Tumor-infiltrating [BRAF.sup.V600E]-specific [CD4.sup.+] 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 canc...

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Bibliographic Details
Published in:The Journal of clinical investigation 2018-04, Vol.128 (4), p.1563
Main Authors: Veatch, Joshua R, Lee, Sylvia M, Fitzgibbon, Matthew, Chow, I.-Ting, Jesernig, Brenda, Schmitt, Tom, Kong, Ying Ying, Kargl, Julia, Houghton, A. McGarry, Thompson, John A, McIntosh, Martin, Kwok, William W, Riddell, Stanley R
Format: Article
Language:English
Subjects:
Cancer genetics
Cancer research
Care and treatment
Development and progression
Genetic aspects
Health aspects
Immunotherapy
Melanoma
Physiological aspects
Proto-oncogenes
T cell antigen receptors
T cells
Tumor antigens
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Summary: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 tumor-infiltrating lymphocytes (TILs). Tumor exome sequencing surprisingly revealed fewer than 30 nonsynonymous somatic mutations, including oncogenic [BRAF.sup.V600E]. Analysis of the specificity of TILs identified rare [CD4.sup.+] T cells specific for [BRAF.sup.V600E] and diverse [CD8.sup.+] 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.sup.V600E]-specific T cell receptor (TCR) conferred recognition of class II MHC-positive cells expressing the BRAF mutation. Therapy with TCR-engineered [BRAF.sup.V600E]-specific [CD4.sup.+] T cells may have direct antitumor effects and augment [CD8.sup.+] T cell responses to self- and/or mutated tumor antigens in patients with BRAF-mutated cancers.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI98689