Cell Stem Cell
Volume 26, Issue 6, 4 June 2020, Pages 832-844.e6
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Clinical and Translational Report
The Rational Development of CD133-Targeting Immunotherapies for Glioblastoma

https://doi.org/10.1016/j.stem.2020.04.008Get rights and content
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Highlights

  • Three immunotherapeutic modalities were developed to target CD133+ cells

  • Anti-CD133 DATEs and CAR-T cells are active in patient-derived glioblastoma (GBM) models

  • CD133-specific CAR-T (CART133) has enhanced activity in orthotopic GBM xenograft models

  • Intra-tumoral CART133 does not induce acute systemic toxicity in humanized mouse models

Summary

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.

Keywords

CD133
immunotherapy
glioblastoma
chimeric antigen receptor T cells
dual-antigen T cell engagers
IgG
humanized mice
GBM

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