In orthotopic patient-derived GBM xenograft models, Vora et al. compared three modalities targeting the putative cancer stem cell marker CD133 – CAR T cells [CART133], dual T cell-engaging antibody [DATE], and CD133 mAb – that bind a novel CD133 epitope. While all three treatments had activity, CART133 showed enhanced antitumor efficacy and robust antigen-specific responses when cocultured with CD133+ tumor cells. In addition, i.t. CART133 was not toxic to CD133+ CD34+ hematopoietic stem cells in a humanized mouse model, suggesting that CART133 may be a viable therapy for CD133+ GBM (known for recurrence and therapy resistance).
Contributed by Katherine Turner
ABSTRACT: 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.
Author Info: (1) McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, L8S 4K1, Canada; Surgery, Faculty of Health Sciences, McMaster University, 1200 Main Street
Author Info: (1) 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. (2) 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. (3) 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. (4) 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. (5) 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. (6) 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. (7) 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. (8) 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. (9) 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. (10) McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, L8S 4K1, Canada. (11) Donnelly Centre, Department of Molecular Genetics, Institute of Biomolecular Engineering, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada. (12) 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. (13) 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. (14) McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, L8S 4K1, Canada. (15) McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, L8S 4K1, Canada. (16) 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. (17) 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. (18) McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, L8S 4K1, Canada. (19) 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. (20) 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. (21) McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, L8S 4K1, Canada. (22) Department of Chemistry and Chemical Biology, McMaster University, Hamilton ON L8S 4M1, Canada. (23) Department of Chemistry and Chemical Biology, McMaster University, Hamilton ON L8S 4M1, Canada. (24) Donnelly Centre, Department of Molecular Genetics, Institute of Biomolecular Engineering, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada. (25) Department of Pathology and Molecular Medicine, McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada. (26) McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, L8S 4K1, Canada. (27) Donnelly Centre, Department of Molecular Genetics, Institute of Biomolecular Engineering, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada. Electronic address: j.moffat@utoronto.ca. (28) 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; Surgery, Faculty of Health Sciences, McMaster University, 1200 Main Street West, Hamilton, ON L8N 3Z5, Canada. Electronic address: ssingh@mcmaster.ca.
