PURPOSE Immunogenicity derived from the murine scFv, a major molecular compomemt of chimeric antigen receptors (CARs), may limit the persistence of CAR T cells, resulting in tumor relapse of patients in complete remission (CR). In this study, we developed a humanized anti-CD19 scFv CAR-T (hCAR-T) to treat patients with relapsed/refractory acute lymphoblastic leukemia (r/r ALL). EXPERIMENTAL DESIGN In this one-arm, open-labeled study, we infused the T cells modified with hCAR to patients with r/r ALL. Patients were evaluated with long-term follow-up for response and safety of the treatment. The study was registered at Clinicaltrials.gov (NCT02349698). RESULTS Ten patients with r/r ALL were recruited for this study. All were response evaluable and all achieved CR; eight patients remained CR, and six were in CR for over 18 months without further treatment. A long-term persistence of hCAR T cells was observed in most of the patients. Among these patients, four of them with high tumor burden and rapidly progressive disease (median, 58%) experienced grade 3-4 cytokine release syndrome (CRS) and neurotoxicity. These severe CRSs were successfully controlled by tocilizumab, glucocorticoid, and plasma exchange. CONCLUSIONS T cells expressing the humanized anti-CD19 scFv CARs exhibited sustained therapeutic efficacy in the treatment of r/r ALL. Low replase rate was associated with the long-term persistence of CAR T cells.

中文翻译：

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人源化抗CD19嵌合抗原受体T细胞在复发/难治性急性淋巴细胞白血病中的持续治疗功效。

目的鼠源scFv是嵌合抗原受体（CAR）的主要分子组成，其免疫原性可能会限制CAR T细胞的持久性，导致完全缓解（CR）患者的肿瘤复发。在这项研究中，我们开发了一种人源化的抗CD19 scFv CAR-T（hCAR-T），用于治疗复发/难治性急性淋巴细胞白血病（r / r ALL）的患者。实验设计在这项开放性单臂研究中，我们向r / r ALL患者输注了经hCAR修饰的T细胞。对患者进行了长期随访，以评估其反应和治疗的安全性。该研究已在Clinicaltrials.gov（NCT02349698）上注册。结果招募了10例r / r ALL患者。所有这些都是可评估的，并且都达到了CR；八名患者仍保持CR，6例接受CR治疗18个月以上，未经进一步治疗。在大多数患者中观察到hCAR T细胞的长期持久性。在这些患者中，其中四名肿瘤负荷高，疾病进展迅速（中位率为58％），发生3-4级细胞因子释放综合征（CRS）和神经毒性。这些严重的CRS受托珠单抗，糖皮质激素和血浆置换成功地控制。结论表达人源化抗CD19 scFv CARs的T细胞在r / r ALL的治疗中表现出持续的治疗功效。低的修复率与CAR T细胞的长期持久性有关。58％的人经历了3-4级细胞因子释放综合征（CRS）和神经毒性。这些严重的CRS受托珠单抗，糖皮质激素和血浆置换成功地控制。结论表达人源化抗CD19 scFv CARs的T细胞在r / r ALL的治疗中表现出持续的治疗功效。低的修复率与CAR T细胞的长期持久性有关。58％的人经历了3-4级细胞因子释放综合征（CRS）和神经毒性。这些严重的CRS受托珠单抗，糖皮质激素和血浆置换成功地控制。结论表达人源化抗CD19 scFv CAR的T细胞在r / r ALL治疗中显示出持续的治疗功效。低的修复率与CAR T细胞的长期持久性有关。