Open Access

ARTICLE

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

by WEITAO ZHENG¹, DONG JIANG², SONGEN CHEN¹, MEILING WU¹, BAOQI YAN², JIAHUI ZHAI², YUNQIANG SHI², BIN XIE¹, XINGWANG XIE², KANGHONG HU^1,*, WENXUE MA^3,*

1 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
2 Center of Research & Development, Beijing CorreGene Biotechnology Co., Ltd., Beijing, 102206, China
3 Department of Medicine, Sanford Stem Cell Institute and Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA

* Corresponding Authors: KANGHONG HU. Email: ; WENXUE MA. Email:

(This article belongs to the Special Issue: Advances in Cancer Immunotherapy)

Oncology Research 2024, 32(12), 1837-1850. https://doi.org/10.32604/or.2024.056565

Received 25 July 2024; Accepted 09 September 2024; Issue published 13 November 2024

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 G12D_7-16 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 G12D_7-16 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*11:01-restricted KRAS G12D_7-16 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.

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