Tumor-infiltrating BRAF(V600E)-specific CD4(+) T cells correlated with complete clinical response in melanoma

T cells specific for neoantigens encoded by mutated genes in cancers are increasingly recognized as mediators of tumor destruction after immune checkpoint inhibitor therapy or adoptive cell transfer. Unfortunately, most neoantigens result from random mutations and are patient specific, and some cancers contain few mutations to serve as potential antigens. We describe a patient with stage IV acral melanoma who achieved a complete response following adoptive transfer of tumorinfiltrating lymphocytes (TILs). Tumor exome sequencing surprisingly revealed fewer than 30 nonsynonymous somatic mutations, including oncogenic BRAF(V600E). Analysis of the specificity of TILs identified rare CD4(+) T cells specific for BRAF(V600E) and diverse CD8(+) T cells reactive to nonmutated self-antigens. These specificities increased in blood after TIL transfer and persisted long-term, suggesting they contributed to the effective antitumor immune response. Gene transfer of the BRAF(V600E)-specific T cell receptor (TCR) conferred recognition of class II MHC-positive cells expressing the BRAF mutation. Therapy with TCR-engineered BRAF(V600E)-specific CD4(+) T cells may have direct antitumor effects and augment CD8(+) T cell responses to self-and/or mutated tumor antigens in patients with BRAF-mutated cancers.