Department of Hematology, Oncology, and Pneumology, University Medical Center (UMC) and University Cancer Center (UCT), Johannes Gutenberg University, Langenbeckstrasse 1, 55131 Mainz, Germany; Research Center for Immunotherapy (FZI), University Medical Center (UMC), Johannes Gutenberg University, Langenbeckstrasse 1, 55131 Mainz, Germany; German Consortium for Translational Cancer Research (DKTK), Frankfurt/Mainz, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany.
Department of Hematology, Oncology, and Pneumology, University Medical Center (UMC) and University Cancer Center (UCT), Johannes Gutenberg University, Langenbeckstrasse 1, 55131 Mainz, Germany.
Mol Ther. 2019 Jan 2;27(1):261-271. doi: 10.1016/j.ymthe.2018.11.006. Epub 2018 Nov 15.
Genetic engineering of T cells with a T cell receptor (TCR) targeting tumor antigen is a promising strategy for cancer immunotherapy. Inefficient expression of the introduced TCR due to TCR mispairing may limit the efficacy and adversely affect the safety of TCR gene therapy. Here, we evaluated the safety and therapeutic efficiency of an optimized single-chain TCR (scTCR) specific for an HLA-A2.1-restricted (non-mutated) p53(264-272) peptide in adoptive T cell transfer (ACT) models using our unique transgenic mice expressing human p53 and HLA-A2.1 that closely mimic the human setting. Specifically, we showed that adoptive transfer of optimized scTCR-redirected T cells does not induce on-target and off-target autoimmunity. Furthermore, ACT resulted in full tumor protection and led to a long-lived effective, antigen-specific memory T cell response in syngeneic and xenograft models. Taken together, the study demonstrated that our scTCR specific for the broadly expressed tumor-associated antigen p53(264-272) can eradicate p53A2.1 tumor cells without inducing off-target or self-directed toxicities in mouse models of ACT. These data strongly support the improved safety and therapeutic efficacy of high-affinity p53scTCR for TCR-based immunotherapy of p53-associated malignancies.
利用针对肿瘤抗原的 T 细胞受体 (TCR) 对 T 细胞进行基因工程改造是癌症免疫治疗的一种有前途的策略。由于 TCR 错配导致引入的 TCR 表达效率低下，可能会限制疗效并对 TCR 基因治疗的安全性产生不利影响。在这里，我们使用我们独特的表达人 p53 和 HLA-A2.1 的转基因小鼠评估了针对 HLA-A2.1 限制（未突变）p53(264-272) 肽的优化单链 TCR(scTCR) 的安全性和治疗效率，这些小鼠在接受过继性 T 细胞转移 (ACT) 模型中非常接近人类环境。具体来说，我们表明，优化的 scTCR 重定向 T 细胞的过继转移不会诱导靶内和靶外自身免疫。此外，ACT 导致完全的肿瘤保护，并导致同种异体和异种移植模型中持久有效的、抗原特异性的记忆 T 细胞反应。总之，这项研究表明，我们针对广泛表达的肿瘤相关抗原 p53(264-272) 的 scTCR 可以消除 p53A2.1 肿瘤细胞，而在 ACT 的小鼠模型中不会引起靶外或自我导向的毒性。这些数据强烈支持了高亲和力 p53scTCR 在基于 TCR 的 p53 相关恶性肿瘤免疫治疗中的安全性和治疗效果的提高。
