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

Purpose: The administration of autologous tumor infiltrating lymphocytes (TIL) can mediate durable tumor regressions in patients with melanoma likely based on the recognition of immunogenic somatic mutations expressed by the cancer. There is limited data regarding the immunogenicity of mutations in breast cancer. We sought to identify immunogenic non-synonymous mutations in a patient with triple-negative breast cancer (TNBC) in order to identify and isolate mutation-reactive TIL for possible use in adoptive cell transfer. <p>            Experimental Design: A TNBC metastasis was resected for TIL generation and whole exome sequencing. Tandem minigenes or long 25mer peptides encoding selected mutations were electroporated or pulsed onto autologous antigen presenting cells, and reactivity of TIL was screened by upregulation of CD137 and IFNg ELISPOT. The nature of the T cell response against a unique non-synonymous mutation was characterized.</p> <p>Results: We identified 72 non-synonymous mutations from the tumor of a patient with TNBC. CD4⁺and HLA-DRB1^*1501-restricted TIL 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.</p> <p>Conclusion: Breast cancers can express naturally processed and presented unique non-synonymous mutations that are recognized by a patient's immune system. TIL recognizing these immunogenic mutations can be isolated from a patient's tumor suggesting that adoptive cell transfer of mutation-reactive TIL could be a viable treatment option for patients with breast cancer.

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