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.