Current State of Immune-Based Therapies for Glioblastoma

Lim, Michael; Weller, Michael; Chiocca, E. Antonio

doi:10.1200/edbk_159084

Cited by 13 publications

(13 citation statements)

References 41 publications

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“…Overall, the results of many phase I/II and III clinical trials were highly disappointing showing, at best, a very limited efficacy often with severe adverse effects [38–40]. The results of the ongoing phase I/II/III trials that include the blockers of “immune checkpoints” PD1 and/or CTLA-4 that have a proved efficacy in other tumors [41] and in preclinical GB models [42] appear promising, although not impressive [43, 44] .…”

Section: Discussionmentioning

confidence: 99%

Small molecules targeting histone demethylase genes (KDMs) inhibit growth of temozolomide-resistant glioblastoma cells

et al. 2017

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In glioblastoma several histone demethylase genes (KDM) are overexpressed compared to normal brain tissue and the development of Temozolomide (TMZ) resistance is accompanied by the transient further increased expression of KDM5A and other KDMs following a mechanism that we defined as “epigenetic resilience”. We hypothesized that targeting KDMs may kill the cells that survive the cytotoxic therapy.We determined the effect of JIB 04 and CPI-455, two KDM inhibitors, on glioblastoma cells and found that both molecules are more effective against TMZ-resistant rather than native cells.Because of its lower IC50, we focused on JIB 04 that targets KDM5A and other KDMs as well. We have shown that this molecule activates autophagic and apoptotic pathways, interferes with cell cycle progression, inhibits cell clonogenicity and dephosphorylates Akt thus inactivating a potent pro-survival pathway. We performed combination temozolomide/JIB 04 in vitro treatments showing that these two molecules, under certain conditions, have a strong synergic effect and we hypothesize that JIB 04 intercepts the cells that escape the G2 block exerted by TMZ. Finally we studied the permeability of JIB 04 across the blood-brain barrier and found that this molecule reaches bioactive concentration in the brain; furthermore a pilot in vivo experiment in an orthotopic GB xenograft model showed a trend toward longer survival in treated mice with an Hazard Ratio of 0.5.In conclusion we propose that the combination between cytotoxic drugs and molecules acting on the epigenetic landscape may offer the opportunity to develop new therapies for this invariably lethal disease.

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Section: Discussionmentioning

confidence: 99%

Small molecules targeting histone demethylase genes (KDMs) inhibit growth of temozolomide-resistant glioblastoma cells

et al. 2017

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“…Anti-PD-1 therapy restores the effector function of exhausted T cells and promotes anti-tumor immune response [ 5 – 8 ]. PD-1 is expressed on T cells and its known ligands, PD-L1 and PD-L2, are expressed by tumor cells, antigen presenting cells, and tumor associated myeloid cells [ 7 , 9 , 10 ]. However, comprehensive biomarker analyses suggest that CB monotherapy may be effective only in a small subset of GBM patients [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Dendritic cell activation enhances anti-PD-1 mediated immunotherapy against glioblastoma

et al. 2018

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IntroductionThe glioblastoma (GBM) immune microenvironment is highly suppressive as it targets and hinders multiple components of the immune system. Checkpoint blockade (CB) is being evaluated for GBM patients. However, biomarker analyses suggest that CB monotherapy may be effective only in a small fraction of GBM patients. We hypothesized that activation of antigen presentation would increase the therapeutic response to PD-1 blockade.ResultsWe show that activating DCs through TLR3 agonists enhances the anti-tumor immune response to CB and increases survival in GBM. Mice treated with TLR3 agonist poly(I:C) and anti-PD-1 demonstrated increased DC activation and increased T cell proliferation in tumor draining lymph nodes. We show that DCs are necessary for the improved anti-tumor immune response.ConclusionsThis study suggests that augmenting antigen presentation is an effective multimodal immunotherapy strategy that intensifies anti-tumor responses in GBM. Specifically, these data represent an expanded role for TLR3 agonists as adjuvants to CB.MethodsUsing a preclinical model of GBM, we tested the efficacy of combinatorial immunotherapy with anti-PD-1 and TLR3 agonist, poly(I:C). Characterization of the immune response in tumor infiltrating immune cells and in secondary lymphoid organs was performed. Additionally, dendritic cell (DC) depletion experiments were performed.

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“…There are multiple phases in the adaptive immune response that can be targeted: TA presentation with DCs, T cell checkpoint blockades to reduce the immunosuppression present in the tumor environment, and direct stimulation of activated T cells to name a few. Even these powerful therapies face challenges when utilized for glioma therapy like the restrictive nature of the BBB and systemic autoimmune generation [ 23 , 25 , 27 , 32 , 109 , 110 ].…”

Section: Discussionmentioning

confidence: 99%

“…As noted already, the uniquely distinct tumor microenvironment of glioma creates immunosuppressive conditions that ordinarily do not allow for significant anti-tumor immune responsiveness. Immunotherapy strives to overcome this intrinsic tumor immunosuppression and promotes a defined immune response against the tumor through immune system modulations [ 23 – 25 ]. Defined by the presence of regulatory T cells, M2 macrophages, and myeloid-derived suppressor cells (MDSCs), the immunosuppressive glioma microenvironment may prove susceptible to approaches that promote an anti-tumor immune response through T cell activation [ 23 – 25 ].…”

Section: Introductionmentioning

confidence: 99%

“…Immunotherapy strives to overcome this intrinsic tumor immunosuppression and promotes a defined immune response against the tumor through immune system modulations [ 23 – 25 ]. Defined by the presence of regulatory T cells, M2 macrophages, and myeloid-derived suppressor cells (MDSCs), the immunosuppressive glioma microenvironment may prove susceptible to approaches that promote an anti-tumor immune response through T cell activation [ 23 – 25 ]. Immunomodulation of the expression of cell surface receptors such as CTLA4, PD-1, and 4-1BB may be capitalized on to thus yield a T cell immune response in order to achieve an anti-tumor response [ 26 – 29 ].…”

Section: Introductionmentioning

confidence: 99%

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Hitting the nail on the head: combining oncolytic adenovirus-mediated virotherapy and immunomodulation for the treatment of glioma

et al. 2017

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Glioblastoma is a highly aggressive malignant brain tumor with a poor prognosis and the median survival 14.6 months. Immunomodulatory proteins and oncolytic viruses represent two treatment approaches that have recently been developed for patients with glioblastoma that could extend patient survival and result in better treatment outcomes for patients with this disease. Together, these approaches could potentially augment the treatment efficacy and strength of these anti-tumor therapies. In addition to oncolytic activities, this combinatory approach introduces immunomodulation locally only where cancerous cells are present. This thereby results in the change of the tumor microenvironment from immune-suppressive to immune-vulnerable via activation of cytotoxic T cells or through the removal of glioma cells immune-suppressive capability. This review discusses the strengths and weaknesses of adenoviral oncolytic therapy, and highlights the genetic modifications that result in more effective and targeted viral agents. Additionally, the mechanism of action of immune-activating agents is described and the results of previous clinical trials utilizing these treatments in other solid tumors are reviewed. The feasibility, synergy, and limitations for treatments that combine these two approaches are outlined and areas for which more work is needed are considered.

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Current State of Immune-Based Therapies for Glioblastoma

Cited by 13 publications

References 41 publications

Small molecules targeting histone demethylase genes (KDMs) inhibit growth of temozolomide-resistant glioblastoma cells

Small molecules targeting histone demethylase genes (KDMs) inhibit growth of temozolomide-resistant glioblastoma cells

Dendritic cell activation enhances anti-PD-1 mediated immunotherapy against glioblastoma

Hitting the nail on the head: combining oncolytic adenovirus-mediated virotherapy and immunomodulation for the treatment of glioma

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