Immunotherapy for glioblastoma: the promise of combination strategies

Abstract

Glioblastoma (GBM) treatment has remained almost unchanged for more than 20 years. The current standard of care involves surgical resection (if possible) followed by concomitant radiotherapy and chemotherapy. In recent years, immunotherapy strategies have revolutionized the treatment of many cancers, increasing the hope for GBM therapy. However, mostly due to the high, multifactorial immunosuppression occurring in the microenvironment, the poor knowledge of the neuroimmune system and the presence of the blood-brain barrier, the efficacy of immunotherapy in GBM is still low. Recently, new strategies for GBM treatments have employed immunotherapy combinations and have provided encouraging results in both preclinical and clinical studies. The lessons learned from clinical trials highlight the importance of tackling different arms of immunity. In this review, we aim to summarize the preclinical evidence regarding combination immunotherapy in terms of immune and survival benefits for GBM management. The outcomes of recent studies assessing the combination of different classes of immunotherapeutic agents (e.g., immune checkpoint blockade and vaccines) will be discussed. Finally, future strategies to ameliorate the efficacy of immunotherapy and facilitate clinical translation will be provided to address the unmet medical needs of GBM.

Keywords: Brain cancer; Cancer vaccine; Combination immunotherapy; Glioblastoma; Immune checkpoint blockade.

Fig. 1

Schematic representation of GBM TME. A GBM TME is composed of various cell types. B Factors impeding translation of GBM immunotherapy treatments: (i) the BBB limiting drug delivery efficacy, (ii) the relatively low infiltration of T cells as well as their high exhaustion marker expression, (iii) the high infiltration of immunosuppressive cells (such as Tregs, TAMs and MDSCs) in the TME and (iv) the infiltrative and heterogeneous characteristics of GBM cells. (Abbreviations: GBM = Glioblastoma; LAG-3 = Lymphocyte activation gene 3 protein; MDSC = Myeloid-derived suppressive cell; NK = Natural killer; PD-1 = Programmed cell death-1; TAM = Tumor-associated microglia and macrophage; TIM-3 = T cell immunoglobulin and mucin domain containing-3)

Fig. 2

The GBM immunity cycle and associated treatments. The immune response in GBM can be divided into six steps, starting with antigen release from GBM cells and ending with the killing of GBM cells. Potential treatments impacting the immune response steps are written in blue. Step 1 – Antigens are released from dying GBM cells. Step 2 – Tumor antigens are captured by APCs, processed and displayed on MHC-I and -II molecules for presentation to T cells. Step 3 – Effector T cells are primed and activated in response to tumor antigen presentation. Step 4 – Activated T cells traffic through the BBB and infiltrate the tumor site. Step 5 – The immunosuppressive TME must be overcome to allow activated T cells to recognize and bind to GBM cells. Step 6 – Activated T cells kill GBM cells after binding to GBM tumor antigen on MHC-I through the T cell receptor (TCR). The boxes * and ** represent the CTLA-4 and PD-1/PD-L1 pathways. * T cells are activated after the binding of TCR with antigens displayed on MHC and the simultaneous CD28:CD80/86 costimulatory signal. CTLA-4 mediates T cell inhibition by competitively binding to CD80/86. ** T cells are activated after recognizing GBM cells, secreting inflammatory cytokines and inducing GBM cell death. PD-1:PD-L1 binding induces T cell inhibition by reducing T cell proliferation and cytokine production. (Abbreviations: APC = Antigen-presenting cell; Chemo = Chemotherapy; CTLA-4 = Cytotoxic T-lymphocyte antigen 4; CXCR4 = C-X-C chemokine receptor 4; GBM = Glioblastoma; GITR = Glucocorticoid-induced tumor necrosis factor-related protein; IDO = Indoleamine 2,3-dioxygenase; LAG-3 = Lymphocyte activation gene 3 protein; MDSC = Myeloid-derived suppressive cell; MHC = Major histocompatibility complex; PD-1 = Programmed cell death-1; PD-L1 = Programmed death ligand-1; RT = Radiotherapy; TAM = Tumor-associated microglia and macrophage; TCR = T cell receptor; TIGIT = T cell immunoreceptor with Ig and ITIM domains; TIM-3 = T cell immunoglobulin and mucin domain containing-3; VEGF = Vascular endothelial growth factor)