McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, L8S 4K1, Canada; Surgery, Faculty of Health Sciences, McMaster University, 1200 Main Street West, Hamilton, ON L8N 3Z5, Canada.
McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, L8S 4K1, Canada; Departments of Biochemistry and Biomedical Sciences, McMaster University, 1200 Main Street West, Hamilton, ON L8N 3Z5, Canada.
Cell Stem Cell. 2020 Jun 4;26(6):832-844.e6. doi: 10.1016/j.stem.2020.04.008. Epub 2020 May 27.
CD133 marks self-renewing cancer stem cells (CSCs) in a variety of solid tumors, and CD133+ tumor-initiating cells are known markers of chemo- and radio-resistance in multiple aggressive cancers, including glioblastoma (GBM), that may drive intra-tumoral heterogeneity. Here, we report three immunotherapeutic modalities based on a human anti-CD133 antibody fragment that targets a unique epitope present in glycosylated and non-glycosylated CD133 and studied their effects on targeting CD133+ cells in patient-derived models of GBM. We generated an immunoglobulin G (IgG) (RW03-IgG), a dual-antigen T cell engager (DATE), and a CD133-specific chimeric antigen receptor T cell (CAR-T): CART133. All three showed activity against patient-derived CD133+ GBM cells, and CART133 cells demonstrated superior efficacy in patient-derived GBM xenograft models without causing adverse effects on normal CD133+ hematopoietic stem cells in humanized CD34+ mice. Thus, CART133 cells may be a therapeutically tractable strategy to target CD133+ CSCs in human GBM or other treatment-resistant primary cancers.
CD133 标记多种实体瘤中的自我更新癌症干细胞 (CSC)，并且 CD133+肿瘤起始细胞是多种侵袭性癌症（包括胶质母细胞瘤 (GBM)）中化疗和放疗耐药性的已知标志物，它们可能驱动肿瘤内异质性。在这里，我们报告了三种基于针对存在于糖基化和非糖基化 CD133 中的独特表位的人抗 CD133 抗体片段的免疫治疗方式，并研究了它们在靶向 GBM 患者来源模型中的 CD133+细胞方面的作用。我们生成了免疫球蛋白 G (IgG) (RW03-IgG)、双抗原 T 细胞接合器 (DATE) 和 CD133 特异性嵌合抗原受体 T 细胞 (CAR-T)：CART133。所有三种方法都对患者来源的 CD133+GBM 细胞表现出活性，并且 CART133 细胞在人源化 CD34+小鼠中对正常 CD133+造血干细胞没有不良影响的情况下，在患者来源的 GBM 异种移植模型中显示出更好的疗效。因此，CART133 细胞可能是针对人类 GBM 或其他治疗抵抗性原发性癌症中的 CD133+CSC 的一种有治疗潜力的策略。
