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Review
. 2020 Jun;20(6):579-591.
doi: 10.1080/14712598.2020.1727436. Epub 2020 Feb 17.

CAR T cells and checkpoint inhibition for the treatment of glioblastoma

Steven H Shen  1   2   3 , Karolina Woroniecka  1   2   3 , Andrew B Barbour  1 , Peter E Fecci  1   2   4 , Luis Sanchez-Perez  1   2   4 , John H Sampson  1   2   3   4
Affiliations
Review

CAR T cells and checkpoint inhibition for the treatment of glioblastoma

Steven H Shen et al. Expert Opin Biol Ther. 2020 Jun.

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; Program Death-1 (PD-1); exhaustion; glioblastoma; immunotherapy; inhibitory immune checkpoint blockade; solid malignancy.

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Figures

Figure 1.
Figure 1.
Strategies combining monoclonal antibody therapy, gene transduction, and gene editing to examine the role of checkpoint blockade on CAR T cells A) checkpoint blockade through the administration of monoclonal antibody therapy; B&C) genetic manipulation of CAR T cells to force secretion of a full monoclonal blocking antibody or scFv against the inhibitory immune checkpoint receptor, respectively; D) genetic editing of the inhibitory immune checkpoint receptor gene by CRISPR/Cas9; and E) siRNA gene silencing of the inhibitory immune checkpoint receptor.
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