Department of Hematology and Oncology, Shenzhen Children's Hospital, No. 7019 Yitian Rd, Shenzhen, Guangdong, PR China.
Department of Hematology and Oncology, Shenzhen Children's Hospital, No. 7019 Yitian Rd, Shenzhen, Guangdong, PR China.
Int Immunopharmacol. 2021 Jul;96:107731. doi: 10.1016/j.intimp.2021.107731. Epub 2021 May 6.
Effective systemic treatments for relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) are limited. Recent clinical application of chimeric antigen receptor (CAR) immunotherapy has demonstrated successful control of B-cell malignancies by CAR-T cells; however, designing CARs for T-ALL remains a challenge. CD7 overexpression in T-cell malignancies may be an attractive target for immunotherapy in T-ALL. This study aimed to describe the safe and effective use of autologous CD7-CAR T cells (4SCAR7) for the treatment of T-ALL with induction failure in an 11-year-old patient. Based on The Chinese Children's Cancer Group-ALL (CCCG-ALL) study protocol, minimal residual disease (MRD) by flow cytometry (FC) analysis was detected on days 19 and 46 of remission induction. At the end of remission-induction chemotherapy, the patient achieved morphologic complete remission, though with MRD 16.13% and RT-PCR of KMT2A-MLLT1 fusion positive, which indicated induction failure. The cerebrospinal fluid (CSF) was negative for blasts at diagnosed. CAR-T therapy and allogeneic transplant were recommended as the next treatment options. CD3 lymphocytes were collected from the patient 18 days after the high-dose MTX chemotherapy through leukapheresis. The 4SCAR7 CD7-targeting CAR-T cells were generated thereafter. The patient received lymphodepleting chemotherapy prior to 4SCAR7 infusion. Oral administration of itraconazole and sulfamethoxazole was performed from day 0 after CAR-T cell infusion. The patient did not have hypotension, hypoxia, or serious biochemical change or abnormality, but had fever on day 9. Although grade 1 cytokine-release syndrome (CRS) was diagnosed, it was successfully treated with ibuprofen. Anti-CD7 CAR transgene copy numbers in peripheral blood were determined by qPCR, which showed effective expansion initially, then dropped quickly, and persisted at a low level. Although experienced cytopenia from days 14 to 21, the patient achieved remission on day 17. After complete remission, the patient received hematopoietic stem cell transplantation (HSCT) and has recovered well to thisdate. Overall, this report suggested that 4SCAR7 could be a safe and effective strategy for the treatment of pediatric patients with high-risk T-cell malignancies.
针对复发或难治性 T 细胞急性淋巴细胞白血病（T-ALL）的有效系统治疗方法有限。嵌合抗原受体（CAR）免疫疗法的最近临床应用已经证明了 CAR-T 细胞可以成功控制 B 细胞恶性肿瘤；然而，设计用于 T-ALL 的 CAR 仍然是一个挑战。T 细胞恶性肿瘤中 CD7 的过表达可能是 T-ALL 免疫治疗的一个有吸引力的靶点。本研究旨在描述 11 岁患者在诱导失败的情况下使用自体 CD7-CAR T 细胞（4SCAR7）治疗 T-ALL 的安全性和有效性。根据中国儿童癌症协作组 ALL（CCCG-ALL）研究方案，在缓解诱导的第 19 天和第 46 天通过流式细胞术（FC）分析检测微小残留病（MRD）。在缓解诱导化疗结束时，患者达到形态学完全缓解，但 MRD 为 16.13%，且 RT-PCR 检测到 KMT2A-MLLT1 融合阳性，提示诱导失败。在诊断时，脑脊液（CSF）中未检出白血病细胞。CAR-T 治疗和异基因移植被推荐作为下一步治疗选择。患者在高剂量 MTX 化疗后第 18 天通过白细胞分离术采集 CD3 淋巴细胞。此后生成 4SCAR7 CD7 靶向 CAR-T 细胞。患者在输注 4SCAR7 前接受淋巴细胞耗竭化疗。CAR-T 细胞输注后第 0 天开始口服伊曲康唑和磺胺甲噁唑。患者没有低血压、缺氧或严重的生化变化或异常，但在第 9 天发热。尽管诊断为 1 级细胞因子释放综合征（CRS），但用布洛芬成功治疗。通过 qPCR 测定外周血中抗 CD7 CAR 转基因拷贝数，最初显示有效扩增，然后迅速下降，并持续在低水平。尽管从第 14 天到第 21 天经历了明显的血细胞减少，但患者在第 17 天达到缓解。完全缓解后，患者接受了造血干细胞移植（HSCT），至今恢复良好。总体而言，该报告表明 4SCAR7 可能是治疗儿科高危 T 细胞恶性肿瘤患者的一种安全有效的策略。
