Isolation of neoantigen-specific T cells from tumor and peripheral lymphocytes

Cyrille J. Cohen, Jared J. Gartner, Miryam Horovitz-Fried, Katerina Shamalov, Kasia Trebska-McGowan, Valery V. Bliskovsky, Maria R. Parkhurst, Chen Ankri, Todd D. Prickett, Jessica S. Crystal, Yong F. Li, Mona El-Gamil, Steven A. Rosenberg, Paul F. Robbins

Research output: Contribution to journalArticlepeer-review

296 Scopus citations

Abstract

Adoptively transferred tumor-infiltrating T lymphocytes (TILs) that mediate complete regression of metastatic melanoma have been shown to recognize mutated epitopes expressed by autologous tumors. Here, in an attempt to develop a strategy for facilitating the isolation, expansion, and study of mutated antigen-specific T cells, we performed whole-exome sequencing on matched tumor and normal DNA isolated from 8 patients with metastatic melanoma. Candidate mutated epitopes were identified using a peptide-MHC-binding algorithm, and these epitopes were synthesized and used to generate panels of MHC tetramers that were evaluated for binding to tumor digests and cultured TILs used for the treatment of patients. This strategy resulted in the identification of 9 mutated epitopes from 5 of the 8 patients tested. Cells reactive with 8 of the 9 epitopes could be isolated from autologous peripheral blood, where they were detected at frequencies that were estimated to range between 0.4% and 0.002%. To the best of our knowledge, this represents the first demonstration of the successful isolation of mutation-reactive T cells from patients' peripheral blood prior to immune therapy, potentially providing the basis for designing personalized immunotherapies to treat patients with advanced cancer.

Original languageEnglish
Pages (from-to)3981-3991
Number of pages11
JournalJournal of Clinical Investigation
Volume125
Issue number10
DOIs
StatePublished - 1 Oct 2015

Bibliographical note

We thank Arnold Mixon and Shawn Farid for their excellent technical assistance during the cell-sorting procedures; the Adelson Medical Research Foundation (AMRF) for their generous support; and the NIH Tetramer Core Facility (contract HHSN272201300006C) for the provision of MHC tetramers.

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