Harnessing the immune system in glioblastoma

Abstract

Glioblastoma is the most common primary malignant brain tumour. Survival is poor and improved treatment options are urgently needed. Although immunotherapies have emerged as effective treatments for a number of cancers, translation of these through to brain tumours is a distinct challenge, particularly due to the blood-brain barrier and the unique immune tumour microenvironment afforded by CNS-specific cells. This review discusses the immune system within the CNS, mechanisms of immune escape employed by glioblastoma, and the immunological effects of conventional glioblastoma treatments. Novel therapies for glioblastoma that harness the immune system and their current clinical progress are outlined, including cancer vaccines, T-cell therapies and immune checkpoint modulators.

Fig. 1

Immune gateways (left). In addition to the resident microglia, there are three distinct macrophage populations within the CNS present at so-called ‘immune gateways’ that act as ports of entry for activated T cells into the CNS. Perivascular macrophages, derived from the embryonic yolk sac, are located around parenchymal vessels (top). The other two populations, derived from bone marrow, are located in the meningeal spaces (middle) and the choroid plexus (bottom) (adapted from ref. ). Immune evasion in glioblastoma (right): the immunosuppressive tumour microenvironment (TME) of glioblastoma is the result of complex interactions between tumour cells, microglia, tumour-associated macrophages (TAMs), components of the extracellular matrix and tumour infiltrating lymphocytes (TILs), which are predominantly regulatory in phenotype (T-regs). Hypoxia promotes angiogenesis of abnormal blood vessels, further driving tumour growth (adapted from ref. )

Fig. 2

Immunotherapeutic approaches in glioblastoma. From top: Tumour vaccines: There are two main approaches; In dendritic cell vaccination (left) tumour cells are isolated at surgery (a), and processed to form a tumour lysate (b). Apheresis is done to isolate immature monocytes (c), which are then activated ex vivo into immature dendritic cells (d). Finally, these dendritic cells are matured and activated using tumour lysate and then returned to patients as intra-dermal injection (e). In peptide vaccination (right) tumour cells are isolated after surgery (1), and then further processed to isolate tumour antigens (2). These are then artificially produced and processed into a HLA-matched vaccine (3), which is then returned to the patient as an intradermal injection. Immune Checkpoint Inhibitors: While T-cell responses are initiated through the interaction of MHC Class I/II bound antigen with the T-cell receptor (TCR), the amplitude and quality of this response is regulated by a balance of co-inhibitory and co-stimulatory signals; commonly referred to as immune checkpoints. Checkpoint inhibitors function to either mimic co-stimulatory signals or prevent co-inhibitory signals. Therapies targeting a number of checkpoints are in development, including 4-1BB (a), CTLA-4 (b), PD-L1 (c) and PD-1 (d). T-cell therapies: In CAR-T cell therapy (left), autologous T cells are isolated and expanded (a) and the CAR construct inserted with viral vectors (b). Autologous CAR-T cells are then returned to the patient as an infusion (c). In adoptive cell transfer (right), following T-cell isolation and expansion (1), T cells are either activated ex vivo using lymphokines (2A) or selected for a specific tumour antigen (2B). Cells are then expanded and returned to patients as an infusion (3). Bevacizumab: Right: Unopposed VEGF signalling within tumours induces new blood vessel formation, inhibitors dendritic cell (DC) maturation, antigen presentation and T-cell trafficking. Left: In the presence of bevacizumab, VEGF signalling is blocked resulting in vessel normalisation, formation of high endothelial venules (HEVs) and facilitation of T-cell trafficking, augmenting response to immune checkpoint inhibitors. Oncolytic viral therapies: Oncolytic viruses are engineered to replicate preferentially in glioblastoma cells (due to lack of tumour suppressor function). Viruses are delivered either directly into tumours (a) or intravenously (b) if able to travel across the BBB. Within normal cells, viruses do not replicate due to intact tumour suppressor apparatus. However, within tumour cells, viruses replicate and induce apoptosis