通过体外开发探索精准 T 细胞受体 (TCR) 针对 KRAS G12D 癌症的治疗潜力。

IF 2 4区医学 Q3 ONCOLOGY Oncology Research Pub Date : 2024-11-13 eCollection Date: 2024-01-01 DOI:10.32604/or.2024.056565

Weitao Zheng, Dong Jiang, Songen Chen, Meiling Wu, Baoqi Yan, Jiahui Zhai, Yunqiang Shi, Bin Xie, Xingwang Xie, Kanghong Hu, Wenxue Ma

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引用次数: 0

摘要

目的：柯氏大鼠肉瘤病毒（KRAS）G12D致癌突变是治疗实体瘤的重大挑战，因为缺乏特异性的有效治疗干预措施。本研究旨在探索针对 KRAS G12D7-16 突变的 T 细胞受体（TCR）工程和表征的创新方法，为克服这一治疗难题提供潜在策略：在这项创新性研究中，我们设计并鉴定了两种对 KRAS G12D7-16 突变具有高亲和力的 T 细胞受体 (TCR)：KDA11-01 和 KDA11-02。这些TCR是从KRAS G12D突变患者的肿瘤组织中提取的肿瘤浸润淋巴细胞（TIL）中分离出来的。我们利用各种癌细胞系对它们的特异性和体外抗肿瘤活性进行了评估：结果：KDA11-01和KDA11-02对HLA-A*11:01限制的KRAS G12D7-16表位表现出了极高的特异性，能显著诱导IFN-γ的释放并清除肿瘤细胞，且无交叉反应或异体反应：KDA11-01和KDA11-02的成功开发为基于TCR的针对KRAS G12D突变的新型精准治疗策略提供了可能，有望在癌症免疫治疗领域取得重大进展。

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

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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来源期刊

Oncology Research 医学-肿瘤学

CiteScore

4.40

自引率

0.00%

发文量

审稿时长

3 months

期刊介绍： Oncology Research Featuring Preclinical and Clincal Cancer Therapeutics publishes research of the highest quality that contributes to an understanding of cancer in areas of molecular biology, cell biology, biochemistry, biophysics, genetics, biology, endocrinology, and immunology, as well as studies on the mechanism of action of carcinogens and therapeutic agents, reports dealing with cancer prevention and epidemiology, and clinical trials delineating effective new therapeutic regimens.