MAGE-A4 pMHC-targeted CAR-T cells exploiting TCR machinery exhibit significantly improved in vivo function while retaining antigen specificity

• Published in: Journal for immunotherapy of cancer 2024-11, Vol.12 (11), p.e010248
• Main Authors: Liu, Meiou, Akahori, Yasushi, Imai, Naoko, Wang, Linan, Negishi, Kohei, Kato, Takuma, Fujiwara, Hiroshi, Miwa, Hiroshi, Shiku, Hiroshi, Miyahara, Yoshihiro
• Format: Article
• Language: English
• Subjects: Adoptive cell therapy - ACT; Animals; Antigens, Neoplasm - immunology; Cell Line, Tumor; Chimeric antigen receptor - CAR; Humans; Immune Cell Therapies and Immune Cell Engineering; Immunotherapy, Adoptive - methods; Major Histocompatibility Complex - immunology; Major histocompatibility complex - MHC; Mice; Neoplasm Proteins - immunology; Neoplasm Proteins - metabolism; Neoplasms - immunology; Neoplasms - therapy; Original Research; Receptors, Antigen, T-Cell - immunology; Receptors, Antigen, T-Cell - metabolism; Receptors, Chimeric Antigen - immunology; Receptors, Chimeric Antigen - metabolism; Solid tumor; T cell Receptor - TCR; Xenograft Model Antitumor Assays
• ISSN: 2051-1426; 2051-1426
• DOI: 10.1136/jitc-2024-010248

BackgroundThe development of chimeric antigen receptor (CAR)-T cell therapies for solid tumors has attracted considerable attention, yet their clinical efficacy remains limited. Therefore, various efforts have been made to improve the efficacy of CAR-T cell therapy. As one promising strategy, incorporating the T-cell receptor (TCR) machinery into CAR structures has been reported to improve the efficacy of CAR-T cells in studies using conventional CARs targeting such as EGFR. However, in the case of peptide/major histocompatibility complex (pMHC)-targeted CARs, the advantages of exploiting TCR machinery have not been fully elucidated. We recently developed MAGE-A4-derived pMHC (MAGE-A4 pMHC)-targeted CAR-T cells (MA-CAR-T cells) using a highly specific human scFv antibody against MAGE-A4p230-239/HLA-A*02:01. We aimed to determine whether MAGE-A4 pMHC-targeted CAR-T cells using the TCR machinery (Hybrid MA-TCR-T cells) exhibit superior functionality without compromising antigen specificity.MethodsWe constructed a retroviral vector expressing Hybrid MA-TCR where MAGE-A4 pMHC-specific scFv are fused to human TCR constant chains.ResultsHybrid MA-TCR-T cells demonstrated superior in vitro functions compared with MA-CAR-T cells, while maintaining strict antigen specificity. In addition, functional superiority of Hybrid MA-TCR-T cells to MA-CAR-T cells became more pronounced on repetitive antigen stimulation. In particular, Hybrid MA-TCR-T cells significantly inhibited tumor growth in an immunodeficient mouse model more effectively than MA-CAR-T cells. Ex vivo analyses indicated that their enhanced therapeutic efficacy might result from higher infiltration of functionally active, less differentiated Hybrid MA-TCR-T cells in tumor tissues.ConclusionsThese findings suggest that leveraging the TCR machinery is a promising strategy for enhancing pMHC-targeted CAR-T cell therapy for solid tumors, potentially leading to more effective treatments.