特定CD4+:CD8+组成的CD19 CAR-T细胞治疗成人B细胞急性淋巴细胞白血病
CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients
此前制备的CAR-T细胞产品中T细胞类型混杂，难以判断哪些因素决定疗效和毒性。这项1/2期临床试验改用组成明确的CD4+和CD8+ T细胞亚群，按固定比例制成CD19 CAR-T细胞，输给淋巴清除化疗后的成人B细胞急性淋巴细胞白血病患者。29例中27例（93%）达到骨髓缓解。研究发现高CAR-T剂量和高肿瘤负荷会增加严重细胞因子释放综合征和神经毒性风险，据此按骨髓病灶多少分层给药可降低毒性；在淋巴清除方案中加入氟达拉滨可改善CAR-T细胞持续存在和无病生存。该结果说明，产品组成标准化有助于找到与疗效、毒性相关的因素并优化治疗策略。
为什么推荐给您：CAR-T产品组成标准化的早期人体试验，首次系统识别疗效与毒性相关因素。
不需要生物学背景，多打比方
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摘要Abstract
BACKGROUND: T cells that have been modified to express a CD19-specific chimeric antigen receptor (CAR) have antitumor activity in B cell malignancies; however, identification of the factors that determine toxicity and efficacy of these T cells has been challenging in prior studies in which phenotypically heterogeneous CAR-T cell products were prepared from unselected T cells.
METHODS: We conducted a clinical trial to evaluate CD19 CAR-T cells that were manufactured from defined CD4+ and CD8+ T cell subsets and administered in a defined CD4+:CD8+ composition to adults with B cell acute lymphoblastic leukemia after lymphodepletion chemotherapy.
RESULTS: The defined composition product was remarkably potent, as 27 of 29 patients (93%) achieved BM remission, as determined by flow cytometry. We established that high CAR-T cell doses and tumor burden increase the risks of severe cytokine release syndrome and neurotoxicity. Moreover, we identified serum biomarkers that allow testing of early intervention strategies in patients at the highest risk of toxicity. Risk-stratified CAR-T cell dosing based on BM disease burden decreased toxicity. CD8+ T cell-mediated anti-CAR transgene product immune responses developed after CAR-T cell infusion in some patients, limited CAR-T cell persistence, and increased relapse risk. Addition of fludarabine to the lymphodepletion regimen improved CAR-T cell persistence and disease-free survival.
CONCLUSION: Immunotherapy with a CAR-T cell product of defined composition enabled identification of factors that correlated with CAR-T cell expansion, persistence, and toxicity and facilitated design of lymphodepletion and CAR-T cell dosing strategies that mitigated toxicity and improved disease-free survival.
TRIAL REGISTRATION: ClinicalTrials.gov NCT01865617.
FUNDING: R01-CA136551; Life Science Development Fund; Juno Therapeutics; Bezos Family Foundation.