Prospects of immune checkpoint modulators in the treatment of glioblastoma

Abstract

Glioblastoma is the most common primary brain tumour in adults. Prognosis is poor: even with the current gold-standard first-line treatment—maximal safe resection and combination of radiotherapy with temozolomide chemotherapy—the median overall survival time is only approximately 15-17 months, because the tumour recurs in virtually all patients, and no commonly accepted standard treatment for recurrent disease exists. Several targeted agents have failed to improve patient outcomes in glioblastoma. Immunotherapy with immune checkpoint inhibitors such as ipilimumab, nivolumab, and pembrolizumab has provided relevant clinical improvements in other advanced tumours for which conventional therapies have had limited success, making immunotherapy an appealing strategy in glioblastoma. This Review summarizes current knowledge on immune checkpoint modulators and evaluates their potential role in glioblastoma on the basis of preclinical studies and emerging clinical data. Furthermore, we discuss challenges that need to be considered in the clinical development of drugs that target immune checkpoint pathways in glioblastoma, such as specific properties of the immune system in the CNS, issues with radiological response assessment, and potential interactions with established and emerging treatment strategies.

Figures

Figure 1

Overview of the immune response and major immune checkpoint molecules in the immune cycle of glioblastoma. Antigens released from degenerating tumour cells are taken up by antigen-presenting cells, microglia and macrophages (1). Antigens are trafficked to lymph nodes via migration of antigen-presenting cells, and via drainage through lymphatic vessels in the meningeal sinuses (2). In the lymphatic tissues, antigen presentation and T-cell priming takes place. This interaction is tightly regulated by a multitude of co-inhibitory (CTLA4) and co-stimulatory (CD80, CD86, CD28) immune checkpoint molecules, and could be modulated by specific therapeutic antibodies, such as the CTLA4 inhibitor ipilimumab (3). Activated T cells reach the tumour via the blood stream and migration through the blood–brain or blood–tumour barrier (4). Tumour-associated immunosuppressive factors, including immune checkpoint molecules, inhibit tumour cell destruction by T cells. PDL1 is expressed on tumour cells and microglia and inhibits T cells via binding to PD1. PD1–PDL1 inhibitors (for example, nivolumab, pembrolizumab) block this immunosuppressive mechanism and thereby increase tumour cell lysis by lymphocytes (5). Abbreviations: CTLA4, cytotoxic T-lymphocyte-associated antigen 4; MHC, major histocompatibility complex; PDL1, programmed cell death 1 ligand 1; PD1, programmed cell death protein 1; TCR, T-cell receptor.

Figure 2

PDL1 expression and tumour-infiltrating lymphocytes in glioblastoma. Expression of the immunosuppressive molecule PDL1 and sparse infiltration with cytotoxic lymphocytes are found in the majority of glioblastoma cases. a | Most samples from glioblastoma show prominent expression of PDL1 on tumour cells. Brown indicates areas immunolabelled with monoclonal anti-PDL1 antibody 5H1. b | Glioblastoma typically harbours sparse infiltration with tumour-infiltrating lymphocytes, accentuated around microvessels. Brown indicates immunolabelled CD8+ T cells. Both light microscopy images taken with an original magnification of ×200. Abbreviation: PD1, programmed cell death protein 1; PDL1, programmed cell death 1 ligand 1.