CD4/CD8 T-Cell Selection Affects Chimeric Antigen Receptor (CAR) T-Cell Potency and Toxicity: Updated Results From a Phase I Anti-CD22 CAR T-Cell Trial

医学 细胞因子释放综合征 嵌合抗原受体 内科学 肿瘤科 CD8型 T细胞 免疫学 抗原 胃肠病学 免疫疗法 免疫系统 癌症
作者
Nirali N. Shah,Steven L. Highfill,Haneen Shalabi,Bonnie Yates,Jianjian Jin,Pamela L. Wolters,Amanda K. Ombrello,Seth M. Steinberg,Staci Martin,Cindy Delbrook,Leah Hoffman,Lauren Little,Anusha Ponduri,Haiying Qin,Haris Qureshi,Alina Dulau‐Florea,Dalia Salem,Hao‐Wei Wang,Constance M. Yuan,Maryalice Stetler‐Stevenson
出处
期刊:Journal of Clinical Oncology [American Society of Clinical Oncology]
卷期号:38 (17): 1938-1950 被引量:328
标识
DOI:10.1200/jco.19.03279
摘要

PURPOSE 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. PATIENTS AND METHODS 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. RESULTS 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. CONCLUSION 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.
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