Optimized BCMA/CS1 bispecific TRuC-T cells secreting IL-7 and CCL21 robustly control multiple myeloma

Front Immunol. 2024 Dec 24:15:1502936. doi: 10.3389/fimmu.2024.1502936. eCollection 2024.

Abstract

Introduction: Challenges remain in reducing antigen escape and tumor recurrence while CAR-T cell therapy has substantially improved outcomes in the treatment of multiple myeloma. T cell receptor fusion construct (TRuC)-T cells, which utilize intact T cell receptor (TCR)-CD3 complex to eliminate tumor cells in a non-major histocompatibility complex (MHC)-restricted manner, represent a promising strategy. Moreover, interleukin-7 (IL-7) is known to enhance the proliferation and survival of T cells. C-C motif chemokine ligand 21 (CCL21) is a ligand for chemokine C-C motif receptor 7 (CCR7) and exhibits strong chemotaxis against naïve T cells and antigen-presenting cells such as dendritic cells.

Methods: The bispecific TRuC-T cells simultaneously targeting B cell maturation antigen (BCMA) and CD2 subset 1 (CS1) were constructed by pairing two of five subunits (i.e., TCRαC, TCRβC, CD3γ, CD3δ, and CD3ϵ) in the TCR/CD3 complex and were named C-AC-B-3E, C-BC-B-3E, C-3G-B-3E, C-3D-B-3E, C-3E-B-3E, B-3E-C-3E, B-3G-C-3E, and B-3D-C-3E. Additionally, the BCMA/CS1 bispecific TRuC-T cells secreting IL-7 and CCL21, named BC-7×21 TRuC-T cells, were generated. All of the bispecific TRuC-T cells were characterized and tested in vitro and in vivo.

Results: Following the optimization of various pairs of two subunits of TCR/CD3 complex, B-3G-C-3E TRuC-T cells, characterized by incorporating CD3γ and CD3ε, exhibited the strongest myeloma-specific cytotoxicity. Furthermore, the bispecific BC-7×21 TRuC-T cells had stronger proliferation, chemotaxis, and cytotoxicity in vitro. Accordingly, the bispecific BC-7×21 TRuC-T cells showed better persistence in vivo so as to effectively suppress tumor growth in the NCG mouse xenograft model of MM.1S multiple myeloma.

Discussion: This study demonstrated that BC-7×21 TRuC-T cells, engineered through the optimization of the two subunits of TCR/CD3 complex and a co-expression cytokine strategy, may offer a novel and effective therapy for relapsed/refractory multiple myeloma.

Keywords: B cell maturation antigen; C-C motif chemokine ligand 21; CD2 subset 1; T cell receptor fusion construct T cell; interleukin-7; multiple myeloma.

MeSH terms

  • Animals
  • B-Cell Maturation Antigen* / immunology
  • B-Cell Maturation Antigen* / metabolism
  • Cell Line, Tumor
  • Chemokine CCL21* / metabolism
  • Humans
  • Immunotherapy, Adoptive / methods
  • Interleukin-7* / immunology
  • Interleukin-7* / metabolism
  • Mice
  • Mice, SCID
  • Multiple Myeloma* / immunology
  • Multiple Myeloma* / metabolism
  • Multiple Myeloma* / therapy
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Antigen, T-Cell / metabolism
  • Receptors, Chimeric Antigen / genetics
  • Receptors, Chimeric Antigen / immunology
  • Receptors, Chimeric Antigen / metabolism
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • B-Cell Maturation Antigen
  • Interleukin-7
  • Chemokine CCL21
  • TNFRSF17 protein, human
  • CCL21 protein, human
  • IL7 protein, human
  • Receptors, Chimeric Antigen
  • Receptors, Antigen, T-Cell

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. The study was partially supported by Guangdong Provincial Natural Science Foundation (2019A1515110831), Wenzhou Municipal Science and Technology Research Program (2018ZY001), Shandong Provincial Key R & D programs (2021CXGC011102), Construction Fund of Key Medical Disciplines of Hangzhou, Basic Public Welfare Research Program of Zhejiang Province (LQ21C080002), and “Pioneer” and “Leading Goose” R&D Program of Zhejiang (2024C03163).