Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
Clin Cancer Res. 2017 Oct 15;23(20):6012-6020. doi: 10.1158/1078-0432.CCR-17-1012. Epub 2017 Jun 23.
Adoptive therapy with T-cell receptor (TCR)-engineered T cells has shown promising results in the treatment of patients with tumors, and the number of TCRs amenable for clinical testing is expanding rapidly. Notably, adoptive therapy with T cells is challenged by treatment-related side effects, which calls for cautious selection of target antigens and TCRs that goes beyond their mere ability to induce high T-cell reactivity. Here, we propose a sequence of assays to improve selection of TCRs and exemplify risk assessments of on-target as well as off-target toxicities using TCRs directed against cancer germline antigens. The proposed panel of assays covers parameters considered key to safety, such as expression of target antigen in healthy tissues, determination of a TCR's recognition motif toward its cognate peptide, and a TCR's cross-reactivity toward noncognate peptides. .
过继性细胞受体（TCR）工程 T 细胞治疗在肿瘤患者的治疗中显示出良好的效果，并且可用于临床检测的 TCR 数量正在迅速增加。值得注意的是，T 细胞过继治疗受到治疗相关副作用的挑战，这需要谨慎选择靶抗原和 TCR，不仅要考虑它们诱导高 T 细胞反应的能力。在这里，我们提出了一系列的检测方法来改善 TCR 的选择，并通过针对癌症种系抗原的 TCR 来举例说明针对靶毒性和脱靶毒性的风险评估。建议的检测方法组涵盖了被认为是安全性关键的参数，例如健康组织中靶抗原的表达、确定 TCR 对其同源肽的识别基序，以及 TCR 对非同源肽的交叉反应性。
