Current Options and Future Directions in Immune Therapy for Glioblastoma

Abstract

Glioblastoma is in need of innovative treatment approaches. Immune therapy for cancer refers to the use of the body's immune system to target malignant cells in the body. Such immune therapeutics have recently been very successful in treating a diverse group of cancerous lesions. As a result, many new immune therapies have gained Food and Drug Administration approval for the treatment of cancer, and there has been an explosion in the study of immune therapeutics for cancer treatment over the past few years. However, the immune suppression of glioblastoma and the unique immune microenvironment of the brain make immune therapeutics more challenging to apply to the brain than to other systemic cancers. Here, we discuss the existing barriers to successful immune therapy for glioblastoma and the ongoing development of immune therapeutics. We will discuss the discovery and classification of immune suppressive factors in the glioblastoma microenvironment; the development of vaccine-based therapies; the use of convection-enhanced delivery to introduce tumoricidal viruses into the tumor microenvironment, leading to secondary immune responses; the emerging use of adoptive cell therapy in the treatment of glioblastoma; and future frontiers, such as the use of cerebral microdialysis for immune monitoring and the use of sequencing to develop patient-specific therapeutics. Armed with a better understanding of the challenges inherent in immune therapy for glioblastoma, we may soon see more successes in immune-based clinical trials for this deadly disease.

Keywords: cell therapy; checkpoint; glioblastoma; immunotherapy; sequencing; vaccination; virus.

Figure 1

Normal Inflammation vs. Immunosuppression Mechanisms. Antigen presenting cells (APCs) phagocytose tumor antigens and present to cytotoxic T cells as well as naïve CD4+ cells. Via coactivation signals, the APCS activate the cytotoxic T cells (A) and skew helper T cells to a proinflammatory Th1 lineage (B). The activated cytotoxic T cells then recognize and attack malignant cells (C). T regulatory cells, M2 macrophages, and MDSCs are major mediators of immune suppression. M0 macrophages may be skewed toward a pro-inflammatory M1 phenotype by IFN-γ (D), which directly phagocytose target cells and release proinflammatory cytokines. (E) Glioblastoma cells also signal M0 macrophages to skew toward an M2 phenotype which release immunosuppressive cytokines. Immune checkpoints induce anergy and apoptosis of CD8+ cytotoxic T cells (F) and CD4+ cells.

Figure 2

Immune checkpoint inhibition. (A) Immune checkpoints hinder T-cell activation and promote an immunosuppressive state. However, these checkpoint molecules can be neutralized by targeted antibodies. (B) After the checkpoint molecules are negated by these blocking antibodies, T effector cells are better able to recognize and attack tumor cells.

Figure 3

DC vaccine development.(A) The general process of DC vaccine development and immunization requires tumor lysate isolation. Patients first undergo resection of the tumor for production of lysate as well as patient leukapheresis to collect dendritic cells. (B) The tumor associated antigen, mRNA, or lysate is used to pulse mature or immature DCs obtained through patient leukopharesis. (C) Primed DCs are then administered as a vaccine to patients peripherally.

Figure 4

Peptide vaccine. (A) In the peptide vaccine, rindopepimut, EGFRvIII peptide is fused with highly immunogenic KLH (PEPvIII-KLH) for vaccine preparation. (B) The vaccine is administered intradermally and the antigen is recognized by APCs. (C) APCs present to T-cells and CTLs. (D) T-cells activate B-cells which then produce antibodies to EGFRvIII in the tumor. CTLs cross the blood brain barrier and target GBM cells with EGFRvIII on the surface. This activation of T-cells and CTLs results in anti-tumor response.

Figure 5

HSP vaccine. (A) The glioblastoma is resected. (B) HSPs bound to the tumor antigen are released by ex-vivo tumor cell lysis. (C) The desired HSPs are isolated and peripherally administered back to the patient as a vaccine. (D) Once injected, the HSP-tumor peptide complexes are taken up by antigen presenting cells, likely facilitated by CD91, and these peptide complexes are presented on MHC Class 1 molecules for recognition by CTLs (E) CTLs cross the blood brain barrier and target GBM cells. This activation of T-cells and CTLs results in anti-tumor response.

Figure 6

Chimeric Antigen Receptor (CAR) T-cells each directed at a specific GBM-specific tumor antigen. Each CAR T-cell therapy developed for the treatment of glioblastoma utilizes a CAR directed toward one antigen such as HER2, EGFRvIII, or IL-13Rα2. (A) Engagement of tumor-specific CAR T-cells with target cell surface antigen present on tumor cells causes CAR T-cell activation. (B) Second and third generation CAR T-cells are synthesized with co-stimulatory molecules such as 41BB, CD28, and CD3 which lower the CAR T-cell barrier to activation. (C) Fully activated CARs attack target cells causing tumor cell lysis. (D) Cells negative for the CAR T-cell target demonstrate the heterogeneity of the tumor and represent a barrier to treat as these cells not targeted continue to proliferate.

Figure 7

Prototypical mechanism of oncolytic viral therapy. The modified virus is infused into the tumor environment. (A) Normal cells exposed to viruses may have introduction of viral genetic information, but the viruses are modified to not replicate. (B) Viral particles then recognize enter cell based on specific surface proteins, such as CD155 in PVSRIPO and α_Vβ_3/5 in Delta-24-RGD oncolytic adenovirus. (C) Oncolytic viral particles in tumors are replication-competent and recruit tumor cell replication machinery. (D) Viral replication results in cell lysis and release of viral particles to continue targeting tumor cells. (E) Macrophages detect and target virally infected cells, recruiting other APCs and effector T cells for secondary immune response against released tumor antigens.