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探索通过开发精准 T 细胞受体（TCR）来靶向 KRAS G12D 癌症的治疗潜力。

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

机构信息

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.

出版信息

Oncol Res. 2024 Nov 13;32(12):1837-1850. doi: 10.32604/or.2024.056565. eCollection 2024.

DOI:10.32604/or.2024.056565
PMID:39574477
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11576958/
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 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 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 using various cancer cell lines.

RESULTS

KDA11-01 and KDA11-02 demonstrated exceptional specificity for the HLA-A*11:01-restricted KRAS G12D 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.

摘要

目的

克氏大鼠肉瘤病毒（KRAS）G12D 致癌突变在治疗实体瘤方面带来了重大挑战，因为缺乏特异性和有效的治疗干预措施。本研究旨在探索 T 细胞受体（TCR）工程和表征的创新方法，以靶向 KRAS G12D 突变，为克服这一治疗挑战提供潜在策略。

方法

在这项创新性研究中，我们设计并表征了两种高亲和力靶向 KRAS G12D 突变的 T 细胞受体（TCR），即 KDA11-01 和 KDA11-02。这些 TCR 是从携带 KRAS G12D 突变的患者肿瘤组织中的肿瘤浸润淋巴细胞（TIL）中分离出来的。我们使用各种癌细胞系评估了它们的特异性和抗肿瘤活性。

结果

KDA11-01 和 KDA11-02 对 HLA-A*11:01 限制性 KRAS G12D 表位具有出色的特异性，可显著诱导 IFN-γ 释放并消除肿瘤细胞，而无交叉反应或同种反应性。

结论

KDA11-01 和 KDA11-02 的成功开发引入了一种针对 KRAS G12D 突变的新型精确 TCR 治疗策略，为癌症免疫治疗的重大进展展示了潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d38/11576958/dfcfbbb91146/OncolRes-32-56565-f007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d38/11576958/3d4f536115b2/OncolRes-32-56565-f001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d38/11576958/b2a866d6d89e/OncolRes-32-56565-f002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d38/11576958/8bc9ed60f656/OncolRes-32-56565-f003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d38/11576958/5154538bf1fd/OncolRes-32-56565-f004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d38/11576958/538e7ad32ba2/OncolRes-32-56565-f005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d38/11576958/f063f3702a2f/OncolRes-32-56565-f006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d38/11576958/dfcfbbb91146/OncolRes-32-56565-f007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d38/11576958/3d4f536115b2/OncolRes-32-56565-f001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d38/11576958/b2a866d6d89e/OncolRes-32-56565-f002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d38/11576958/8bc9ed60f656/OncolRes-32-56565-f003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d38/11576958/5154538bf1fd/OncolRes-32-56565-f004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d38/11576958/538e7ad32ba2/OncolRes-32-56565-f005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d38/11576958/f063f3702a2f/OncolRes-32-56565-f006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d38/11576958/dfcfbbb91146/OncolRes-32-56565-f007.jpg

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本文引用的文献

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