Department of Medicine, The University of Chicago, Chicago, Illinois.
Institute of Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Clin Cancer Res. 2018 Nov 1;24(21):5357-5367. doi: 10.1158/1078-0432.CCR-18-0142. Epub 2018 May 2.
Current evolution of cancer immunotherapies, such as immune checkpoint blockade, has implicated neoantigens as major targets of anticancer cytotoxic T cells. Adoptive T-cell therapy with neoantigen-specific T-cell receptor (TCR)-engineered T cells would be an attractive therapeutic option for advanced cancers where the host antitumor immune function is strongly inhibited. We previously developed a rapid and efficient pipeline for production of neoantigen-specific TCR-engineered T cells using peripheral blood from an HLA-matched healthy donor. Our protocol required only 2 weeks from stimulation of T cells with neoantigen-loaded dendritic cells to the identification of neoantigen-specific TCRs. We conducted the pilot study to validate our protocol. We used tumors from 7 ovarian cancer patients to validate our protocol. We chose 14 candidate neoantigens from 7 ovarian tumors (1-3 candidates for each patient) and then successfully induced three neoantigen-specific T cells from 1 healthy donor and identified their TCR sequences. Moreover, we validated functional activity of the three identified TCRs by generating TCR-engineered T cells that recognized the corresponding neoantigens and showed cytotoxic activity in an antigen dose-dependent manner. However, one case of neoantigen-specific TCR-engineered T cells showed cross-reactivity against the corresponding wild-type peptide. This pilot study demonstrated the feasibility of our efficient process from identification of neoantigen to production of the neoantigen-targeting cytotoxic TCR-engineered T cells for ovarian cancer and revealed the importance of careful validation of neoantigen-specific TCR-engineered T cells to avoid severe immune-related adverse events. .
当前癌症免疫疗法的发展，如免疫检查点阻断，表明新抗原是抗癌细胞毒性 T 细胞的主要靶点。使用针对新抗原的 T 细胞受体 (TCR) 工程化 T 细胞的过继性 T 细胞疗法将是一种有吸引力的治疗选择，适用于宿主抗肿瘤免疫功能受到强烈抑制的晚期癌症。我们之前开发了一种使用 HLA 匹配的健康供体外周血生产新抗原特异性 TCR 工程化 T 细胞的快速有效的流水线。我们的方案仅需 2 周时间，从用负载新抗原的树突状细胞刺激 T 细胞到鉴定新抗原特异性 TCR。我们进行了这项验证性研究来验证我们的方案。我们使用 7 名卵巢癌患者的肿瘤来验证我们的方案。我们从 7 个卵巢肿瘤中选择了 14 个候选新抗原（每个患者 1-3 个候选），然后成功地从 1 名健康供体中诱导出 3 个新抗原特异性 T 细胞，并鉴定了它们的 TCR 序列。此外，我们通过生成识别相应新抗原并以抗原剂量依赖性方式显示细胞毒性活性的 TCR 工程化 T 细胞，验证了这 3 个鉴定的 TCR 的功能活性。然而，一个新抗原特异性 TCR 工程化 T 细胞的例子显示出对相应野生型肽的交叉反应性。这项验证性研究表明，从鉴定新抗原到生产针对卵巢癌的新抗原靶向细胞毒性 TCR 工程化 T 细胞的高效流程是可行的，并揭示了仔细验证新抗原特异性 TCR 工程化 T 细胞以避免严重的免疫相关不良事件的重要性。
