The Rational Development of CD133-Targeting Immunotherapies for Glioblastoma

Parvez Vora; Chitra Venugopal; Sabra Khalid Salim; Nazanin Tatari; David Bakhshinyan; Mohini Singh; Mathieu Seyfrid; Deepak Upreti; Stefan Rentas; Nicholas Wong; Rashida Williams; Maleeha Ahmad Qazi; Chirayu Chokshi; Avrilynn Ding; Minomi Subapanditha; Neil Savage; Sujeivan Mahendram; Emily Ford; Ashley Ann Adile; Dillon McKenna; Nicole McFarlane; Vince Huynh; Ryan Gavin Wylie; James Pan; Jonathan Bramson; Kristin Hope; Jason Moffat; Sheila Singh

doi:10.1016/j.stem.2020.04.008

The Rational Development of CD133-Targeting Immunotherapies for Glioblastoma

Cell Stem Cell. 2020 Jun 4;26(6):832-844.e6. doi: 10.1016/j.stem.2020.04.008. Epub 2020 May 27.

Authors

Parvez Vora¹, Chitra Venugopal¹, Sabra Khalid Salim², Nazanin Tatari², David Bakhshinyan², Mohini Singh², Mathieu Seyfrid¹, Deepak Upreti¹, Stefan Rentas², Nicholas Wong³, Rashida Williams⁴, Maleeha Ahmad Qazi², Chirayu Chokshi², Avrilynn Ding³, Minomi Subapanditha³, Neil Savage², Sujeivan Mahendram¹, Emily Ford³, Ashley Ann Adile², Dillon McKenna¹, Nicole McFarlane³, Vince Huynh⁵, Ryan Gavin Wylie⁵, James Pan⁴, Jonathan Bramson⁶, Kristin Hope³, Jason Moffat⁷, Sheila Singh⁸

Affiliations

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; Departments of Biochemistry and Biomedical 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.
⁴ Donnelly Centre, Department of Molecular Genetics, Institute of Biomolecular Engineering, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada.
⁵ Department of Chemistry and Chemical Biology, McMaster University, Hamilton ON L8S 4M1, Canada.
⁶ Department of Pathology and Molecular Medicine, McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada.
⁷ 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.
⁸ 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.

PMID: 32464096
DOI: 10.1016/j.stem.2020.04.008

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.

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

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

AC133 Antigen
Animals
Brain Neoplasms* / therapy
Glioblastoma* / therapy
Humans
Immunotherapy
Mice
Neoplastic Stem Cells

Substances

AC133 Antigen

Grants and funding

CIHR/Canada