PD-1 Inhibitors: Do they have a Future in the Treatment of Glioblastoma?

Abstract

Glioblastoma (WHO grade IV glioma) is the most common malignant primary brain tumor in adults. Survival has remained largely static for decades, despite significant efforts to develop new effective therapies. Immunotherapy and especially immune checkpoint inhibitors and programmed cell death (PD)-1/PD-L1 inhibitors have transformed the landscape of cancer treatment and improved patient survival in a number of different cancer types. With the exception of few select cases (e.g., patients with Lynch syndrome) the neuro-oncology community is still awaiting evidence that PD-1 blockade can lead to meaningful clinical benefit in glioblastoma. This lack of progress in the field is likely to be due to multiple reasons, including inherent challenges in brain tumor drug development, the blood-brain barrier, the unique immune environment in the brain, the impact of corticosteroids, as well as inter- and intratumoral heterogeneity. Here we critically review the clinical literature, address the unique aspects of glioma immunobiology and potential immunobiological barriers to progress, and contextualize new approaches to increase the efficacy of PD-1/PD-L1 inhibitors in glioblastoma that may identify gaps and testable relevant hypotheses for future basic and clinical research and to provide a novel perspective to further stimulate preclinical and clinical research to ultimately help patients with glioma, including glioblastoma, which is arguably one of the greatest areas of unmet need in cancer. Moving forward, we need to build on our existing knowledge by conducting further fundamental glioma immunobiology research in parallel with innovative and methodologically sound clinical trials.

Figure 1.

The immune response to glioblastoma and cancer in general, is a dynamic and complex process involving multiple interactions as outlined. The cancer immunity cycle encompasses stimulatory and inhibitory components with an immune regulatory feedback mechanisms. There are unique aspects specific to the brain (e.g., microglia, brain specific immune trafficking… etc.), that pose additional challenges to the development of effective immunotherapy strategies for treatment of glioblastoma. Adapted from an image created with BioRender.com. Abbreviations; GBM: Glioblastoma; TMB: Tumor Mutational Burden; MHC: Major Histocompatibility Complex; PD-L1: Programmed Death Ligand 1; GBM: Glioblastoma; DC: Dendritic Cells; IDO1: Indoleamine 2,3-Dioxygenase 1; TAMs: Tumor Associated Macrophages; MDSC: Myeloid-Derived Suppressor Cells; Tregs: Regulatory T cells.