The Landscape of Tumor intrinsic Genetic Resistance to T cell Therapy

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PROJECT SUMMARY/ABSTRACT Epithelial cancers are common malignancies that account for 80 to 90 percent of human cancers. Despite breakthroughs in chemotherapy, targeted therapy, and immunotherapy, they generally are incurable in advanced stages. Cell therapy has shown remarkable efficacy in certain advanced stage hematologic cancers, but application of the approach to epithelial cancers has been more difficult. The short-term goal of this project is to elucidate principles of cell therapy in epithelial cancers using human papillomavirus (HPV)-associated cancers as a disease model. The long-term goal of this project is to discover and develop cellular therapy for HPV-associated cancers and other common malignancies. Research in the Si2 phase demonstrated that tumor- infiltrating lymphocytes can cause durable, complete tumor responses in HPV-associated cancers; genetically engineered T cells targeting an HPV oncoprotein can induce robust tumor regression in HPV-associated cancers – including immune checkpoint blockade resistant tumors; and tumor-intrinsic genetic defects in antigen processing machinery (APM) and interferon (IFN) response pathways control resistance to engineered TCR-T cell therapy. Research in the R00 phase will build on the Si2 findings with the goals to 1) elucidate in HPV- associated cancers a multidimensional picture of tumor-intrinsic immune related genetic resistance (IRGR) and 2) investigate the impact of cell therapy and immune pressure on IRGR and of IRGR on tumor response to cell therapy. HPV-associated cancers will be profiled for alterations in genes with defined function in tumor recognition and killing by T cells. In addition, exploratory analyses will be conducted to identify candidate immune evasion genes that are altered at frequencies greater than expected or that drive clonal evolution based on spatial clonal architecture mapping. The impact of cell therapy on IRGR and vice versa will be investigated by study of HPV-associated cancers from patients treated with tumor-infiltrating lymphocyte therapy and engineered TCR-T cell therapy. The longitudinal impact of immune pressure on IRGR will be investigated by comparing primary versus metastatic tumors and by analyzing serial intra-patient, metachronous tumor resections. This research will provide an integrated understanding of the reciprocal effects of immune response and IRGR in HPV-associated cancers. The work is critical to understanding immune editing and tumor resistance in the context of cell therapy and is necessary to guide the discovery of predictive biomarkers and the rational design of next- generation treatment strategies.