Neoantigen-reactive CD8(+) T cells affect clinical outcome of adoptive cell therapy with tumor-infiltrating lymphocytes in melanoma

BACKGROUND: Neoantigen-driven recognition and T cell–mediated killing contribute to tumor clearance following adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TILs). Yet how diversity, frequency, and persistence of expanded neoepitope-specific CD8(+) T cells derived from TIL infusion products affect patient outcome is not fully determined. METHODS: Using barcoded pMHC multimers, we provide a comprehensive mapping of CD8(+) T cells recognizing neoepitopes in TIL infusion products and blood samples from 26 metastatic melanoma patients who received ACT. RESULTS: We identified 106 neoepitopes within TIL infusion products corresponding to 1.8% of all predicted neoepitopes. We observed neoepitope-specific recognition to be virtually devoid in TIL infusion products given to patients with progressive disease outcome. Moreover, we found that the frequency of neoepitope-specific CD8(+) T cells in TIL infusion products correlated with increased survival and that neoepitope-specific CD8(+) T cells shared with the infusion product in posttreatment blood samples were unique to responders of TIL-ACT. Finally, we found that a transcriptional signature for lymphocyte activity within the tumor microenvironment was associated with a higher frequency of neoepitope-specific CD8(+) T cells in the infusion product. CONCLUSIONS: These data support previous case studies of neoepitope-specific CD8(+) T cells in melanoma and indicate that successful TIL-ACT is associated with an expansion of neoepitope-specific CD8(+) T cells. FUNDING: NEYE Foundation; European Research Council; Lundbeck Foundation Fellowship; Carlsberg Foundation.