Immunotherapy for Glioblastoma: Current State, Challenges, and Future Perspectives

Abstract

Glioblastoma is the most lethal intracranial primary malignancy by no optimal treatment option. Cancer immunotherapy has achieved remarkable survival benefits against various advanced tumors, such as melanoma and non-small-cell lung cancer, thus triggering great interest as a new therapeutic strategy for glioblastoma. Moreover, the central nervous system has been rediscovered recently as a region for active immunosurveillance. There are vibrant investigations for successful glioblastoma immunotherapy despite the fact that initial clinical trial results are somewhat disappointing with unique challenges including T-cell dysfunction in the patients. This review will explore the potential of current immunotherapy modalities for glioblastoma treatment, especially focusing on major immune checkpoint inhibitors and the future strategies with novel targets and combo therapies. Immune-related adverse events and clinical challenges in glioblastoma immunotherapy are also summarized. Glioblastoma provides persistent difficulties for immunotherapy with a complex state of patients' immune dysfunction and a variety of constraints in drug delivery to the central nervous system. However, rational design of combinational regimens and new focuses on myeloid cells and novel targets to circumvent current limitations hold promise to advent truly viable immunotherapy for glioblastoma.

Keywords: glioblastoma; immune-checkpoint inhibitors; immune-related adverse events; tumor microenvironment; tumor-associated macrophages and microglia.

Figure 1

Immunity-related microenvironment of glioblastoma. (1) The immune microenvironment involving glioblastoma (GBM) is characterized by large amounts of CD8+ and CD4+ T cells, M1 and M2 polarized macrophages, microglia, and regulatory T (Treg) cells in addition to a limited number of natural killer (NK) cells. Tumor-associated macrophages and microglia (TAMs) have considerable plasticity toward anti-tumor M1 (inflammatory TAMs) and pro-tumor M2 (anti-inflammatory TAMs) phenotypes. Pharmacological strategies to re-educate tumorigenic M2 TAMs to tumoricidal M1 TAMs may help to relieve immune suppression in the tumor microenvironment (TME), as well as enhance the related anti-tumor activity. (2) GBM normally expressed high levels of immunosuppressive factors, such as programmed cell death 1 ligand 1 (PD-L1) and indolamine 2,3-dioxygenase (IDO), while limiting the presentation of antigens by decreasing major histocompatibility complex (MHC) presentation. The application of IDO inhibitors has effects on Treg cell accumulation. (3) CD47 is highly expressed in various types of tumors. Signal regulatory protein α (SIRPα) is an inhibitory receptor expressed on macrophages and other myeloid immune cells. Upon CD47 binding to SIRPα, src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1) and SHP-2 phosphatases are activated to further abrogate phagocytosis via downstream mediators. Disruption of the CD47/SIRPα axis using anti-CD47 antibody (CD47 Ab) can interrupt the inhibitory signaling mediated by SIRPα, thereby promoting phagocytosis of tumor cells. (4) T-cell immunoglobulin and mucin domain-containing protein-3 (TIM3) is a strong negative regulator of lymphocyte function and survival, acting as a marker of CD4+ and CD8+ T-cell exhaustion similarly to programmed cell death 1 (PD-1). It has been verified that the co-expression of PD-1 and TIM3 in lymphocytes is positively correlated with the tumor grade, but it is negatively correlated with progression-free survival (PFS) in different types of tumors including GBM. (5) In the context of microglial cells, these often secrete transforming growth factor β (TGFβ) and/or interleukin 10 (IL-10) to decrease the amount of myeloid and/or lymphoid immune cells, resulting in a systemic immunosuppression and immune evasion of GBM cells. Th, helper T cell; ADCC, antibody-dependent-cell-mediated cytotoxicity; Treg, regulatory T cell; CTL, cytotoxic T lymphocyte; CAR T, chimeric antigen receptor T cell; DC, dendritic cell.

Figure 2

Current immunotherapy strategies for glioblastoma. (1) Vaccines for glioblastoma (GBM) treatment have been relied on dendritic cell (DC)-mediated presentation of GBM-related antigens and peptides for T-cell activation in the adaptive immune system. (2) The immunosuppression status of cytotoxic T lymphocytes (CTLs) can be relieved by the application of immune-checkpoint inhibitors (ICIs), including anti-programmed cell death protein 1 (PD-1), anti-cytotoxic T lymphocyte protein 4 (CTLA-4) and anti-programmed cell death 1 ligand 1 (PD-L1). (3) Genetically engineered chimeric antigen receptor (CAR) T cells can generate artificial T-cell receptors with high affinity to cancer-specific antigens. (4) Genetic engineering has also been applied in oncolytic viral treatment to medicate cancer cell lysis and promote tumor necrosis. MHC, Major histocompatibility complex; TCR, T-cell receptor; EGFRvIII, Epidermal growth factor receptor variant III.

Figure 3

Immunotherapy with Controlled Nano-drug Delivery System for Glioblastoma. (1) Doxorubicin (DOX)-loaded mesoporous silica nanoparticle (MSN) coated with IL13Rα2-targeted peptide (IP) using polyethylene glycol (PEG) (MPI/D) is a promising vehicle for the targeted delivery of DOX to glioblastoma (GBM) in vitro and in vivo. (2) Interleukin-13 receptor subunit alpha-2 (IL13Rα2) has a function of restraining the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway activation by inhibiting IL13-targeted IL13Rα1, thus reducing the expression of tumor protein p63 (p63) and STAT6, which was already proven to be a hindrance of tumor formation. TIM3, T-cell immunoglobulin and mucin domain-containing protein-3; IDO, Idolamine 2, 3-dioxygenase; APC, Antigen-presenting cell; PD1, Programmed cell death 1; PD-L1, Programmed cell death 1 ligand 1; CTLA-4, Cytotoxic T lymphocyte protein 4; MHC I, Major histocompatibility complex I.