RenTCR-derived natural MAGE-A4-specific TCRs outperformed affinity-enhanced TCRs in antitumor efficacy

Background: MAGE-A4 is a clinically validated target highly expressed in multiple solid tumors, but its expression in healthy tissues is restricted to the testis and placenta. TCR-T cell therapies targeting MAGE-A4 show promising efficacy in synovial sarcoma but exhibit limited efficacy in other solid tumors. Biocytogen's proprietary TCR discovery platform, RenTCR, showed advantages including lower costs and higher efficiency in screening high-reactivity TCRs. Using this platform, we successfully identified TCRs against MAGE-A4 with high reactivity, high specificity, and superior anti-tumor activity. ‌ Methods: TCRs targeting MAGE-A4 were identified using the RenTCR platform. Reporter cell lines were used to rapidly screen reactive TCRs, followed by TCR transduction into primary human T cells to evaluate cytotoxicity, IFN-gamma release, and peptide sensitivity. Candidate TCRs underwent cross-reactivity screening and X-scan analysis for safety assessment. To assess in vivo antitumor efficacy, NDG mice bearing MAGE-A4 + HLA-A2.1 + human tumor xenografts were administered human primary T cells transduced via lentiviral vectors with candidate TCRs. ‌Results: The RenTCR platform identified TCRs targeting two distinct epitopes of MAGE-A4. Two TCRs demonstrated excellent cytotoxicity, IFN-gamma release, and specificity in vitro . The candidate TCRs also induced tumor regression in vivo . RenTCR Platform-derived natural TCRs exhibited better antitumor activity than clinical-stage affinity-enhanced TCRs. Conclusion: These findings highlight the therapeutic potential of two MAGE-A4-targeting TCR candidates as an effective strategy for treating melanoma, lung cancer, and other solid tumors expressing MAGE-A4.