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Article | Open Access

Exploring the therapeutic potential of precision T-Cell Receptors (TCRs) in targeting KRAS G12D cancer through in vitro development

WEITAO ZHENG1, DONG JIANG2, SONGEN CHEN1, MEILING WU1, BAOQI YAN2, JIAHUI ZHAI2, YUNQIANG SHI2, BIN XIE1, XINGWANG XIE2, KANGHONG HU1( ), WENXUE MA3( )
Sino-German Biomedical Center, National “111” Center for Cellular Regulation and Molecular Pharmaceutics, Cooperative Innovation Center of Industrial Fermentation (Ministry of Education of China & Hubei Province), Hubei University of Technology, Wuhan, 430068, China
Center of Research & Development, Beijing CorreGene Biotechnology Co., Ltd., Beijing, 102206, China
Department of Medicine, Sanford Stem Cell Institute and Moores Cancer Center, University of California San Diego, La Jolla, CA92093, USA
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Highlights

• We developed two high-affinity TCRs, KDA11-01 and KDA11-02, specifically targeting the KRAS G12D mutation to enhance precision.

• The TCRs demonstrated precise recognition and elimination of tumor cells with the KRAS G12D mutation, advancing targeted therapies.

• The TCRs exhibited strong in vitro anti-tumor effects, including significant IFN-γ production and cytotoxicity, with no cross-reactivity observed.

• Comprehensive testing confirmed minimal alloreactivity, supporting the safety and specificity of these TCRs for therapeutic applications.

• This study highlights the potential of TCR-based therapies for targeting tumors with specific mutations, providing new opportunities in personalized cancer immunotherapy.

Abstract

Objectives

The Kirsten rat sarcoma virus (KRAS) G12D oncogenic mutation poses a significant challenge in treating solid tumors due to the lack of specific and effective therapeutic interventions. This study aims to explore innovative approaches in T cell receptor (TCR) engineering and characterization to target the KRAS G12D7-16 mutation, providing potential strategies for overcoming this therapeutic challenge.

Methods

In this innovative study, we engineered and characterized two T cell receptors (TCRs), KDA11-01 and KDA11-02 with high affinity for the KRAS G12D7-16 mutation. These TCRs were isolated from tumor-infiltrating lymphocytes (TILs) derived from tumor tissues of patients with the KRAS G12D mutation. We assessed their specificity and anti-tumor activity in vitro using various cancer cell lines.

Results

KDA11-01 and KDA11-02 demonstrated exceptional specificity for the HLA-A*:01-restricted KRAS G12D7-16 epitope, significantly inducing IFN-γ release and eliminating tumor cells without cross-reactivity or alloreactivity.

Conclusions

The successful development of KDA11-01 and KDA11-02 introduces a novel and precise TCR-based therapeutic strategy against KRAS G12D mutation, showing potential for significant advancements in cancer immunotherapy.

Keywords

T cell receptor (TCR)TCR therapyTumor-infiltrating lymphocytes (TILs)Kirsten rat sarcoma virus (KRAS)G12DAlloreactivity

References

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Oncology Research
Volume 32 Issue 12,
November 2024
Pages 1837-1850
DOI: 10.32604/or.2024.056565

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Cite this article:
ZHENG W, JIANG D, CHEN S, et al. Exploring the therapeutic potential of precision T-Cell Receptors (TCRs) in targeting KRAS G12D cancer through in vitro development. Oncology Research, 2024, 32(12): 1837-1850. https://doi.org/10.32604/or.2024.056565

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Received: 25 July 2024
Accepted: 09 September 2024
Published: 13 November 2024
© The Authors 2024.

This work is licensed under a Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.