CAR T cells and checkpoint inhibition for the treatment of glioblastoma

ABSTRACT

Introduction: Glioblastoma (GBM) is a highly aggressive brain tumor and is one of the most lethal human cancers. Chimeric antigen receptor (CAR) T cell therapy has markedly improved survival in previously incurable disease; however, this vanguard treatment still faces challenges in GBM. Likewise, checkpoint blockade therapies have not enjoyed the same victories against GBM. As it becomes increasingly evident that a mono-therapeutic approach is unlikely to provide anti-tumor efficacy, there evolves a critical need for combined treatment strategies.

Areas covered: This review highlights the clinical successes observed with CAR T cell therapy as well the current efforts to overcome its perceived limitations. The review also explores employed combinations of CAR T cell approaches with immune checkpoint blockade strategies, which aim to potentiate immunotherapeutic benefits while restricting the impact of tumor heterogeneity and T cell exhaustion.

Expert opinion: Barriers such as tumor heterogeneity and T cell exhaustion have exposed the weaknesses of various mono-immunotherapeutic approaches to GBM, including CAR T cell and checkpoint blockade strategies. Combining these potentially complementary strategies, however, may proffer a rational means of mitigating these barriers and advancing therapeutic successes against GBM and other solid tumors.

KEYWORDS:

• CAR T cells
• exhaustion
• solid malignancy
• immunotherapy
• inhibitory immune checkpoint blockade
• Program Death-1 (PD-1)
• glioblastoma

Article highlights

• The current standard-of-care regimen for glioblastoma using resection, radiotherapy, and chemotherapy only modestly improves survival in patients due to its inability to effectively eradicate all malignant cells

• Chimeric antigen receptor T cell therapy is highly effective at treating cancer in hematologic malignancies but has shown limited efficacy in solid tumors like glioblastoma

• Checkpoint blockade therapy, a mainstay of cancer immunotherapy also fails in glioblastoma due to a lack of functional, non-exhausted endogenous T cells at the tumor

• Given the complexity of the disease, it is becoming increasingly evident that mono-therapeutic approaches are unlikely to provide anti-tumor efficacy, thus prompting the use of a combined therapeutic approach

• By combining both chimeric antigen T cell therapy and checkpoint blockade, glioblastoma can be treated in two specific approaches with each treatment also mitigating the other’s limitations

This box summarizes key points contained in the article.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This work was supported by grants from the National Institutes of Health (NIH) National Cancer Institute [P50-CA190991 (JH Sampson)] and the NIH National Institute of Neurological Disorders and Stroke [R01-NS099463 (JH Sampson), R01-NS085412 (JH Sampson), and U01-NS090284 (JH Sampson)]. Additional support was provided by aNational Science Foundation Graduate Research Fellowship (KAR).