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Potential of Glioblastoma-Targeted Chimeric Antigen Receptor (CAR) T-Cell Therapy

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Abstract

Despite the established efficacy of chimeric antigen receptor (CAR) T-cell therapy in hematologic malignancies, translating CAR T therapy to solid tumors has remained investigational. Glioblastoma, the most aggressive and lethal form of primary brain tumor, has recently been among the malignancies being trialed clinically with CAR T cells. Glioblastoma in particular holds several unique features that have hindered clinical translation, including its vast intertumoral and intratumoral heterogeneity, associated immunosuppressive environment, and lack of clear experimental models to predict response and analyze resistant phenotypes. Here, we review the history of CAR T therapy development, its current progress in treating glioblastoma, as well as the current challenges and future directions in establishing CAR T therapy as a viable alternative to the current standard of care. Tremendous efforts are currently ongoing to identify novel CAR targets and target combinations for glioblastoma, to modify T cells to enhance their efficacy and to enable them to resist tumor-mediated immunosuppression, and to utilize adjunct therapies such as lymphodepletion, checkpoint inhibition, and bi-specific engagers to improve CAR T persistence. Furthermore, new preclinical models of CAR T therapy are being developed that better reflect the clinical features seen in human trials. Current clinical trials that rapidly incorporate key preclinical findings to patient translation are emerging.

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Authors and Affiliations

  1. Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Ryan D. Salinas, Joseph S. Durgin & Donald M. O’Rourke

  2. Glioblastoma Translational Center of Excellence, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Donald M. O’Rourke

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  1. Ryan D. Salinas
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  2. Joseph S. Durgin
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Correspondence to Donald M. O’Rourke.

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Conflict of interest

Donald M. O’Rourke has received research grants related to the development of CAR T cells in glioblastoma (Novartis), and holds patents pending and patents filed for CAR T cells in glioblastoma (Novartis, University of Pennsylvania). Ryan D. Salinas and Joseph S. Durgin declare they have no conflicts of interest that might be relevant to the contents of this article.

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Salinas, R.D., Durgin, J.S. & O’Rourke, D.M. Potential of Glioblastoma-Targeted Chimeric Antigen Receptor (CAR) T-Cell Therapy. CNS Drugs 34, 127–145 (2020). https://doi.org/10.1007/s40263-019-00687-3

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