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Optimizing CAR-T Therapy for Glioblastoma

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Abstract

Chimeric antigen receptor T-cell therapies have transformed the management of hematologic malignancies but have not yet demonstrated consistent efficacy in solid tumors. Glioblastoma is the most common primary malignant brain tumor in adults and remains a major unmet medical need. Attempts at harnessing the potential of chimeric antigen receptor T-cell therapy for glioblastoma have resulted in glimpses of promise but have been met with substantial challenges. In this focused review, we discuss current and future strategies being developed to optimize chimeric antigen receptor T cells for efficacy in patients with glioblastoma, including the identification and characterization of new target antigens, reversal of T-cell dysfunction with novel chimeric antigen receptor constructs, regulatable platforms, and gene knockout strategies, and the use of combination therapies to overcome the immune-hostile microenvironment.

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  1. Oliver Y. Tang and Zev A. Binder equal co-author contribution status.

Authors and Affiliations

  1. Warren Alpert Medical School, Brown University, Providence, RI, 02903, USA

    Oliver Y. Tang

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

    Zev A. Binder & Donald M. O’Rourke

  3. Department of Medicine, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA, 19104, USA

    Stephen J. Bagley

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Zev A. Binder has an inventorship interest in intellectual property owned by the University of Pennsylvania and has received royalties related to CAR-T therapy in solid tumors. Donald M. O’Rourke is an inventor of intellectual property (US patent numbers 7,625,558 and 6,417,168 and related families) and has received royalties related to targeted ErbB therapy in solid cancers previously licensed by the University of Pennsylvania. Stephen J. Bagley has an inventorship interest in intellectual property owned by Novartis and the University of Pennsylvania: US Patent 62/809,245: “Combination therapies of EGFRvIII chimeric antigen receptors and PD-1 inhibitors”.

Authors’ Contributions

Literature review: Z.A.B., O.Y.T, and S.J.B. Initial draft of manuscript: Z.A.B., O.Y.T, and S.J.B. Critical review and editing of manuscript: Z.A.B., O.Y.T, D.M.O, and S.J.B.

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Tang, O.Y., Binder, Z.A., O’Rourke, D.M. et al. Optimizing CAR-T Therapy for Glioblastoma. Mol Diagn Ther 27, 643–660 (2023). https://doi.org/10.1007/s40291-023-00671-0

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