(1) Li M (2) Zheng R (3) Liu Z (4) Zhang P (5) Zhu T (6) Xin X (7) Zhao H (8) Chen W (9) Zheng B (10) Zhao A (11) Gao J
(1) Li M (2) Zheng R (3) Liu Z (4) Zhang P (5) Zhu T (6) Xin X (7) Zhao H (8) Chen W (9) Zheng B (10) Zhao A (11) Gao J
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 nave 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., TCR_C, TCR_C, CD3_, CD3_, and CD3_) 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 CD3_ and CD3_, 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.
Author Info: (1) Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, China. (2) Key Laboratory of
Author Info: (1) Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, China. (2) Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, China. Yicheng County People's Hospital, Linfen, Shanxi, China. (3) Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, China. Ningbo Hangzhou Bay Hospital, Ningbo, Zhejiang, China. (4) Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, China. (5) Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, China. Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Taizhou, Zhejiang, China. (6) Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, China. Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, China. (7) Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, China. (8) Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, China. (9) Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, China. (10) Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, Zhejiang, China. (11) Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, China. Zhejiang Qixin Biotech, Wenzhou, Zhejiang, China.
Citation: Front Immunol 2024 15:1502936 Epub12/24/2024
