but the continued need for novel therapeutics and treatment protocols is clear. Lung cancer is typically subcategorized into NSCLC and SCLC, where SCLC is a highly aggressive neuroendocrine tumor and NSCLC arises from lung epithelium. NSCLC accounts for 85% of overall cases and can be further divided into two main subtypes: lung adenocarcinoma (LADC) and lung squamous cell carcinoma (LSCC). The LADC subtype accounts for approximately 45% of diagnoses, whereas LSCC comprises 18% of cases. LADCs are histologically glandular and often found in the distal lung with alveolar type 2 (AT2) markers. Conversely, LSCCs have fully stratified epithelium, produce keratin pearls around the squamous tissue, and are marked by SOX2, p63, and KRT5. In contrast to LADC, LSCC is most often caused by loss of suppressor genes and is believed to be more difficult to treat for this reason.
My interests - TIL Therapy in NSCLC*
My interests - TIL Therapy in NSCLC*
Cellular Therapies (an overview)
Cellular Therapies (an overview)
The novel immunotherapy techniques of adoptive cell transfer (ACT) have gained momentum over the last decade and continue to show promise moving forward. The three main types of ACT include chimeric antigen receptor T cell (CAR-T), modified T cell receptor (TCR), and TIL therapies (Figure Left). Both CAR and TCR therapies can pull T cells from peripheral blood, however, TIL therapy requires solid tumor infiltrates. Counter to standard therapeutics, ACT is a “living” treatment where re-infused lymphocytes can expand more than 1000-fold after administration and can remain in circulation for several years (or more). TIL as second line therapy (or above) in advanced stage cancers after failure of PD1/L1 checkpoint inhibitors appears to be feasible and effective. (A) CAR-T cells are now up to 5 generations, all containing CD3ζ chains and mixtures of co-stimulatory molecules (CM) or transgenes (TG). (B) Modified-TCR cells include altered variable alpha and beta chains of the TCR to recognize specific tumor (neo)antigens. (C) TILs are isolated from solid tumors, are polyclonal (indicated here by various colored TCRs), and can be cultured in bulk, further selected for specificity, or cultured for a shorter duration (young).
TIL Therapy Generalized
TIL Therapy Generalized
The origins of clinical TIL research are credited to Dr. Steven A. Rosenberg beginning in the late 1980’s at the National Cancer Institute in Bethesda, Maryland. But it was not until February 2024 that FDA approved the first TIL therapy as second-line therapy in advanced melanoma. At a surface level, the process of producing TILs appears straightforward. First, tumors are resected and dissociated, TILs are then expanded in culture with IL-2, tested for quality and reactivity, and finally re-infused into the patient. However, depending on the protocol chosen (bulk, selected, young, or hybrid), there are various caveats along the way that add to the complexity of development. Yet, at each step there are multiple options for procedural variation, manual labor can be time consuming, and the space required to achieve the necessary TIL counts under good manufacturing practices (GMP) can quickly overcome a standard research lab. Additionally, there are various subsets of TILs, which depending on expansion, can accelerate or further complicate the process.
Depending on which rapid expansion procedure (REP) chosen, different TIL products can be achieved. Bulk TILs offer simplicity and broad responsiveness but can become exhausted or terminally differentiated (darker depiction). Selected TILs are more specific but can take longer because of a smaller starting population. Young (minimal) TILs have more proliferative potential and persistence (lighter depiction) but have fewer cell totals at infusion.
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