Overview of current immunotherapeutic strategies for glioma

Abstract

In the last decade, numerous studies of immunotherapy for malignant glioma (glioblastoma multiforme) have brought new knowledge and new hope for improving the prognosis of this incurable disease. Some clinical trials have reached Phase III, following positive outcomes in Phase I and II, with respect to safety and immunological end points. Results are encouraging especially when considering the promise of sustained efficacy by inducing antitumor immunological memory. Progress in understanding the mechanisms of tumor-induced immune suppression led to the development of drugs targeting immunosuppressive checkpoints, which are used in active clinical trials for glioblastoma multiforme. Insights related to the heterogeneity of the disease bring new challenges for the management of glioma and underscore a likely cause of therapeutic failure. An emerging therapeutic strategy is represented by a combinatorial, personalized approach, including the standard of care: surgery, radiation, chemotherapy with added active immunotherapy and multiagent targeting of immunosuppressive checkpoints.

Keywords: clinical trials; dendritic cells; gene therapy; glioma; immune checkpoints blockade; immunotherapy; vaccination.

Figure 1.. Timeline of clinical trials for glioma using immunotherapy.

A search for ‘immunotherapy’ and ‘glioma’ in the ClinicalTrials.gov database (March 2015) yields a list of 61 clinical trials: 14 with dendritic cell vaccines, 9 testing synthetic peptide vaccines, 8 using autologous T-cell transfer, 6 gene therapy, 4 with tumor cell lysate vaccine combined with T-cell transfer, 2 with autologous NK or NKT cell transfer, 2 with allogeneic T-cell transfer, 4 targeting immunosuppressive checkpoints and 7 using other immune treatment strategies. Limitations of the search engine may not allow a comprehensive listing; nonetheless, the graph illustrates the extensive interest in antiglioma vaccines and an emerging trend of testing immunosuppressive checkpoints. NK: Natural killer; NKT: NK T cell.

Figure 2.. CTLA-4 and PD-L1 immune checkpoints in glioma immune escape.

The CTLA-4 immune checkpoint (left panel) occurs during the priming phase of the immune response, primarily within secondary lymphoid organs. The inhibitory CTLA-4 T-cell receptor binds with higher affinity to the CD80/86 ligands on the surface of APCs and prevents their binding to and signaling through the costimulatory receptor CD28. This leads to decreased T-cell activation and proliferation in the context of antigen presenting MHC class I. PD-1 signaling (right panel) occurs during the effector phase of the immune response within the tumor microenvironment. The PD-1 receptor on the T-cell surface interacts with one of two PD-1 ligands that are expressed on the surface of tumor cells: PD-L1 or PD-L2. This interaction, in the context of tumor antigen presenting MHC class I, decreases the T-cell tumor lytic capacity and induces T-cell anergy. APC: Antigen-presenting cell.

Figure 3.. Gene therapy for glioma with Ad-TK and Ad-Flt3L.

(A) Thymidine kinase and Flt3L-expressing adenoviruses are injected directly into the tumor. (B) Following GCV administration, TK will convert GCV to GCV-triphosphate that is incorporated into the DNA of actively proliferating cells, that is, tumor cells, causing them to undergo apoptosis and release tumor antigens, including HMGB1. Flt3L entering systemic circulation will induce the trafficking of DCs into the tumor and their exposure to tumor antigens. (C) DCs exposed to tumor antigens process them into peptides presented on MHC class I/II molecules and increase the expression of the costimulatory molecules CD80/86 on their surface. (D) Activated DCs travel to the draining lymph nodes where they present antigenic peptides in combination with the costimulatory signals to naive CD4⁺ and CD8⁺ T cells, inducing clonal expansion and maturation of glioma-specific T cells, secretion of stimulatory cytokines, trafficking into the tumor and cytolytic killing of glioma cells. DC: Dendritic cell; GCV: Gancyclovir.

Figure 4.. Dendritic cell vaccination for glioma therapy.

Mononuclear cells extracted from bone marrow are cultured with GM-CSF and IL-4 or Flt3L and IL-6 to induce their differentiation into DCs. Tumor cells are killed by irradiation or other cytotoxic stimuli to generate tumor antigens. DCs are then pulsed with tumor antigens by co-culturing DCs with whole tumor lysates, purified and injected subcutaneously or intradermally as a vaccine together with costimulatory agents such as CpG oligonucleotide (CpG-ODN). CpG-ODNs stimulate DCs thorough signaling via Toll-like receptors. Injected DCs migrate to lymph nodes, where they encounter CD8⁺ and CD4⁺ T cells. MHC-antigen complexes are recognized by T-cell receptors and IL-12 secreted by the DCs further activates CD8⁺ T cells to become antigen-specific CTLs. CTLs migrate into the tumor where they attack and lyse tumor cells. CTL: Cytotoxic T-lymphocyte; DC: Dendritic cell; GCV: Gancyclovir; TK: Thymidine kinase.