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 con...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-09-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050125001123 |
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| author | Kouta Niizuma Toshinobu Nishimura Jonathan Villanueva Laura Amaya Jonas L. Fowler Taichi Isobe Yusuke Nakauchi Brandon Saavedra Haojun Xu Mahito Nakanishi Adam C. Wilkinson Kyle M. Loh Joseph B. Shrager Hiromitsu Nakauchi |
| author_facet | Kouta Niizuma Toshinobu Nishimura Jonathan Villanueva Laura Amaya Jonas L. Fowler Taichi Isobe Yusuke Nakauchi Brandon Saavedra Haojun Xu Mahito Nakanishi Adam C. Wilkinson Kyle M. Loh Joseph B. Shrager Hiromitsu Nakauchi |
| author_sort | Kouta Niizuma |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-282442704baa4981a2fef529b577376e |
| institution | Kabale University |
| issn | 2329-0501 |
| language | English |
| publishDate | 2025-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj-art-282442704baa4981a2fef529b577376e2025-08-20T03:34:13ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012025-09-0133310151710.1016/j.omtm.2025.101517Development of iPSC-derived T cells targeting EGFR neoantigens in non-small cell lung cancerKouta Niizuma0Toshinobu Nishimura1Jonathan Villanueva2Laura Amaya3Jonas L. Fowler4Taichi Isobe5Yusuke Nakauchi6Brandon Saavedra7Haojun Xu8Mahito Nakanishi9Adam C. Wilkinson10Kyle M. Loh11Joseph B. Shrager12Hiromitsu Nakauchi13Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USAInstitute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USAInstitute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USAInstitute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USAInstitute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USAInstitute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USAInstitute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USAInstitute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USADepartment of Neurology, Stanford University School of Medicine, Stanford, CA 94305, USATOKIWA-Bio, Inc., Tsukuba Center Inc. (TCI), Building G, 2-1-6 Sengen, Tsukuba, Ibaraki 305-0047, Japan; Biotechnology Research Institute for Drug Discovery, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki 305-8562, JapanInstitute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; MRC Weatherall Institute of Molecular Medicine and NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford OX3 9DS, UKInstitute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USADepartment of Thoracic Surgery, Stanford University School of Medicine, Stanford, CA 94305, USAInstitute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Stem Cell Therapy Division, Institute of Integrated Research, Institute of Science Tokyo, Bunkyo-ku, Tokyo 113-8510, Japan; Corresponding author: Hiromitsu Nakauchi, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.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.http://www.sciencedirect.com/science/article/pii/S2329050125001123T celliPS cellsrejuvenationcancer antigenneoepitopeTCR |
| spellingShingle | Kouta Niizuma Toshinobu Nishimura Jonathan Villanueva Laura Amaya Jonas L. Fowler Taichi Isobe Yusuke Nakauchi Brandon Saavedra Haojun Xu Mahito Nakanishi Adam C. Wilkinson Kyle M. Loh Joseph B. Shrager Hiromitsu Nakauchi Development of iPSC-derived T cells targeting EGFR neoantigens in non-small cell lung cancer Molecular Therapy: Methods & Clinical Development T cell iPS cells rejuvenation cancer antigen neoepitope TCR |
| title | Development of iPSC-derived T cells targeting EGFR neoantigens in non-small cell lung cancer |
| title_full | Development of iPSC-derived T cells targeting EGFR neoantigens in non-small cell lung cancer |
| title_fullStr | Development of iPSC-derived T cells targeting EGFR neoantigens in non-small cell lung cancer |
| title_full_unstemmed | Development of iPSC-derived T cells targeting EGFR neoantigens in non-small cell lung cancer |
| title_short | Development of iPSC-derived T cells targeting EGFR neoantigens in non-small cell lung cancer |
| title_sort | development of ipsc derived t cells targeting egfr neoantigens in non small cell lung cancer |
| topic | T cell iPS cells rejuvenation cancer antigen neoepitope TCR |
| url | http://www.sciencedirect.com/science/article/pii/S2329050125001123 |
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