Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2024 Apr 23;13(9):726.
doi: 10.3390/cells13090726.

A Roadmap of CAR-T-Cell Therapy in Glioblastoma: Challenges and Future Perspectives

Megan Montoya  1   2 , Marco Gallus  1   2 , Su Phyu  1   2 , Jeffrey Haegelin  1   2 , John de Groot  1   2 , Hideho Okada  1   2   3
Affiliations
Review

A Roadmap of CAR-T-Cell Therapy in Glioblastoma: Challenges and Future Perspectives

Megan Montoya et al. Cells. .

Abstract

Glioblastoma (GBM) is the most common primary malignant brain tumor, with a median overall survival of less than 2 years and a nearly 100% mortality rate under standard therapy that consists of surgery followed by combined radiochemotherapy. Therefore, new therapeutic strategies are urgently needed. The success of chimeric antigen receptor (CAR) T cells in hematological cancers has prompted preclinical and clinical investigations into CAR-T-cell treatment for GBM. However, recent trials have not demonstrated any major success. Here, we delineate existing challenges impeding the effectiveness of CAR-T-cell therapy for GBM, encompassing the cold (immunosuppressive) microenvironment, tumor heterogeneity, T-cell exhaustion, local and systemic immunosuppression, and the immune privilege inherent to the central nervous system (CNS) parenchyma. Additionally, we deliberate on the progress made in developing next-generation CAR-T cells and novel innovative approaches, such as low-intensity pulsed focused ultrasound, aimed at surmounting current roadblocks in GBM CAR-T-cell therapy.

Keywords: CAR-T-cell therapy; glioblastoma; tumor immune microenvironment.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Challenges of CAR-T-cell therapy for glioma. (A). Immune privilege of the brain poses physical and cellular barriers to CAR-T-cell homing. One of these barriers is the blood–brain barrier, which is composed of the endothelial cells of the capillary wall, astrocyte end-feet sheathing the capillary, and pericytes embedded in the capillary basement membrane. At the level of the postcapillary venules, the adjacent basement membranes leave a virtual perivascular space in which occasional APCs are embedded that play an important role in reactivating T cells, enabling them to cross the glia limitans. (B). The immunosuppressive TME comprises pro-tumoral myeloid cells, immunosuppressive cytokines/chemokines, and checkpoint molecules, all of which contribute to inhibiting CAR-T-cell efficacy and activation. (C). Hypoxia in GBM creates an inhospitable environment that severely limits oxygen and nutrients to CAR-T cells. (D). Chronic stimulation and exposure to antigen results in CAR-T-cell exhaustion. (E). Inter and intra-tumoral heterogeneity pose a significant impediment to designing CAR constructs and choosing target antigens.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Alexander B.M., Cloughesy T.F. Adult Glioblastoma. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2017;35:2402–2409. doi: 10.1200/JCO.2017.73.0119. - DOI - PubMed
    1. Louis D.N., Ohgaki H., Wiestler O.D., Cavenee W.K., Burger P.C., Jouvet A., Scheithauer B.W., Kleihues P. The 2007 WHO Classification of Tumours of the Central Nervous System. Acta Neuropathol. 2007;114:97–109. doi: 10.1007/s00401-007-0243-4. - DOI - PMC - PubMed
    1. Ostrom Q.T., Patil N., Cioffi G., Waite K., Kruchko C., Barnholtz-Sloan J.S. CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2013–2017. Neuro-Oncology. 2020;22:iv1–iv96. doi: 10.1093/neuonc/noaa200. - DOI - PMC - PubMed
    1. Tamimi A.F., Juweid M. Epidemiology and Outcome of Glioblastoma. In: De Vleeschouwer S., editor. Glioblastoma. Codon Publications; Brisbane, Australia: 2017. - PubMed
    1. Fernandes C., Costa A., Osório L., Lago R.C., Linhares P., Carvalho B., Caeiro C. Current Standards of Care in Glioblastoma Therapy. In: De Vleeschouwer S., editor. Glioblastoma. Codon Publications; Brisbane, Australia: 2017. - PubMed

Publication types

Substances