CRISPR 基因编辑 CAR19 通用 T 细胞治疗儿童难治性 B 细胞白血病的 1 期临床试验
Phase 1 clinical trial of CRISPR-engineered CAR19 universal T cells for treatment of children with refractory B cell leukemia
自体 CAR-T 细胞疗法需要为每位患者单独制备，成本高、等待时间长。这项研究用 CRISPR 基因编辑技术改造来自健康供者的 T 细胞：敲除 T 细胞受体 α 链基因以防移植物抗宿主病，并去除 CD52 基因使其在阿仑单抗存在下仍能存活，从而制成可预先批量冻存的“通用型”细胞。研究共治疗 6 名复发或难治的 CD19 阳性 B 细胞急性淋巴细胞白血病（B-ALL）患儿，未出现立即毒性；4 名患儿体内细胞扩增并达到流式细胞学缓解，随后接受异基因干细胞移植。2 名患儿因二度细胞因子释放综合征需要干预，1 名出现短暂的四度神经毒性，1 名出现皮肤移植物抗宿主病，移植预处理后缓解。研究初步证明 CRISPR 编辑的通用免疫细胞疗法安全可行，具有治疗潜力。
为什么推荐给您：CRISPR 多重编辑通用 CAR-T 首次用于儿童难治白血病的人体试验，属新模态早期阳性结果。
不需要生物学背景，多打比方
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摘要Abstract
Genome editing of allogeneic T cells can provide "off-the-shelf" alternatives to autologous chimeric antigen receptor (CAR) T cell therapies. Disruption of T cell receptor α chain (TRAC) to prevent graft-versus-host disease (GVHD) and removal of CD52 (cluster of differentiation 52) for a survival advantage in the presence of alemtuzumab have previously been investigated using transcription activator-like effector nuclease (TALEN)-mediated knockout. Here, we deployed next-generation CRISPR-Cas9 editing and linked CAR expression to multiplexed DNA editing of TRAC and CD52 through incorporation of self-duplicating CRISPR guide RNA expression cassettes within the 3' long terminal repeat of a CAR19 lentiviral vector. Three cell banks of TT52CAR19 T cells were generated and cryopreserved. A phase 1, open-label, non-randomized clinical trial was conducted and treated six children with relapsed/refractory CD19-positive B cell acute lymphoblastic leukemia (B-ALL) (NCT04557436). Lymphodepletion included fludarabine, cyclophosphamide, and alemtuzumab and was followed by a single infusion of 0.8 × 10^6 to 2.0 × 10^6 CAR19 T cells per kilogram with no immediate toxicities. Four of six patients infused with TT52CAR19 T cells exhibited cell expansion, achieved flow cytometric remission, and then proceeded to receive allogeneic stem cell transplantation. Two patients required biological intervention for grade II cytokine release syndrome, one patient developed transient grade IV neurotoxicity, and one patient developed skin GVHD, which resolved after transplant conditioning. Other complications were within expectations, and primary safety objectives were met. This study provides a demonstration of the feasibility, safety, and therapeutic potential of CRISPR-engineered immunotherapy.