Third-generation chimeric antigen receptor T cells (CARTs) for relapsed or refractory (r/r) chronic lymphocytic leukemia (CLL) may improve efficacy compared to second-generation CARTs due to their enhanced CAR design. We performed the first phase 1/2 investigator-initiated trial evaluating escalating doses of third-generation CARTs (HD-CAR-1) targeting CD19 in patients with r/r CLL and B-cell lymphoma. CLL eligibility criteria were failure to two therapy lines including at least one pathway inhibitor and/or allogeneic hematopoietic cell transplantation. Nine heavily pretreated patients received HD-CAR-1 at dose levels ranging from 1 × 10⁶ to 200 × 10⁶ CART/m². In-house HD-CAR-1 manufacturing was successful for all patients. While neurotoxicity was absent, one case of grade 3 cytokine release syndrome was observed. By day 90, six patients (67%) attained a CR, five of these (83%) with undetectable MRD. With a median follow-up of 27 months, 2-year PFS and OS were 30% and 69%, respectively. HD-CAR-1 products of responders contained significantly more CD4 + T cells compared to non-responders. In non-responders, a strong enrichment of effector memory-like CD8 + T cells with high expression of CD39 and/or CD197 was observed. HD-CAR-1 demonstrated encouraging efficacy and exceptionally low treatment-specific toxicity, presenting new treatment options for patients with r/r CLL. Trial registration: #NCT03676504.

与第二代 CART 相比，用于复发或难治性 （r/r） 慢性淋巴细胞白血病 （CLL） 的第三代嵌合抗原受体 T 细胞 （CART） 可能会提高疗效，因为它们的 CAR 设计增强。我们进行了第一个 1/2 期研究者发起的试验，评估了在 r/r CLL 和 B 细胞淋巴瘤患者中靶向 CD19 的递增剂量的第三代 CARTs （HD-CAR-1）。CLL 合格标准是两种治疗线失败，包括至少一种通路抑制剂和/或同种异体造血细胞移植。9 例既往接受过大量治疗的患者接受 HD-CAR-1，剂量水平为 1 × 10⁶ 至 200 × 10⁶ CART/m²。内部 HD-CAR-1 生产对所有患者均取得成功。虽然没有神经毒性，但观察到 1 例 3 级细胞因子释放综合征。到第 90 天，6 例患者 （67%） 达到 CR，其中 5 例 （83%） MRD 检测不到。中位随访 27 个月，2 年 PFS 和 OS 分别为 30% 和 69%。与无反应者相比，反应者的 HD-CAR-1 产物含有显着更多的 CD4 + T 细胞。在无反应者中，观察到具有高表达 CD39 和/或 CD197 的效应记忆样 CD8 + T 细胞的强烈富集。HD-CAR-1 显示出令人鼓舞的疗效和极低的治疗特异性毒性，为 r/r CLL 患者提供了新的治疗选择。试用注册：#NCT03676504。