A prototype chimeric antigen receptor T cell (CAR-T cell) therapy for glioblastoma that specifically targets cancer stem cells (CSCs) expressing the CD133 marker, when tested in mice bearing human glioblastoma tumors, resulted in reduced tumor burden and improved survival according to researchers at McMaster University and the University of Toronto who developed the potential new therapy.
The researchers’ developments are reported in Cell Stem Cell, in a paper titled, “The Rational Development of CD133-Targeting Immunotherapies for Glioblastoma.” The reported study data have led to the formation of a new start-up brain cancer immunotherapy company, Empirica Therapeutics, which aims to start clinical trials of the CD133-targeting CAR-T-cell therapy in recurrent glioblastoma patients by 2022.
“Recent advances in immunotherapy have offered hope to patients with previously untreatable cancers,” said Jason Moffat, Ph.D., professor of molecular genetics at the University of Toronto and the Canada Research Chair in Functional Genomics of Cancer. Moffat is chief scientific officer at Empirica Therapeutics. “We hope that our approach of specifically targeting glioblastoma cells with CAR-T therapy will give the patients a better quality of life and increase their chances of survival.”
Glioblastoma (GBM) is the most common primary adult malignant brain tumor and has a dire prognosis, said the study’s first author Parvez Vora, PhD, a former member of the laboratory team of corresponding author Sheila Singh, Ph.D., at McMaster. Vora is director of preclinical development at Empirica Therapeutics. “Upon initial diagnosis, glioblastoma patients undergo aggressive treatment, including surgery to remove the tumor, radiation therapy, and chemotherapy. However, cancer relapses in less than seven months, resulting in less than 15 months overall median survival. Almost all the glioblastoma tumors come back as a more aggressive recurrent tumor, which has no standard-of-care treatment.” Singh, at the department of surgery at McMaster, is the Canada Research Chair in Human Cancer Stem Cell Biology, and chief executive officer Empirica Therapeutics.
CD133 is a marker of self-renewing cancer stem cells in different types of solid tumor, and “ … CD133+ tumor-initiating cells are known markers of chemo- and radio-resistance in multiple aggressive cancers, including glioblastoma,” the authors continued. The Singh lab has been studying the role of CD133 protein in brain tumors for more than a decade, and identified that the protein is a marker of cancer stem cells that have the properties necessary to grow glioblastoma tumors that are difficult to treat.
“Within the evolution of GBM, the pentaspan transmembrane glycoprotein CD133 may mark cells with various properties necessary for tumor initiation, persistence, and recurrence,” the team wrote. “ … CD133 has proven to be a necessary and sufficient factor in enabling GBM cells to adapt to current therapies …” Recent reports have also suggested that CD133 is a prognostic marker for relapse, time to malignant progression from low-grade-gliomas, and poor survival.
For the reported work, led by the Singh lab at McMaster in collaboration with the Moffat lab at the University of Toronto’s Donnelly Centre for Cellular and Biomolecular Research, the scientists investigated if targeting of CD133+ glioblastoma using immunotherapy could eradicate the most aggressive subpopulation of cells in the tumor. They also looked at the safety of CD133-targeting therapies on normal, non-cancerous human stem cells, including hematopoietic stem cells that create blood cells and progenitor cells.
The researchers designed three types of treatment and tested them both in lab experiments and in mice. The first was developed as a novel human synthetic IgG antibody, which can bind to the CD133 protein on glioblastoma cells and halt tumor growth. The second was designed as a dual antigen T cell engager antibody, which uses the patient’s own immune T cells to eliminate the CD133+ glioblastoma. The third was developed as a CAR-T therapy. “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,” they continued. While all three strategies showed activity against patient-derived CD133+ GBM cells, tests demonstrated that the CART133 cells were the most effective against human glioblastomas in mice.
“We found that the CAR-T therapy had enhanced activity compared to the other two therapeutics in preclinical models of human glioblastoma,” said Vora.”The accompanying safety studies in humanized mouse models address the potential impact on hematopoiesis, a vital process in the human body that leads to the formation of different blood cells. CD133-specific CAR-T therapy did not induce any acute systemic toxicity in humanized mouse models that harbored the human hematopoietic system.”
The authors concluded that their CART13 cell development represents “a therapeutically tractable” strategy to target self-renewing, chemoradioresistant CD133+ brain tumor initiating cells that can drive GBM recurrence and resistance to treatment. “Our study has provided many novel conceptual insights into the value of targeting an aggressive CD133+ cancer stem cell population in glioblastoma,” said Singh. “We hope that our work will now advance the development of really new and promising treatment options for these patients.”
The same immunotherapeutic strategy could also potentially be used to treat other forms of CD133+ tumors. “CART133 therapy may also offer a feasible and effective immunotherapeutic strategy for patients with other treatment-resistant primary cancers with detectable CD133+ BTIC populations, including melanoma, ovarian cancer, lung cancer, and pancreatic cancer, as well as lung-to-brain and melanoma-to-brain metastases,” they wrote.
Researchers are exploring combinatorial strategies, together with CD133-specific CAR-T cell immunotherapy, as an approach to blocking glioblastoma tumor recurrence completely. This type of therapy could feasibly prove to be effective in patients with other types of treatment-resistant cancers characterized by CD133+ tumor initiating cell populations.