Exploring high-affinity MAGE-A3-specific T-cell receptors derived from healthy donor PBMCs: A preclinical evaluation

T cell receptor (TCR) therapy is a promising immunotherapy for cancers, leveraging tumor-associated antigens (TAAs) for targeted treatment. MAGE-A3, a cancer-testis antigen, is highly expressed in multiple malignancies, making it an attractive target. However, efficient identification of high-affinity, tumor-specific TCRs remains a challenge.

Healthy donor peripheral blood mononuclear cells (PBMCs) were stimulated ex vivo with multi-epitope mRNA or peptide pools to isolate MAGE-A3-specific TCRs. Functional assays, in vivo xenograft models, and structural modeling were used to evaluate TCR efficacy, specificity, and safety.

Seven MAGE-A3-specific TCRs were identified, with G0507 showing the highest clinical potential. G0507 TCR-T cells demonstrated robust cytotoxicity against MAGE-A3-expressing tumor cells, minimal cross-reactivity, and significant tumor growth inhibition in xenograft models without toxicity. Structural modeling revealed key residues critical for TCR-pMHC interaction, aiding epitope selection and TCR optimization.

This study demonstrates the feasibility of deriving functional TCRs from healthy donors and highlights the importance of epitope selection for advancing TCR-based therapies. G0507 represents a promising candidate for clinical development, providing a foundation for future cancer immunotherapy strategies targeting MAGE-A3.