Development and preclinical validation of a therapeutic γδ TCR-engineered cell product for pan-cancer targeting 3442

Description Adoptive cellular therapies have revolutionized cancer treatment, yet significant challenges remain, including antigen escape, toxicity and patient accessibility. γδ TCR-engineered cells offer the potential to overcome these barriers due to their ability to recognize upregulated stress ligands in an MHC-independent manner. Our lab has characterized T cells expressing a γδ TCR that was significantly expanded in a cancer patient who demonstrated a complete response to anti-PD-1 therapy. When cloned and expressed in Jurkats, this γδ TCR demonstrated wide reactivity to a variety of cancer cell lines including lung, melanoma, breast and myeloma, but not healthy cells. CRISPR editing of lines confirmed recognition of antigen independently of HLA and known γδ TCR ligands, thus positioning this TCR as a potentially novel, pan-cancer therapy. To advance this γδ TCR towards clinical application, we have optimized lentiviral transduction protocols to generate large quantities of γδ TCR-T cells capable of mediating potent and specific killing of target cells. Ongoing whole-genome screens aim to identify its ligand in an unbiased manner. Complementary efforts to expand its preclinical evaluation involve use of 3D organoid models, PDXs and NSG mice, to assess its safety and efficacy in physiologically relevant systems. This HLA-independent γδ TCR represents an innovative strategy for treating a more diverse patient population and overcoming current challenges of adoptive cell therapy. Funding Sources This work is supported by the Canadian Institutes of Health Research (CIHR) through the C-GSM program & UHN Innovation Accelerator (IA). Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)