肿瘤细胞治疗研究
英文原题：High-Specificity CRISPR-Mediated Genome Engineering in Anti-BCMA Allogeneic CAR T Cells Suppresses Allograft Rejection in Preclinical Models.
异基因嵌合抗原受体（CAR）T细胞疗法有望克服许多与患者自体来源（自体）CAR T细胞相关的挑战。
异基因嵌合抗原受体（CAR）T细胞疗法有潜力克服许多与患者来源（自体）CAR T细胞相关的挑战。异基因CAR T细胞疗法开发中的关键考虑因素包括预防移植物抗宿主病（GvHD）和抑制同种异体移植排斥。在此，我们描述了支持正在进行的首次人体临床研究CaMMouflage试验（NCT05722418）的临床前数据，该试验评估CB-011在复发/难治性多发性骨髓瘤患者中的应用。CB-011是一种低免疫原性、异基因抗B细胞成熟抗原（BCMA）CAR T细胞疗法候选产品。CB-011细胞具有4个基因组改变，并使用Cas12a CRISPR杂交RNA-DNA（chRDNA）基因组编辑技术平台从健康供者来源的T细胞工程化改造而成。为解决同种异体移植排斥，CAR T细胞被工程化改造以防止内源性HLA I类复合物表达，并过表达由β-2微球蛋白（B2M）连接至HLA-E组成的单链多蛋白复合物。此外，T细胞受体（TCR）表达在TCRα恒定基因座被破坏，同时定点插入人源化BCMA特异性CAR。CB-011细胞在来自多发性骨髓瘤患者的细胞共培养物中，于混合淋巴细胞反应中表现出强效的浆细胞母细胞细胞毒性。此外，CB-011细胞表现出被HLA错配T细胞识别和细胞毒性作用受到抑制。由于内源性启动子驱动的B2M-HLA-E表达，CB-011细胞在体外和体内均受到保护，免受NK 细胞介导的细胞毒性。与免疫伪装装甲策略相结合以减弱同种异体移植排斥反应时，强效抗肿瘤疗效为多发性骨髓瘤提供了优化的治疗潜力。参见Caimi和Melenhorst撰写的相关Spotlight，第385页。
Allogeneic chimeric antigen receptor (CAR) T cell therapies hold the potential to overcome many of the challenges associated with patient-derived (autologous) CAR T cells. Key considerations in the development of allogeneic CAR T cell therapies include prevention of graft-vs-host disease (GvHD) and suppression of allograft rejection. Here, we describe preclinical data supporting the ongoing first-in-human clinical study, the CaMMouflage trial (NCT05722418), evaluating CB-011 in patients with relapsed/refractory multiple myeloma. CB-011 is a hypoimmunogenic, allogeneic anti-B-cell maturation antigen (BCMA) CAR T cell therapy candidate. CB-011 cells feature 4 genomic alterations and were engineered from healthy donor-derived T cells using a Cas12a CRISPR hybrid RNA-DNA (chRDNA) genome-editing technology platform. To address allograft rejection, CAR T cells were engineered to prevent endogenous HLA class I complex expression and overexpress a single-chain polyprotein complex composed of beta-2 microglobulin (B2M) tethered to HLA-E. In addition, T-cell receptor (TCR) expression was disrupted at the TCR alpha constant locus in combination with the site-specific insertion of a humanized BCMA-specific CAR. CB-011 cells exhibited robust plasmablast cytotoxicity in vitro in a mixed lymphocyte reaction in cell cocultures derived from patients with multiple myeloma. In addition, CB-011 cells demonstrated suppressed recognition by and cytotoxicity from HLA-mismatched T cells. CB-011 cells were protected from natural killer cell-mediated cytotoxicity in vitro and in vivo due to endogenous promoter-driven expression of B2M-HLA-E. Potent antitumor efficacy, when combined with an immune-cloaking armoring strategy to dampen allograft rejection, offers optimized therapeutic potential in multiple myeloma. See related Spotlight by Caimi and Melenhorst, p. 385.
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