Development of iPSC-derived T cells targeting EGFR neoantigens in non-small cell lung cancer.

Development of iPSC-derived T cells targeting EGFR neoantigens in non-small cell lung cancer. Molecular therapy. Methods & clinical development Niizuma, K., Nishimura, T., Villanueva, J., Amaya, L., Fowler, J. L., Isobe, T., Nakauchi, Y., Saavedra, B., Xu, H., Nakanishi, M., Wilkinson, A. C., Loh, K. M., Shrager, J. B., Nakauchi, H. 2025; 33 (3): 101517

Abstract

A long-sought goal of cancer immunotherapy is to mass-produce T cells that specifically target tumor neoantigens. One decisive challenge is the identification of neoantigens derived from cancer driver genes. Here, we identify T cells that recognize the NSCLC-associated EGFR C797S mutation, which confers resistance to current inhibitors and is linked to poor prognosis. To overcome limitations in T cell availability, we reprogrammed EGFR C797S-specific T cells into induced pluripotent stem cells (iPSCs) and re-differentiated them into CD8+ T cells. These iPSC-derived T cells specifically recognized the EGFR C797S mutation and effectively killed cancer cells expressing this mutation. Our findings underscore the potential of targeting driver mutation-derived neoantigens for immunotherapy and demonstrate that iPSC-derived T cells can mediate antitumor effects. Collectively, this approach combining neoantigen identification with T cell reprogramming may offer a promising strategy for targeting drug-resistant tumors.

View details for DOI 10.1016/j.omtm.2025.101517

View details for PubMedID 40687378

View details for PubMedCentralID PMC12274810