Characterization of an Immunogenic Mutation in a Patient with Metastatic Triple-Negative Breast Cancer

作者：Yasmine Assadipour, Nikolaos Zacharakis, Jessica S. Crystal, Todd D. Prickett, Jared J. Gartner, Robert Somerville, Hui Xu, Mary A. Black, Li Jia, Harshini Chinnasamy, Isaac Kriley, Lily Lu, John R. Wunderlich, Zhili Zheng, Yong‐Chen Lu, Paul F. Robbins, Steven A. Rosenberg, Stephanie L. Goff, Steven A. Feldman · 发表于：Clinical Cancer Research · 年份：2017 · DOI：10.1158/1078-0432.ccr-16-1423 · 被引用次数：33 · 研究领域：CAR-T cell therapy research、Immunotherapy and Immune Responses、Cancer Genomics and Diagnostics

Abstract Purpose: The administration of autologous tumor-infiltrating lymphocytes (TILs) can mediate durable tumor regressions in patients with melanoma likely based on the recognition of immunogenic somatic mutations expressed by the cancer. There are limited data regarding the immunogenicity of mutations in breast cancer. We sought to identify immunogenic nonsynonymous mutations in a patient with triple-negative breast cancer (TNBC) to identify and isolate mutation-reactive TILs for possible use in adoptive cell transfer. Experimental Design: A TNBC metastasis was resected for TIL generation and whole-exome sequencing. Tandem minigenes or long 25-mer peptides encoding selected mutations were electroporated or pulsed onto autologous antigen-presenting cells, and reactivity of TIL was screened by upregulation of CD137 and IFNγ ELISPOT. The nature of the T-cell response against a unique nonsynonymous mutation was characterized. Results: We identified 72 nonsynonymous mutations from the tumor of a patient with TNBC. CD4+ and HLA-DRB1*1501–restricted TILs isolated from this tumor recognized a single mutation in RBPJ (recombination signal binding protein for immunoglobulin kappa J region). Analysis of 16 metastatic sites revealed that the mutation was ubiquitously present in all samples. Conclusions: Breast cancers can express naturally processed and presented unique nonsynonymous mutations that are recognized by a patient's immune system. TILs recognizing these immunogenic mutat...