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Development of iPSC-derived T cells targeting EGFR neoantigens in non-small cell lung cancer
Kouta Niizuma1,2, Toshinobu Nishimura1,2, Jonathan Villanueva1,2
1Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
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.
Insights
Researchers identified T cells targeting the EGFR C797S mutation in non-small cell lung cancer. Reprogramming these T cells into induced pluripotent stem cells (iPSCs) and re-differentiating them created effective cancer-fighting cells.
Area of Science:
- Oncology
- Immunotherapy
- Cancer Genetics
Background:
- Identifying neoantigens from cancer driver genes is crucial for effective cancer immunotherapy.
- The EGFR C797S mutation in non-small cell lung cancer (NSCLC) is associated with resistance to targeted therapies and poor prognosis.
- Limited availability of tumor-specific T cells poses a challenge for developing personalized immunotherapies.
Purpose of the Study:
- To identify and characterize T cells that recognize the EGFR C797S neoantigen.
- To develop a method for expanding EGFR C797S-specific T cells for therapeutic use.
- To evaluate the anti-tumor efficacy of reprogrammed T cells targeting the EGFR C797S mutation.
Main Methods:
- Identification of T cells recognizing the EGFR C797S mutation in NSCLC patients.
- Reprogramming of EGFR C797S-specific T cells into induced pluripotent stem cells (iPSCs).
- Re-differentiation of iPSCs into functional CD8+ T cells.
- Assessment of iPSC-derived T cell specificity and cytotoxic activity against EGFR C797S-mutated cancer cells.
Main Results:
- Successfully identified T cells that specifically recognize the EGFR C797S mutation.
- Demonstrated the feasibility of reprogramming and re-differentiating these T cells into functional, tumor-specific CD8+ T cells.
- iPSC-derived T cells effectively killed cancer cells harboring the EGFR C797S mutation in vitro.
Conclusions:
- Targeting neoantigens derived from cancer driver mutations, like EGFR C797S, holds significant potential for cancer immunotherapy.
- Induced pluripotent stem cell (iPSC) technology can overcome T cell availability limitations, generating therapeutic T cells.
- This combined approach of neoantigen identification and T cell reprogramming offers a promising strategy for treating drug-resistant tumors.
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