Durable complete response in a patient with metastatic melanoma following adoptive transfer of autologous T cells recognizing 10 mutated tumor antigens

Abstract

Durable complete response rates of 20% have been observed in clinical trials of patients with metastatic melanoma employing adoptive cell transfer (ACT) of patient derived tumor infiltrating lymphocytes (TIL). Here we provide a detailed analysis of the response of TIL administered to a patient with metastatic melanoma who exhibited a complete response ongoing greater than 3 years. Using whole exome and RNA sequencing and bioinformatic analysis of the patient’s matched tumor and normal gDNA we identified over 4,000 non-synonymous somatic mutation variants. We screened 745 somatically mutated genes using tandem minigene constructs expressing transcripts expressed in autologous tumor cells whose expression levels were greater than 0.1% of the levels of bactin. These tandem minigenes were then transfected into autologous B cells and then analyzed for their ability to stimulate the administered T cells. Our results indicated that the autologous TIL distinctly recognized 10 somatically mutated gene products, each of which was recognized in the context of three different HLA class I restriction elements expressed by the patient’s tumor. Detailed T cell clonal analysis revealed that 9 of the top 20 most prevalent clones present in the infused TIL, comprised over 1⁄4 of total infused cells and recognized mutated antigens. These results further supported our efforts to identify and enrich mutation-reactive T cells for the treatment of patients with metastatic cancer. Authors’ details National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. National Cancer Institute, National Institutes of Health, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA. Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

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@inproceedings{Prickett2015DurableCR, title={Durable complete response in a patient with metastatic melanoma following adoptive transfer of autologous T cells recognizing 10 mutated tumor antigens}, author={Todd D. Prickett and Jessica S. Crystal and Jared J. Gartner and Yao Xin and Pasetto Anna and Alena Gros and Yong-Chen Lu and Yong Li and Mona El-Gamil and Steven Aaron Rosenberg and Paul F. Robbins}, year={2015} }