肿瘤细胞治疗研究
英文原题：Sequential CD7 CAR T-Cell Therapy and Allogeneic HSCT without GVHD Prophylaxis.
我们的研究结果提示，序贯 CD7 CAR-T 细胞治疗与单倍体相合 HSCT 安全有效，可获得缓解，并出现严重但可逆的不良事件。
背景：复发或难治性血液系统恶性肿瘤患者预后较差。将嵌合抗原受体（CAR）T 细胞疗法作为异基因造血干细胞移植（HSCT）的桥接治疗，有望长期清除肿瘤。但 HSCT 前的清髓治疗和移植物抗宿主病（GVHD）预防药物具有毒性，可能清除残留 CAR-T 细胞并削弱抗肿瘤作用。CAR-T 与异基因 HSCT 联合应用能否维持 CAR-T 功能并改善肿瘤控制尚不清楚。 方法：研究在 10 例复发或难治性 CD7 阳性白血病或淋巴瘤患者中，评估一种新型“一体化”策略，即先进行 CD7 CAR-T 治疗，再实施单倍体 HSCT。CAR-T 治疗使患者达到完全缓解但血液学恢复不完全后，患者接受单倍体 HSCT，不进行药物清髓或使用 GVHD 预防药物。研究密切监测毒性和疗效。 结果：CAR-T 治疗后，10 例患者均达到完全缓解但血液学恢复不完全，并出现 4 级全血细胞减少。单倍体 HSCT 后，1 例患者第 13 天死于感染性休克和脑炎，8 例实现完全供者嵌合，1 例恢复自体造血。3 例发生 2 级 HSCT 相关急性 GVHD。CAR-T 治疗后的中位随访时间为 15.1 个月（范围 3.1–24.0）。6 例持续微小残留病阴性完全缓解，2 例复发为 CD7 阴性白血病，1 例在 3.7 个月时死于感染性休克。估计 1 年总生存率为 68%（95% 置信区间〔CI〕43–100），1 年无病生存率为 54%（95% CI 29–100）。 结论：结果提示，序贯 CD7 CAR-T 治疗和单倍体 HSCT 安全有效，可实现缓解；严重不良事件可逆。该策略为不适合常规异基因 HSCT 的 CD7 阳性肿瘤患者提供了可行方案。（本研究由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。）
BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.).
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