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.

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。我们对表达新型抗 CD19 CAR Hu19-CD828Z (NCT02659943) 的 T 细胞进行了 I 期首次人体临床试验，治疗了 20 名 B 细胞淋巴瘤患者。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、第二次输注和免疫原性。所有目标均已实现。接受 Hu19-CD828Z T 细胞治疗的患者中有 55% 获得了完全缓解。 Hu19-CD828Z T 细胞具有与表达 FMC63-28Z 的 T 细胞相似的临床抗淋巴瘤活性，FMC63-28Z 是我们小组之前测试的一种抗 CD19 CAR，它包含鼠结合域，用于 axicabtagene ciloleucel。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-CD828Z 的 T 细胞释放的细胞因子水平低于表达 FMC63-28Z 的 T 细胞。在接受 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，这可以解释与 Hu19-CD828Z 相关的神经毒性水平较低。表达 CAR 的 T 细胞释放的细胞因子水平尤其取决于 CAR 设计中包含的铰链和跨膜结构域。