美国国立卫生研究院James N. Kochenderfer小组的一项最新研究，完成了具有完整人结合域的抗CD19 CAR T细胞在B细胞淋巴瘤患者中的安全性和可行性测试。相关论文2020年1月20日在线发表于国际学术期刊《自然—医学》。

表达抗CD19嵌合抗原受体（CAR）的T细胞是治疗B细胞淋巴瘤的有效方法，但通常会引起神经毒性。研究人员在表达新的抗CD19 CAR Hu19-CD828Z（NCT02659943）T细胞人类试验的首次临床试验中，对20例处于一期的B细胞淋巴瘤患者进行了治疗。主要目的是评估Hu19-CD828Z T细胞疗法的安全性和可行性。次要目标包括评估CAR T细胞的血液水平、抗淋巴瘤活性、二次输注和免疫原性。所有目的均达到。接受Hu19-CD828Z T细胞的患者中有55％完全缓解。Hu19-CD828Z T细胞具有与表达FMC63-28ZT细胞类似的临床抗淋巴瘤活性，FMC63-28Z是研究人员先前测试的抗CD19 CAR，它含有鼠类结合域，被在新药axicabtagene ciloleucel中。然而，接受Hu19-CD828Z T细胞的患者中只有5％发生严重的神经毒性，而接受FMC63-28Z T细胞的患者中有50％经历了这种程度的毒性（P=0.0017）。表达Hu19-CD828ZT细胞释放的细胞因子水平低于表达FMC63-28Z的T细胞。接受Hu19-CD828Z T细胞的患者血液中检测到的细胞因子水平低于接受FMC63-28Z T细胞的患者血液中的细胞因子水平，这可以解释与Hu19-CD828Z相关的神经毒性较低水平。表达CAR的T细胞释放的细胞因子水平尤其取决于CAR设计中包含的铰链区域和跨膜结构域。

附：英文原文

Title: Safety and feasibility of anti-CD19 CAR T cells with fully human binding domains in patients with B-cell lymphoma

Author: Jennifer N. Brudno, Norris Lam, Danielle Vanasse, Yueh-wei Shen, Jeremy J. Rose, John Rossi, Allen Xue, Adrian Bot, Nathalie Scholler, Lekha Mikkilineni, Mark Roschewski, Robert Dean, Raul Cachau, Philippe Youkharibache, Rashmika Patel, Brenna Hansen, David F. Stroncek, Steven A. Rosenberg, Ronald E. Gress, James N. Kochenderfer

Issue&Volume: 2020-01-20

Abstract: Anti-CD19 chimeric antigen receptor (CAR)-expressing T cells are an effective treatment for B-cell lymphoma, but often cause neurologic toxicity. We treated 20 patients with B-cell lymphoma on a phase I, first-in-human clinical trial of T cells expressing the new anti-CD19 CAR Hu19-CD828Z (NCT02659943). The primary objective was to assess safety and feasibility of Hu19-CD828Z T-cell therapy. Secondary objectives included assessments of blood levels of CAR T cells, anti-lymphoma activity, second infusions and immunogenicity. All objectives were met. Fifty-five percent of patients who received Hu19-CD828Z T cells obtained complete remission. Hu19-CD828Z T cells had clinical anti-lymphoma activity similar to that of T cells expressing FMC63-28Z, an anti-CD19 CAR tested previously by our group, which contains murine binding domains and is used in axicabtagene ciloleucel. However, severe neurologic toxicity occurred in only 5% of patients who received Hu19-CD828Z T cells, whereas 50% of patients who received FMC63-28Z T cells experienced this degree of toxicity (P=0.0017). T cells expressing Hu19-CD828Z released lower levels of cytokines than T cells expressing FMC63-28Z. Lower levels of cytokines were detected in blood from patients who received Hu19-CD828Z T cells than in blood from those who received FMC63-28Z T cells, which could explain the lower level of neurologic toxicity associated with Hu19-CD828Z. Levels of cytokines released by CAR-expressing T cells particularly depended on the hinge and transmembrane domains included in the CAR design.

DOI: 10.1038/s41591-019-0737-3

Source: https://www.nature.com/articles/s41591-019-0737-3