Recent advances and future of immunotherapy for glioblastoma

Abstract

Introduction: Outcome for glioma (GBM) remains dismal despite advances in therapeutic interventions including chemotherapy, radiotherapy and surgical resection. The overall survival benefit observed with immunotherapies in cancers such as melanoma and prostate cancer has fuelled research into evaluating immunotherapies for GBM.

Areas covered: Preclinical studies have brought a wealth of information for improving the prognosis of GBM and multiple clinical studies are evaluating a wide array of immunotherapies for GBM patients. This review highlights advances in the development of immunotherapeutic approaches. We discuss the strategies and outcomes of active and passive immunotherapies for GBM including vaccination strategies, gene therapy, check point blockade and adoptive T cell therapies. We also focus on immunoediting and tumor neoantigens that can impact the efficacy of immunotherapies.

Expert opinion: Encouraging results have been observed with immunotherapeutic strategies; some clinical trials are reaching phase III. Significant progress has been made in unraveling the molecular and genetic heterogeneity of GBM and its implications to disease prognosis. There is now consensus related to the critical need to incorporate tumor heterogeneity into the design of therapeutic approaches. Recent data also indicates that an efficacious treatment strategy will need to be combinatorial and personalized to the tumor genetic signature.

Keywords: Glioma; cancer vaccines; checkpoint blockade; gene therapy; immunotherapy; passive immunotherapy.

Figure 1. Role of GBM cells in the generation and maintainance of the immunosuppressive tumor microenvironment

GBM cells have a central role in the immunosuppressive nature of tumor microenvironment. GBM cells express membrane-bound and soluble immunosuppressive proteins. FasL induces apoptosis of tumor infiltrating limphocytes. B7 molecules activate CTLA-4 and PD-L1 are ligands of immunosuppressive recetors CTLA-4 and PD-1, which inhibit effector T cells that infiltrate the tumor microenvironment. Downregulation of HLA-I reduces the immunogenicity of GBM cells, which in turn could activate NK cell response against the tumor. However, GBM cells overexpress an alternative MHCI molecule, HLA-G, which inhibits NK and CTL response. The synthesis of antiinflammatory cytokines and chemokines also contribute to the immunosuppressive microenvironment. GBM cells produce CCL2 and TGF-beta and IL-10 which recruit Tregs, myeloid derived suppressor cells (MDSCs) and tumor associated macrophages (TAMs) that in turn inhibit the T cell response. IL-10 also inhibits the function of antigen presenting cells (APCs) within the tumor.

Figure 2. Schematic showing factors that impact vaccination strategy for glioblastoma

(1) preparation and (2) delivery of tumor associated antigens, (3) immune adjuvant to boost immune reactions against tumor antigens and (4) biomarkers to precisely estimate the efficacy of vaccination and to select proper patient populations. Immune adjuvants are divided in two groups: (1) agonists for pro-inflammatory molecules such as TLR agonists or ligation of B7 and CD28 receptors, and (2) antagonists for anti-inflammatory molecules such as anti-PD-1 blocking antibodies or IDO inhibitors. DC represents dendritic cell; CMV, cytomegalovirus; APC, antigen presenting cell, TLR, toll like receptor.