From the Bone Marrow Transplantation Center, First Affiliated Hospital, and Liangzhu Laboratory, Zhejiang University School of Medicine (Y.H., M.Z., T.Y., Z.M., G.W., R.J., H.Z., R.C., C.Z., T.G., P.X., R.H., J.F., S.F., D.K., H.X., J.C., S.H., X.Y., H.G., Y.F., C.J., D.W., H.H.), the Institute of Hematology (Y.H., M.Z., T.Y., Z.M., G.W., R.J., H.Z., R.C., C.Z., T.G., P.X., R.H., J.F., S.F., D.K., H.X., J.C., S.H., X.Y., H.G., Y.F., C.J., D.W., H.H.) and the Department of Epidemiology and Statistics, School of Public Health (Y.Y.), Zhejiang University, and Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy (Y.H., M.Z., T.Y., Z.M., G.W., R.J., H.Z., R.C., C.Z., T.G., P.X., R.H., J.F., S.F., D.K., H.X., J.C., S.H., X.Y., H.G., Y.F., C.J., D.W., H.H.), Hangzhou, the Department of Medical Oncology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou (B.L.), the Department of Hematology, Beijing Tiantan Hospital, Capital Medical University, Beijing (Q.C.), Nanjing Bioheng Biotech, Nanjing (J.R.), and the Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Fudan University, and Shanghai YaKe Biotechnology, Shanghai (A.H.C.) - all in China.
N Engl J Med. 2024 Apr 25;390(16):1467-1480. doi: 10.1056/NEJMoa2313812.
Patients with relapsed or refractory hematologic cancers have a poor prognosis. Chimeric antigen receptor (CAR) T-cell therapy as a bridge to allogeneic hematopoietic stem-cell transplantation (HSCT) has the potential for long-term tumor elimination. However, pre-HSCT myeloablation and graft-versus-host disease (GVHD) prophylaxis agents have toxic effects and could eradicate residual CAR T cells and compromise antitumor effects. Whether the integration of CAR T-cell therapy and allogeneic HSCT can preserve CAR T-cell function and improve tumor control is unclear.
We tested a novel "all-in-one" strategy consisting of sequential CD7 CAR T-cell therapy and haploidentical HSCT in 10 patients with relapsed or refractory CD7-positive leukemia or lymphoma. After CAR T-cell therapy led to complete remission with incomplete hematologic recovery, patients received haploidentical HSCT without pharmacologic myeloablation or GVHD prophylaxis drugs. Toxic effects and efficacy were closely monitored.
After CAR T-cell therapy, all 10 patients had complete remission with incomplete hematologic recovery and grade 4 pancytopenia. After haploidentical HSCT, 1 patient died on day 13 of septic shock and encephalitis, 8 patients had full donor chimerism, and 1 patient had autologous hematopoiesis. Three patients had grade 2 HSCT-associated acute GVHD. The median follow-up was 15.1 months (range, 3.1 to 24.0) after CAR T-cell therapy. Six patients remained in minimal residual disease-negative complete remission, 2 had a relapse of CD7-negative leukemia, and 1 died of septic shock at 3.7 months. The estimated 1-year overall survival was 68% (95% confidence interval [CI], 43 to 100), and the estimated 1-year disease-free survival was 54% (95% CI, 29 to 100).
Our findings suggest that sequential CD7 CAR T-cell therapy and haploidentical HSCT is safe and effective, with remission and serious but reversible adverse events. This strategy offers a feasible approach for patients with CD7-positive tumors who are ineligible for conventional allogeneic HSCT. (Funded by the National Natural Science Foundation of China and the Key Project of Science and Technology Department of Zhejiang Province; ClinicalTrials.gov numbers, NCT04599556 and NCT04538599.).
复发或难治性血液系统恶性肿瘤患者预后不良。嵌合抗原受体（CAR）T 细胞疗法作为异基因造血干细胞移植（HSCT）的桥梁，具有长期消除肿瘤的潜力。然而，HSCT 前的骨髓清除和移植物抗宿主病（GVHD）预防药物具有毒性作用，可能会消灭残留的 CAR T 细胞并影响抗肿瘤作用。CAR T 细胞疗法与异基因 HSCT 的整合是否能保留 CAR T 细胞功能并改善肿瘤控制尚不清楚。
我们在 10 例复发或难治性 CD7 阳性白血病或淋巴瘤患者中测试了一种新的“一体式”策略，包括序贯 CD7 CAR T 细胞治疗和单倍体相合 HSCT。在 CAR T 细胞治疗导致完全缓解但不完全血液学恢复后，患者接受单倍体相合 HSCT，不使用药物性骨髓清除或 GVHD 预防药物。密切监测毒性作用和疗效。
CAR T 细胞治疗后，所有 10 例患者均获得完全缓解但不完全血液学恢复和 4 级全血细胞减少。单倍体相合 HSCT 后，1 例患者死于败血症性休克和脑炎第 13 天，8 例患者获得完全供者嵌合，1 例患者出现自身造血。3 例患者出现 2 级 HSCT 相关急性 GVHD。CAR T 细胞治疗后中位随访时间为 15.1 个月（范围为 3.1 至 24.0）。6 例患者持续处于微小残留病阴性完全缓解，2 例患者发生 CD7 阴性白血病复发，1 例患者在 3.7 个月时死于败血症性休克。估计 1 年总生存率为 68%（95%CI，43 至 100），估计 1 年无病生存率为 54%（95%CI，29 至 100）。
我们的研究结果表明，序贯 CD7 CAR T 细胞治疗和单倍体相合 HSCT 是安全有效的，缓解率高且严重但可逆转的不良事件发生率低。该策略为不适合常规异基因 HSCT 的 CD7 阳性肿瘤患者提供了一种可行的治疗方法。（国家自然科学基金和浙江省科技厅重点项目资助；ClinicalTrials.gov 注册号：NCT04599556 和 NCT04538599。）
