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Updated: May 15, 2026
Generation of CAR T Cells for Adoptive Therapy in the Context of Glioblastoma Standard of Care
Published on: February 16, 2015
uPAR is highly expressed in recurrent glioblastoma and represents a candidate CAR T cell target
William T Maich1,2, Muhammad Vaseem Shaikh1,2, Anish Puri1
1Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON, Canada.
Abstract:
Glioblastoma (GBM) comprises nearly 15% of primary central nervous system (CNS) tumors and 50% of malignant primary CNS tumors worldwide. Considerable tumoral heterogeneity exists in GBM, leading to inefficacy of current treatments and the absence of meaningful improvements in frontline therapies in the past 20 years. Through multiomic analysis of patient-derived primary and recurrent GBM cell lines, we identified the urokinase plasminogen activator receptor (uPAR) as a protumorigenic marker of putative brain tumor-initiating cells and a potential therapeutic target. We found that genetic disruption of uPAR expression impaired protumorigenic characteristics in vitro and in vivo, highlighting its biological role in tumorigenesis. We then generated uPAR-specific chimeric antigen receptor (CAR) T cells, which demonstrated potent antitumor activity in recurrent GBM patient-derived xenograft models. In addition to direct tumor cell killing, we found that uPAR is expressed on GBM-associated macrophages, enabling uPAR CAR T cells to target both GBM itself and cells in the tumor microenvironment. Together, these data illustrate the potency and therapeutic potential of targeting uPAR in GBM.
Insights
Targeting urokinase plasminogen activator receptor (uPAR) shows promise for glioblastoma (GBM) treatment. uPAR-specific CAR T cells effectively eliminated GBM cells and tumor microenvironment components in preclinical models.
Area of Science:
- Neuro-oncology
- Immunotherapy
- Molecular Biology
Background:
- Glioblastoma (GBM) is a deadly brain cancer with limited treatment options due to tumor heterogeneity.
- Current GBM therapies have shown minimal progress over the last two decades.
- Identifying novel therapeutic targets is crucial for improving patient outcomes.
Purpose of the Study:
- To identify novel therapeutic targets for glioblastoma.
- To investigate the role of urokinase plasminogen activator receptor (uPAR) in GBM.
- To evaluate the efficacy of uPAR-targeted chimeric antigen receptor (CAR) T cell therapy in GBM.
Main Methods:
- Multiomic analysis of patient-derived GBM cell lines.
- Genetic disruption of uPAR expression.
- Generation and testing of uPAR-specific CAR T cells in xenograft models.
- Analysis of uPAR expression in GBM cells and tumor microenvironment.
Main Results:
- uPAR was identified as a protumorigenic marker and therapeutic target in GBM.
- Disrupting uPAR impaired GBM cell tumorigenic properties in vitro and in vivo.
- uPAR-specific CAR T cells demonstrated potent antitumor activity against recurrent GBM.
- uPAR CAR T cells targeted both GBM cells and macrophages in the tumor microenvironment.
Conclusions:
- Targeting uPAR represents a promising therapeutic strategy for glioblastoma.
- uPAR CAR T cell therapy shows potential for direct tumor cell killing and modulating the tumor microenvironment.
- This approach offers a novel strategy to overcome GBM heterogeneity and treatment resistance.
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