Cellular Therapy Group, Department of Medical Oncology, Paterson Institute for Cancer Research, The University of Manchester, Manchester, UK.
J Immunol. 2010 Feb 15;184(4):1885-96. doi: 10.4049/jimmunol.0901440. Epub 2010 Jan 20.
T cells gene-modified to express chimeric Ag receptors (CARs) have shown potent antitumor activity in vivo and are in clinical trials at locations worldwide. However, CAR activity has been investigated in mouse models in which Ag expression is restricted to the tumor. To explore the impact of normal tissue expression of the target Ag, we developed a mouse CD19-specific CAR to investigate antitumor efficacy against a syngeneic B cell lymphoma cell line within a background of normal CD19(+) host B cells. Mouse T cells engrafted with the amCD19CD3zeta CAR specifically lysed A20 lymphoma targets and B cells in vitro. These T cells also eradicated a 12-d established disseminated A20 lymphoma in mice preconditioned with 6 Gy total body irradiation. In the short-term (7 d after adoptive transfer), amCD19z T cells underwent Ag-dependent proliferation in vivo with a concomitant depletion in host B cell levels. However, the levels of amCD19z CAR(+) T cells decreased significantly at later time points, at which point host B cells returned, eventually reaching normal levels. In contrast, CAR(+) T cells lacking a signaling domain or specificity for mCD19 persisted over extended periods in blood and spleen. Importantly, no overt clinical signs of autotoxicity were observed in tumor-free or tumor-bearing mice treated with amCD19z T cells over an extended period of time. These observations highlight the importance of studying the activity of CAR(+) T cells in autologous models that have the normal range of tissue expression of Ag.
经基因修饰表达嵌合抗原受体 (CAR) 的 T 细胞在体内显示出强大的抗肿瘤活性，目前正在全球各地的临床试验中进行研究。然而，CAR 活性已在仅在肿瘤中表达抗原的小鼠模型中进行了研究。为了探索靶抗原在正常组织表达的影响，我们开发了一种小鼠 CD19 特异性 CAR，以研究针对同种异体 B 细胞淋巴瘤细胞系的抗肿瘤疗效，该细胞系在正常 CD19(+)宿主 B 细胞背景下表达。表达 amCD19CD3zeta CAR 的小鼠 T 细胞特异性裂解体外的 A20 淋巴瘤靶标和 B 细胞。这些 T 细胞还根除了在接受 6 Gy 全身照射预处理的小鼠中建立的 12 天传播的 A20 淋巴瘤。在短期（过继转移后 7 天），amCD19z T 细胞在体内进行抗原依赖性增殖，同时宿主 B 细胞水平下降。然而，在稍后的时间点，amCD19z CAR(+) T 细胞的水平显著下降，此时宿主 B 细胞恢复，最终达到正常水平。相比之下，缺乏信号域或对 mCD19 特异性的 CAR(+) T 细胞在血液和脾脏中持续存在较长时间。重要的是，在肿瘤无或肿瘤负荷小鼠中，用 amCD19z T 细胞治疗延长时间后，未观察到明显的自体毒性临床症状。这些观察结果强调了在具有抗原正常组织表达范围的自体模型中研究 CAR(+) T 细胞活性的重要性。
