Neoantigen Identification and Response to Adoptive Cell Transfer in anti PD-1 Naïve and Experienced Patients with Metastatic Melanoma.

PURPOSE Immune checkpoint blockade (ICB) agents and adoptive cell transfer (ACT) of tumor infiltrating lymphocytes (TIL) are prominent immunotherapies used for the treatment of advanced melanoma. Both therapies rely on activation of lymphocytes that target shared tumor antigens or neoantigens. Recent analysis of patients with metastatic melanoma who underwent treatment with TIL ACT at the National Cancer Institute (NCI) demonstrated decreased responses in patients previously treated with anti PD-1 agents. We aimed to find a basis for the difference in response rates between anti PD-1 naïve and experienced patients. EXPERIMENTAL DESIGN We examined the tumor mutational burden (TMB) of resected tumors and the repertoire of neoantigens targeted by autologous TIL in a cohort of 112 anti PD-1 naïve and 69 anti PD-1 experienced patients. RESULTS Anti PD-1 naïve patients were found to have higher TMBs (352.0 vs. 213.5, p = 0.005) and more neoantigens (2 vs. 1, p = 0.003) compared to anti PD-1 experienced patients. Among patients treated with TIL ACT, TMB and number of neoantigens identified were higher in ACT responders than ACT non-responders in both anti PD-1naïve and experienced patients. Among patients with comparable TMBs and predicted neoantigen loads, patients naïve to anti PD-1 therapy were more likely to have identifiable neoantigens and tumor specific lymphocytes in their treatment products (2.5 vs. 1, p = 0.02). CONCLUSIONS These results indicate that decreases in TMB and targeted neoantigens only partially account for the difference in response to ACT and that additional factors likely influence responses in these patients.

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