Glioblastoma is an unusually aggressive malignancy with a dismal 5-year survival rate. That’s at least in part because these tumors employ several molecular mechanisms that suppress and evade patients’ antitumor immune responses.

Given the complex biology of this cancer, the road ahead will be challenging and, ultimately, combinatorial immunotherapies will have to be developed, according to David A. Reardon, MD, professor of medicine at the Harvard Medical School and clinical director of the Center for Neuro-Oncology at the Dana-Farber Cancer Institute in Boston, Massachusetts.1

Yet the blood-brain barrier compounds the impact of anti-immune mechanisms on patients by blocking entry of some immune cells (and drugs) into the brain, noted Teilo Schaller, MSc, of the neurosurgery department at Duke University in Durham, North Carolina. The result is unchecked tumor infiltration.

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Further, the genomic heterogeneity found in glioblastoma samples suggests that targeted therapies select for resistant clones, leading to disease recurrence after an initial response.

“Such immunosuppressive factors are myriad and include inhibitory immune checkpoint-modulating molecules [such as] PD-L1, Lag-3, and Tim-3, immunosuppressive cells infiltrating the tumor microenvironment, [such as] M2 macrophages, microglia, MDSC and Tregs [regulatory T cells], immunosuppressive cytokines secreted by tumors into the tumor microenvironment [such as] TGF-b, IL-10, VEGF, IDO, and TDO, and the hostile factors concentrated in the tumor microenvironment: hypoxia, acidosis, and nutrient deprivation,” Dr Reardon said.

Multi-channel mechanisms of resistance suggest that blocking a particular pathway will be ineffective.

“We will need to better understand the role and contribution of each of these factors and develop treatment strategies to overcome them if cytotoxic T cells — including those sensitized by vaccines — will have a chance to effectively attack cancers,” Dr Reardon noted.