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

Abstract

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.

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“…More recently, TILs have found their place in cancer treatment. Emerging data showed that adoptive cell therapy with TILs can be an effective treatment for metastatic melanoma [ 20 ]. Similarly, a recently published study demonstrated that cell therapy with autologous TILs may constitute a new treatment strategy in metastatic lung cancer [ 21 ].…”

Engineering neoantigen vaccines to improve cancer personalized immunotherapy

“…No dose-limited toxicity or cytokine release syndrome was observed, and no apparent autoimmune response occurred. Kristensen et al 151 performed ACT in patients with melanoma, finding that the number and frequency of new epitope-specific T cells in TILs infusion products were associated with improved clinical outcomes.…”

Neoantigens and NK Cells: “Trick or Treat” the Cancers?

“…A phase II trial showed that 40 days after infusion of ex vivo amplified TILs that contained specific CD8+ T cells targeting neoepitope derived from the KRAS mutation G12D, a patient with metastatic colorectal cancer encountered regression of all the metastatic lung lesions, suggesting an important role of neoepitope-reactive CD8+ T cells in cancer therapy ( 51 ). Further research shows that TIL adoptive treatment is linked to an increase in neoepitope-specific CD8+ T cells ( 55 ). On the other hand, TIL-based ACT responders retained a subset of stem-like neoantigen-specific CD8+ T cells that show self-renewal and superior growth capacity in vitro and in vivo , highlighting the relevance of T-cell phenotypes in ACT response ( 56 ).…”