385 Identification of TCRs targeting shared tumor antigens

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Background The development of immunotherapies has revolutionized cancer treatment. However, despite the success of immune checkpoint inhibitors in a subset of patients, many cancers remain refractory to these treatments. One factor that may contribute to lack of efficacy of immune checkpoint inhibitors is an insufficient number of tumor-specific T cells. This limitation can be overcome by increasing the presence of tumor-specific T cells through adoptive cell transfer. Indeed the transfer of tumor-specific CAR T cells has shown incredible success in hematological malignancies. In contrast, the treatment of solid tumors using adoptive T cell therapy remains challenging, but successful examples of CAR- and TCR-engineered T cell and tumor-infiltrating lymphocyte (TIL) treatment of solid tumors have been reported. Notably, in early 2024 the FDA approved TIL therapy as a treatment for melanoma, resulting in the first approved T cell therapy for the treatment of solid cancers. While TIL therapies enrich for tumor-specific T cells through the expansion of antigen-specific T cells found in the excised tumor, the use of engineered TCR therapies where an exogenous TCR is introduced into a T cell requires a robust process for the selection of tumor antigen-specific TCRs. Methods Here, we describe a workflow for the identification and characterization of TCRs targeting shared tumor antigens. Primary human T cells are engineered using a non-viral approach to express a tumor-specific TCR of interest, and then subjected to a series of in vitro assays to characterize the potency and specificity of the candidate TCR. TCR-engineered T cells are evaluated for reactivity against immortalized cell lines expressing the correct HLA molecule that do or do not express the target antigen of interest, allowing for discrimination of on-target potency and off-target activity. This system allows for the early removal of highly cross-reactive TCRs and the prioritization of less cross-reactive TCRs for more in depth safety characterization. We demonstrate that the established pre-clinical workflow identifies potent, safe tumor-specific TCRs that exhibit activity in in vivo xenograft tumor models. Results We demonstrate that the established pre-clinical workflow identifies potent, safe tumor-specific TCRs that exhibit activity in in vivo xenograft tumor models. Conclusions This is a robust workflow that can be applied for selection of candidate clinical TCRs targeting distinct tumor antigens.

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