Development of iPSC-Derived T Cells Targeting EGFR Neoantigens in Non-Small Cell Lung Cancer

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. C.; Shrager, J. B.; Nakauchi, H.

doi:10.1101/2025.02.15.638388

bioRxiv · 10.1101/2025.02.15.638388

Development of iPSC-Derived T Cells Targeting EGFR Neoantigens in Non-Small Cell Lung Cancer

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. C.·Shrager, J. B.·Nakauchi, H.

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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.

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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. C., Shrager, J. B., Nakauchi, H.. 2025-02-20. Development of iPSC-Derived T Cells Targeting EGFR Neoantigens in Non-Small Cell Lung Cancer. https://doi.org/10.1101/2025.02.15.638388

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