Department of Hematology/Oncology, Cell and Gene Therapy, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Bambino Gesù Children's Hospital, Rome, Italy.
Miltenyi Biomedicine, Bergisch Gladbach, Germany.
Blood. 2023 Jul 13;142(2):146-157. doi: 10.1182/blood.2023020023.
Autologous CD19-directed chimeric antigen receptor (CAR)-T cells have shown unprecedented efficacy in children with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, patients either relapsing after allogeneic hematopoietic stem cell transplantation (allo-HSCT) or displaying profound lymphopenia and/or rapidly progressing disease often cannot access autologous products. These hurdles may be overcome by allogeneic, donor-derived CAR-T cells. We tested donor-derived T cells transduced with a second-generation (4.1BB) CD19-directed CAR for treatment of patients with BCP-ALL in a hospital-exemption setting. Two constructs were tested: a retroviral construct incorporating the suicide gene inducible caspase-9 (CD19-CAR-Retro_ALLO) first and then a lentiviral construct and an automated, Prodigy-based manufacturing process (CD19-CAR-Lenti_ALLO). Thirteen children/young adults received ALLO-CAR-T cells between March 2021 and October 2022. Doses ranged between 1.0 × 106 and 3.0 × 106 CAR-T cells per kg. The toxicity profile was comparable with that of autologous CAR-T cells, characterized mainly by cytopenia, cytokine release syndrome (maximum grade 1), and grade 2 immune-effector cell-associated neurotoxicity syndrome. One case of acute graft-versus-host disease (GVHD) occurred and was rapidly controlled with steroids and ruxolitinib. None of the other patients, including 3 given ALLO-CAR-T cells from an HLA-haploidentical donor, experienced GVHD. Two patients received ALLO-CAR-T cells before HSCT and showed a significant expansion of CAR-T cells without any sign of GVHD. All patients obtained complete remission (CR) with absence of minimal residual disease in the bone marrow. With a median follow-up of 12 months (range, 5-21), 8 of 13 patients maintained CR. Allogeneic anti-CD19 CAR-T cells can effectively treat highly refractory BCP-ALL relapsing after allo-HSCT without showing increased toxicity as compared with autologous CAR-T cells.
自体 CD19 导向嵌合抗原受体 (CAR)-T 细胞在复发/难治性 B 细胞前体急性淋巴细胞白血病 (BCP-ALL) 儿童中显示出前所未有的疗效。然而,接受异基因造血干细胞移植 (allo-HSCT) 后复发或表现出严重淋巴细胞减少症和/或疾病迅速进展的患者通常无法获得自体产品。这些障碍可以通过同种异体、供体来源的 CAR-T 细胞来克服。我们在豁免医院的环境下,测试了用第二代 (4.1BB) CD19 导向 CAR 转导的供体 T 细胞治疗 BCP-ALL 患者。测试了两种构建体:一种是包含自杀基因诱导型半胱天冬酶 9 的逆转录病毒构建体(CD19-CAR-Retro_ALLO),然后是一种慢病毒构建体和一种自动化、基于 Prodigy 的制造工艺(CD19-CAR-Lenti_ALLO)。2021 年 3 月至 2022 年 10 月期间,13 名儿童/年轻成年人接受了 ALLO-CAR-T 细胞治疗。剂量范围为每公斤 1.0×106 至 3.0×106 CAR-T 细胞。毒性谱与自体 CAR-T 细胞相似,主要表现为细胞减少症、细胞因子释放综合征(最高 1 级)和 2 级免疫效应细胞相关神经毒性综合征。发生 1 例急性移植物抗宿主病 (GVHD),用类固醇和鲁索利替尼迅速控制。包括 3 名接受 HLA 单倍体不相合供体 ALLO-CAR-T 细胞的患者在内,没有其他患者发生 GVHD。2 名患者在 HSCT 前接受了 ALLO-CAR-T 细胞治疗,CAR-T 细胞显著扩增,没有任何 GVHD 的迹象。所有患者均获得完全缓解 (CR),骨髓中无微小残留病。中位随访时间为 12 个月(范围为 5-21 个月),13 例患者中有 8 例维持 CR。与自体 CAR-T 细胞相比,同种异体抗 CD19 CAR-T 细胞可有效治疗 allo-HSCT 后复发的高度难治性 BCP-ALL,且毒性没有增加。
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