Genetic engineering approaches to support clinical applications of T cell receptor library targeting
Dr. Cafri started his talk by highlighting the current gap on effective therapeutic strategies for solid tumors, which account for 90% of cancer-related mortality. Therefore, there is a clear need for immunotherapeutic approaches targeting solid tumor antigens. His work focuses on identifying T cells and specifically T cell receptors (TCR) able to recognize oncogenic mutations. An advantage of immunotherapies leveraging TCRs over CART is the ability of these receptors to recognize both cell surface and intracellular processed antigens.
Dr. Cafri has developed a new method to identify T cells reactive to tumor antigens in the blood. In this process, peripheral blood cells from metastatic epithelial cancer patients are sorted to isolate memory T cells to perform in vitro T cell activation assays by-coculturing with neoantigen-loaded dendritic cells. This approach allows for expansion and enrichment of T cells reactive against specific neoantigens. Some of the advantages of this approach include more accessible patient-derived samples and younger T cells. By following this workflow, his team identified HLA-A11 restricted KRASG12V specific TCRs.
Overall, this strategy supports developing personalized T cell therapies and depending on the tumor antigen and HLA restrictions, immunotherapies for a broader patient population. For example, KRAS mutations, such as G12D and G12V, are frequent in pancreatic cancer and could be targeted for immunotherapy to benefit more patients. Armed with a library of TCRs against mutated KRAS, Dr. Cafri’s team is developing a pipeline for autologous T cell immunotherapies leveraging the expression of some of the identified TCRs. Lastly, for T cell gene editing to support clinical applications, his team is considering non-viral approaches, such as non-viral sleeping beauty transposon/integrase system and non-viral CRISPR-Cas9 gene editing.