Immune Checkpoint Blockade Biology in Mouse Models of Glioblastoma

Abstract

Glioblastoma Multiforme (GBM) is a highly malignant primary brain cancer that is associated with abysmal prognosis. The median survival of GBM patients is ~15 months and there have not been any significant advance in therapies in over a decade, leaving treatment options limited. There is clearly an unmet need for GBM treatment. Immunotherapies are treatments based on usurping the power of the host's immune system to recognize and eliminate cancer cells. They have recently proven to be a successful strategy for combating a variety of cancers. Of the various types of immunotherapies, checkpoint blockade approaches have thus far produced significant clinical responses in several cancers including melanoma, non small-cell lung cancer, renal cancer and prostate cancer. This review focuses on the biological rationale for using checkpoint blockade immunotherapeutic approaches in primary brain cancer and an up-to-date summary of current and ongoing checkpoint inhibitors-based clinical trials for malignant glioma. In addition, we expand on new concepts for further improving checkpoint blockade treatments, with a particular focus on the advantages of using genetically engineered mouse models for studies of immunotherapies in GBM.

Responsiveness to anti-PD-1 and anti-CTLA-4 immune checkpoint blockade in SB28 and GL261 mouse glioma models

“…Nevertheless, as recent advances have shown, promising genetically engineered GBM models in immunocompetent mice have been and are still being developed, but to our knowledge have not focused on recapitulating low mutational load. 39 To complement current clinical research, we need to assess those features of a GBM model that matter to anti-tumor immunity. This would appear to be a good starting point to interpret data from experimental immunotherapies.…”

Exploring Long Noncoding RNAs in Glioblastoma: Regulatory Mechanisms and Clinical Potentials

“…In addition, the complex glioma milieu composed of microvessels, immune cells, extracellular vesicles, cytokines, and neural transmitters is indispensable for GBM propagation and invasion [ 42 , 162 ]. Particularly, the latest progress using immune checkpoint inhibitors brings hopes for previously intractable tumors including GBMs [ 163 , 164 ]. Hence, future studies need to identify lncRNAs that have essential roles in regulating the fate and behavior of microenvironment components in GBMs.…”

Anti-PD-1 checkpoint blockade monotherapy in the orthotopic GL261 glioma model: the devil is in the detail

“…The jarring dissonance in the literature regarding anti-PD-1 therapy in the GL261 model, which stretches far beyond the 2 publications quoted above, has been previously noted. 25 In that review, the differences in outcome were largely attributed to varying frequency and dose of anti-PD-1 administration. 25 We view this attribution as insufficiently broad, given the wealth of published knowledge implicating many other experimental variables as well.…”

“… 25 In that review, the differences in outcome were largely attributed to varying frequency and dose of anti-PD-1 administration. 25 We view this attribution as insufficiently broad, given the wealth of published knowledge implicating many other experimental variables as well. We aim to expand this conversation and show that anti-PD-1 CBI monotherapy is not simply effective or simply ineffective against the GL261 glioma model but that its efficacy is influenced by myriad factors, far beyond just dosing, which need to be both appropriately accounted for and clearly communicated with the research community.…”