TFRI-funded researchers in Hamilton and Toronto have come together to develop a promising immunotherapy to treat glioblastoma (GBM), an aggressive form of brain cancer that affects adults.
When tested in mice with human GBM, this chimeric antigen receptor (CAR) T-cell therapy significantly reduced tumour burden and improved survival, according to the study published in Cell Stem Cell (May 2020). The approach developed by the team involves genetically engineering specific T-cells from a patient’s immune system, allowing them to bind to CD133, a protein in glioblastoma cells.
“This study provides a novel method for targeting an aggressive CD133+ cancer stem cell population in glioblastoma, and perhaps, other cancers,” said Dr. Sheila Singh, a professor in the Department of Surgery at McMaster University, who co-led the study.
A novel approach for a devastating disease
New treatments for this type of cancer are sorely needed. Upon initial diagnosis, patients undergo aggressive treatment, including surgery, radiation therapy and chemotherapy. While these treatments initially help, the cancer eventually relapses, and when it does, it is even more aggressive, resulting in less than 15 months overall median survival.
Dr. Singh, who co-led the team with Dr. Jason Moffat, a professor of molecular genetics at the University of Toronto, has been looking for ways to help patients with this deadly disease for over a decade. Her lab identified the presence of CD133 as a marker of cancer stem cells that have the properties necessary to grow hard-to-treat glioblastoma tumours, and is searching for novel ways to target it.
In this study, her team partnered with Dr. Moffat’s to investigate if cutting-edge immunotherapies could be used to target CD133+ glioblastoma cells to eradicate the most aggressive subpopulation of cells in the tumour. To do this, they designed three types of treatments. The first was a novel human synthetic antibody, which can simply bind to CD133 protein on glioblastoma cells and halt the growth of the tumour. The second was a dual antigen T-cell engager antibody, which uses the patient’s own immune T-cells to eliminate the CD133+ glioblastoma. The third, and most effective method, was the CAR T-cell therapy.
The researchers are now exploring combination therapies that use CD133-specific CAR T- cells to block glioblastoma tumour recurrence completely and suggest this type of therapy may prove to be effective in patients with other treatment-resistant cancers with CD133 tumour-initiating cell populations.
“We hope that our approach will move into clinical trials and eventually provide patients with a better quality of life and increase their chances for survival,” said Dr. Moffat.
A unique partnership
Dr. Singh and Dr. Moffat’s lab are working together thanks to a Terry Fox New Frontiers Program Project Grant (PPG), a TFRI-funded program that promotes collaboration amongst scientists with different expertise.
"Our TFRI PPG funding permitted us to build a new, multi-disciplinary program spanning multiple labs that generated the unique foundational data of our paper,” said Dr. Singh. “I really believe that it was the philosophical mandate of the PPG, whereby the whole is greater than the sum of the parts, that led to our innovation and discovery."
This partnership led to the formation of a new Hamilton-based start-up brain cancer immunotherapy company, which was recently purchased by a U.S. therapeutics company. The company aims to run clinical trials in recurrent glioblastoma patients with CD133-specific CAR T-cell and other therapies by 2022.
This story was prepared from a press release provided by McMaster University.
Study
The Rational Development of CD133-Targeting Immunotherapies for Glioblastoma
Authors
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
Funding
This study was partially funded by a Terry Fox New Frontiers Program Project Grant to Targeting clonal heterogeneity in treatment-refractory glioblastoma with novel and empiric immunotherapies