Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
Center for Cellular Engineering, Department of Transfusion Medicine, National Institutes of Health Clinical Center, Bethesda, MD.
J Clin Oncol. 2020 Jun 10;38(17):1938-1950. doi: 10.1200/JCO.19.03279. Epub 2020 Apr 14.
Patients with B-cell acute lymphoblastic leukemia who experience relapse after or are resistant to CD19-targeted immunotherapies have limited treatment options. Targeting CD22, an alternative B-cell antigen, represents an alternate strategy. We report outcomes on the largest patient cohort treated with CD22 chimeric antigen receptor (CAR) T cells.
We conducted a single-center, phase I, 3 + 3 dose-escalation trial with a large expansion cohort that tested CD22-targeted CAR T cells for children and young adults with relapsed/refractory CD22 malignancies. Primary objectives were to assess the safety, toxicity, and feasibility. Secondary objectives included efficacy, CD22 CAR T-cell persistence, and cytokine profiling.
Fifty-eight participants were infused; 51 (87.9%) after prior CD19-targeted therapy. Cytokine release syndrome occurred in 50 participants (86.2%) and was grade 1-2 in 45 (90%). Symptoms of neurotoxicity were minimal and transient. Hemophagocytic lymphohistiocytosis-like manifestations were seen in 19/58 (32.8%) of subjects, prompting utilization of anakinra. CD4/CD8 T-cell selection of the apheresis product improved CAR T-cell manufacturing feasibility as well as heightened inflammatory toxicities, leading to dose de-escalation. The complete remission rate was 70%. The median overall survival was 13.4 months (95% CI, 7.7 to 20.3 months). Among those who achieved a complete response, the median relapse-free survival was 6.0 months (95% CI, 4.1 to 6.5 months). Thirteen participants proceeded to stem-cell transplantation.
In the largest experience of CD22 CAR T-cells to our knowledge, we provide novel information on the impact of manufacturing changes on clinical outcomes and report on unique CD22 CAR T-cell toxicities and toxicity mitigation strategies. The remission induction rate supports further development of CD22 CAR T cells as a therapeutic option in patients resistant to CD19-targeted immunotherapy.
经历过抗 CD19 靶向免疫疗法复发或耐药的 B 细胞急性淋巴细胞白血病患者的治疗选择有限。靶向替代 B 细胞抗原 CD22 是一种替代策略。我们报告了最大的患者队列接受 CD22 嵌合抗原受体（CAR）T 细胞治疗的结果。
我们进行了一项单中心、I 期、3+3 剂量递增试验，有一个大型扩展队列，用于测试针对复发/难治性 CD22 恶性肿瘤的儿童和年轻成人的 CD22 靶向 CAR T 细胞。主要目标是评估安全性、毒性和可行性。次要目标包括疗效、CD22 CAR T 细胞持久性和细胞因子谱。
共输注了 58 名参与者；51 名（87.9%）在接受过抗 CD19 靶向治疗后。50 名参与者（86.2%）发生细胞因子释放综合征，45 名（90%）为 1-2 级。神经毒性症状轻微且短暂。58 名受试者中的 19 名（32.8%）出现噬血细胞性淋巴组织细胞增生症样表现，促使使用阿那白滞素。外周血 CD4/CD8 T 细胞分选改善了 CAR T 细胞制造的可行性，并加剧了炎症毒性，导致剂量下调。完全缓解率为 70%。中位总生存期为 13.4 个月（95%CI，7.7 至 20.3 个月）。在获得完全缓解的患者中，无复发生存期的中位值为 6.0 个月（95%CI，4.1 至 6.5 个月）。13 名参与者进行了干细胞移植。
在我们所知的最大规模的 CD22 CAR T 细胞经验中，我们提供了关于制造变化对临床结果影响的新信息，并报告了独特的 CD22 CAR T 细胞毒性和毒性缓解策略。缓解诱导率支持进一步开发 CD22 CAR T 细胞作为对 CD19 靶向免疫疗法耐药的患者的治疗选择。
