Neoantigen-reactive CD8+ T cells affect clinical outcome of adoptive cell therapy with tumor-infiltrating lymphocytes in melanoma
Nikolaj Pagh Kristensen, Christina Heeke, Siri A. Tvingsholm, Annie Borch, Arianna Draghi, Michael D. Crowther, Ibel Carri, Kamilla K. Munk, Jeppe Sejerø Holm, Anne-Mette Bjerregaard, Amalie Kai Bentzen, Andrea M. Marquard, Zoltan Szallasi, Nicholas McGranahan, Rikke Andersen, Morten Nielsen, Göran B. Jönsson, Marco Donia, Inge Marie Svane, Sine Reker Hadrup
Nikolaj Pagh Kristensen, Christina Heeke, Siri A. Tvingsholm, Annie Borch, Arianna Draghi, Michael D. Crowther, Ibel Carri, Kamilla K. Munk, Jeppe Sejerø Holm, Anne-Mette Bjerregaard, Amalie Kai Bentzen, Andrea M. Marquard, Zoltan Szallasi, Nicholas McGranahan, Rikke Andersen, Morten Nielsen, Göran B. Jönsson, Marco Donia, Inge Marie Svane, Sine Reker Hadrup
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Clinical Research and Public Health Immunology

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.

Authors

Nikolaj Pagh Kristensen, Christina Heeke, Siri A. Tvingsholm, Annie Borch, Arianna Draghi, Michael D. Crowther, Ibel Carri, Kamilla K. Munk, Jeppe Sejerø Holm, Anne-Mette Bjerregaard, Amalie Kai Bentzen, Andrea M. Marquard, Zoltan Szallasi, Nicholas McGranahan, Rikke Andersen, Morten Nielsen, Göran B. Jönsson, Marco Donia, Inge Marie Svane, Sine Reker Hadrup

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Figure 3

Frequency of NARTs correlates with increased survival after TIL-ACT.

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Frequency of NARTs correlates with increased survival after TIL-ACT. (A ...
(A and B) NART diversity represented as the number of NARTs detected in TIL Inf products for each patient according to RECIST (A) and clinical response (B). (C and D) NART frequency represented as the sum of estimated frequency of NARTs detected in TIL Inf products for each patient according to RECIST (C) and clinical response (D). (E and F) PFS for the cohort split by median NART diversity (median = 3.65 NARTs) (E) and median NART frequency (median = 0.63 %) (F). (G and H) PFS for the cohort splits by high (>66th percentile), intermediate (> 33rd percentile), and low groups (≤33rd percentile). (G) NART diversity. 66th percentile = 5.65 NARTs. 33rd percentile = 0.88 NARTs. (H) NART frequency. 66th percentile = 3.26%. 33rd percentile = 0.03%. P values were calculated using Kruskal-Wallis test followed by Dunn’s multiple comparison test in A and C; only significant comparisons are shown. Nonparametric Mann-Whitney U test was used for B and D. Box plot whiskers represent IQR. P values and HRs were calculated using the Mantel-Cox test and log-rank approach, respectively (F). P values for G and H were calculated using log-rank test. Both number of and frequency of NARTs were normalized to absolute HLA coverage (see Methods). n = 26 for all plots. All values displayed on a logarithmic scales were increased by 0.01 to account for 0 values.