Pagh Kristensen, Heeke, and Tvingsholm et al. investigated the neoepitope specificity of tumor-infiltrating lymphocytes in adoptive cell transfer (TIL-ACT) products in 26 patients with metastatic melanoma. Using 5921 barcoded pMHC multimers, 106 CD8+ TIL-ACT recognizing patient-specific neoepitopes (neoantigen-reactive T cells [NARTs]) were detected. NARTs were more diverse and frequent in responders to ACT, NART diversity and frequency correlated with progression-free survival, and NARTs persisted in the periphery of responders. High NART frequency was associated with humoral and B cell-mediated mechanisms and immune signaling pathway gene signatures.
Contributed by Maartje Wouters
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 mela-noma 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 in-creased survival, and that detection of engrafted CD8+ T cells in post-treatment (i.e. originating from the TIL infusion product) 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.