Detection of mutant antigen-specific T cell receptors against multiple myeloma for T cell engineering

Masahiro Okada; Kanako Shimizu; Hiroshi Nakazato; Satoru Yamasaki; Shin-Ichiro Fujii

doi:10.1016/j.omtm.2023.05.014

Detection of mutant antigen-specific T cell receptors against multiple myeloma for T cell engineering

Mol Ther Methods Clin Dev. 2023 May 16:29:541-555. doi: 10.1016/j.omtm.2023.05.014. eCollection 2023 Jun 8.

Authors

Masahiro Okada¹, Kanako Shimizu¹, Hiroshi Nakazato¹, Satoru Yamasaki¹, Shin-Ichiro Fujii^{1

2}

Affiliations

¹ Laboratory for Immunotherapy, RIKEN Center for Integrative Medical Sciences, 1-7-22, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
² RIKEN Program for Drug Discovery and Medical Technology Platforms, RIKEN, 1-7-22, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.

Abstract

Multiple myeloma (MM) remains an incurable hematological neoplasm. Neoantigen-specific T cell receptor (TCR)-engineered T (TCR-T) cell therapy is a potential alternative treatment. Particularly, TCRs derived from a third-party donor may cover broad ranges of neoantigens, whereas TCRs in patients suffering from immune disorders are limited. However, the efficacy and feasibility of treating MM have not been evaluated thoroughly. In this study, we established a system for identifying immunogenic mutant antigens on MM cells and their corresponding TCRs using healthy donor-derived peripheral blood mononuclear cells (PBMCs). Initially, the immune responses to 35 candidate peptides predicted by the immunogenomic analysis were investigated. Peptide-reactive T lymphocytes were enriched, and subsequently, TCR repertoires were determined by single-cell TCR sequencing. Eleven reconstituted TCRs showed mutation-specific responses against 4 peptides. Particularly, we verified the HLA-A∗24:02-binding QYSPVQATF peptide derived from COASY S55Y as the naturally processed epitope across MM cells, making it a promising immune target. Corresponding TCRs specifically recognized COASY S55Y⁺HLA-A∗24:02⁺ MM cells and augmented tumoricidal activity. Finally, adoptive cell transfer of TCR-T cells showed objective responses in the xenograft model. We initiatively proposed the utility of tumor mutated antigen-specific TCR genes to suppress MM. Our unique strategy will facilitate further identification of neoantigen-specific TCRs.

Keywords: TCR cloning; TCR-T cell; adoptive cell transfer; multiple myeloma; neoantigens; single-cell TCR sequence.