248 Exploitation of endogenous TCR signaling using an oncolytic virus for modulation of CAR T phenotype and function against solid tumors

Background Both chimeric antigen receptor (CAR) T cell and oncolytic virus (OV) therapies face limited efficacy alone against solid tumors. We have shown that combining CAR T cell and VSV (vesicular stomatitis virus) OV therapy provides increased benefit over either therapy alone, at least in part by generating a population of hyper-functional, persistent CAR T cells primed against viral antigens. 1 In murine solid tumor models, these TCR-primed CAR T cells demonstrate superior target cell cytotoxicity ex vivo, acquire a unique KLRG1hiCD127loCD62Llo phenotype, downregulate T cell activation via NFAT, and clonally expand via their endogenous TCRs against viral antigens.Methods We used C57BL/6 mice treated with CAR T cells against the EGFRviii antigen along with VSV to study the emerging CAR T phenotypes. TCR signaling in CAR T cells was investigated using the novel Tocky transgenic mouse model, which reports T cell activation as a function of time using an unstable fluorescent protein reporter of Nr4a3, a protein downstream of NFAT. CyTOF and single cell RNA sequencing were performed on tumor-infiltrating lymphocytes.Results Using an MHC I tetramer specific to the dominant VSV N-derived epitope N 52-59, we found that 20-50% of transfused CAR T cells adopted TCR specificity for this immunodominant VSV antigen, far above the predicted frequency in a naïve T cell repertoire. Ex vivo, these TCR-primed CAR T produced significantly increased levels of granzyme B and IFNγ over tetramer negative CAR T when activated with either TCR or CAR targets. TCR-primed CAR T cells had decreased levels of persistent T cell activation as compared to non-TCR-primed CAR T. CyTOF and single cell RNA-seq analyses demonstrated a hyper-effector phenotype among TCR-primed CAR, with increased expression of T-bet, KLRG1, CD11c, and CD44 and effector molecules granzyme B, IFNγ, and perforin. Single cell TCR sequencing revealed targeted hyper-expansion of VSV N-specific TCR-primed CAR T cells and little overlap in TCR clonotypes between the CAR T co-treated with PBS versus VSV in vivo.Conclusions Overall, CAR T cells that undergo targeted endogenous anti-viral TCR priming and signaling appear to adopt a unique phenotype that promotes their cytotoxic function and in vivo persistence. These data suggest a novel mechanism by which OV-CAR T combination therapy can be exploited to engage the CAR T endogenous TCR and that engineering specific anti-viral TCRs into CAR T cells could be used to improve efficacy with OV boosting.Reference Evgin L, Kottke T, Tonne J, Thompson J, Huff AL, van Vloten J, et al. Oncolytic virus-mediated expansion of dual-specific CAR T cells improves efficacy against solid tumors in mice. Sci Transl Med. 2022;14(640):eabn2231.

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