Identification of neoantigen-specific T cells and their targets: implications for immunotherapy of head and neck squamous cell carcinoma. (3rd April 2019)

• Record Type: Journal Article
• Authors: Ren, Lili; Leisegang, Matthias; Deng, Boya; Matsuda, Tatsuo; Kiyotani, Kazuma; Kato, Taigo; Harada, Makiko; Park, Jae-Hyun; Saloura, Vassiliki; Seiwert, Tanguy; Vokes, Everett; Agrawal, Nishant; Nakamura, Yusuke
• Is Part Of: Oncoimmunology. Volume 8:Number 4(2019)
• Publication Date: 2019-04-03
• Subjects: Head and neck squamous cell carcinoma (HNSCC) -- T cell receptor (TCR) -- adoptive T cell therapy -- neoantigen -- cytotoxic T lymphocyte (CTL) -- engineered T cells; Tumors -- Immunological aspects -- Periodicals; Neoplasms -- therapy -- Periodicals; Immunotherapy -- Periodicals; 616.994
• DOI: 10.1080/2162402X.2019.1568813
• Languages: English
• ISSNs: 2162-402X

Abstract

ABSTRACT: To develop a practically applicable method for T-cell receptor (TCR)-engineered T cell immunotherapy targeting neoantigens, we have been attempting to identify neoantigen-specific T cell receptors (TCRs) and establish TCR-engineered T cells in a 3–4-month period. In this study, we report the characterization of T cell repertoires in tumor microenvironment (TME) and identification of neoantigen-specific TCRs after stimulation of patient-derived T cells. We screened 15 potential neoantigen peptides and successfully identified two CD8 + HLA-dextramer + T cells, which recognized MAGOHBG17A and ZCCHC14P368L . All three dominant TCR clonotypes from MAGOHBG17A -HLA dextramer-sorted CD8 + T cells were also found in T cells in TME, while none of dominant TCR clonotypes from ZCCHC14P368L -HLA dextramer-sorted CD8 + T cells was found in the corresponding TME. The most dominant TCRA/TCRB pairs for these two neoantigens were cloned into HLA-matched healthy donors' T lymphocytes to generate TCR-engineered T cells. The functional assay showed MAGOHBG17A TCR-engineered T cells could be significantly activated in a mutation-specific, HLA-restricted and peptide-dose-dependent manner while ZCCHC14P368L TCR-engineered T cells could not. Our data showed neoantigen-reactive T cell clonotypes that were identified in the patient's peripheral blood could be present in the corresponding TME and might be good TCRs targeting neoantigens.