Development of iPSC-derived T cells targeting EGFR neoantigens in non-small cell lung cancer
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<sup>+</sup> 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.
Authors
- Kyle M. Loh (ORCID: https://orcid.org/0000-0002-8042-0149)
- Haojun Xu (ORCID: https://orcid.org/0000-0001-9600-1945)
- Mahito Nakanishi (ORCID: https://orcid.org/0000-0002-7068-7587)
- Kouta Niizuma (ORCID: https://orcid.org/0000-0003-1183-1873)
- Jonas L. Fowler (ORCID: https://orcid.org/0000-0003-0766-4320)
- Adam C. Wilkinson (ORCID: https://orcid.org/0000-0001-7406-0151)
- Jonathan Villanueva (ORCID: https://orcid.org/0000-0002-1789-6822)
- Hiromitsu Nakauchi (ORCID: https://orcid.org/0000-0002-9841-6973)
- Laura Amaya (ORCID: https://orcid.org/0000-0002-8742-9111)
- Toshinobu Nishimura (ORCID: https://orcid.org/0000-0002-5425-1708)
- Taichi Isobe (ORCID: https://orcid.org/0000-0001-5686-1940)
- Joseph B. Shrager (ORCID: https://orcid.org/0000-0003-0859-0589)
- Brandon Saavedra (ORCID: https://orcid.org/0000-0003-4211-9993)
- Yusuke Nakauchi (ORCID: https://orcid.org/0000-0002-6943-3811)
Institutions
- MRC Weatherall Institute of Molecular Medicine (GB)
- MRC Human Immunology Unit (GB)
- Oxford BioMedica (United Kingdom) (GB)
- National Institute of Advanced Industrial Science and Technology (JP)
- The University of Tokyo (JP)
- Stanford University (US)
Publication Details
- Journal
- Molecular Therapy — Methods & Clinical Development
- Published
- 2025-06-18
- DOI
- https://doi.org/10.1016/j.omtm.2025.101517
- Citations
- 2
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 2.09
Funders
- California Institute for Regenerative Medicine
- Lung Cancer Research Foundation
- Johns Hopkins University
- Weston Havens Foundation
- University of Toronto
- Kyushu University
- Medizinische Universität Wien
- National Institutes of Health
- University of California, Los Angeles
- National Defense Science and Engineering Graduate
- Japan Society for the Promotion of Science