Immunosuppression In Glioblastoma Research Articles

Phase 2 study to evaluate the clinical efficacy and safety of MEDI4736 (durvalumab) in patients with glioblastoma (GBM).

TPS2080Background: Outcome among newly diagnosed and recurrent GBM patients remains poor, and novel therapeutic approaches are needed. Blockade of Programmed death-1 (PD-1) and PD-ligand 1 (PD-L1) has shown promising clinical benefit among solid tumors, and data implicate PD-1/PD-L1 signaling as a significant contributor to immunosuppression in GBM. Specifically, PD-1 is expressed by many GBM infiltrating lymphocytes, PD-L1 is expressed by 61-100% of GBM tumors, and loss of the PTEN tumor suppressor gene, occurring in 40-50% of GBM tumors, leads to increased transcription and expression of PD-L1. Durvalumab (DUR) is a human IgG1 mAb against PD-L1. Bevacizumab (BEV) is a mAb against VEGF, and data suggest that VEGF inhibition may enhance the antitumor benefit of immunotherapies. Methods: This ongoing Phase 2, multicenter, open-label study (NCT02336165) is designed to evaluate the clinical efficacy and safety of DUR (10 mg/kg i.v. Q2W for 12 months) in 5 cohorts of newly diagnosed and recurrent GBM patients...

Abstract A046: Phase 2 study to evaluate the clinical efficacy and safety of MEDI4736 in patients with glioblastoma (GBM)

Abstract Background: Programmed cell death ligand-1 (PD-L1) is widely expressed on antigen presenting cells (APC) and other immune cells. PD-L1 binds two important regulatory receptors on T-cells: programmed cell death-1 (PD-1) and CD80/B7. Targeting Programmed Death-1 (PD-1) and its ligand, PD-L1, have demonstrated promising anti-tumor activity among other challenging solid tumors and growing data implicates PD-1/PD-L1 signaling as a significant contributor to immunosuppression in glioblastoma (GBM). PD-1 is expressed by many GBM infiltrating lymphocytes while PD-L1 is expressed by 61-100% of GBM tumors. Furthermore, loss of the PTEN tumor suppressor gene, which occurs in 40-50% of GBM tumors, leads to increased transcription and expression of PD-L1 in GBM. These findings indicate that PD-L1 is an attractive and important therapeutic target in GBM. MEDI4736 (M), a human IgG1κ blocking monoclonal antibody against PD-L1, represents a compelling immune-mediated anti-tumor treatment for GBM. Methods: Phase 2, multicenter, open-label study (NCT02336165) is evaluating the clinical efficacy and safety of M in GBM patients. Eligible patients include those who are newly diagnosed with unmethylated MGMT GBM scheduled for standard radiotherapy (Cohort A); Bevacizumab-naïve patients with recurrent GBM (Cohort B); and Bevacizumab-refractory patients with recurrent GBM (Cohort C). Cohort A patients will receive M at 10 mg/kg i.v. Q2W for up to 12 months beginning with standard radiotherapy. Cohort B will receive M at 10 mg/kg i.v. Q2W for up to 12 months as monotherapy. Cohort C will receive M at 10 mg/kg i.v. Q2W for up to 12 months in combination with continued bevacizumab at 10 mg/kg Q2W. Primary endpoints include overall survival (OS) at 12 months (cohort A), progression free survival rate at 6 months (PFS-6) (cohort B) and OS-6 (cohort C). Secondary endpoints are safety/tolerability, PFS, median OS, radiographic response, and quality of life (QoL) by EORTC QLQ-C30/BN20. Exploratory endpoints are patient neurologic function using the Neurologic Assessment in Neuro-Oncology (NANO) scale, as well as immuno-correlative biomarkers and pharmacokinetics. Cohort A represents the first time MEDI4736 is being given in combination with radiation, so a 3+3 subject safety run-in is required by protocol. Subjects must clear a 10 week DLT observation period before enrollment opens to the remainder of the cohort. If 2 or more DLTs are noted within the first 6 patients, then the MEDI4736 dose will be de-escalated. Cohort C represents the first time MEDI4736 is being given in combination with bevacizumab, so a 3+3 subject safety run-in period similar to that for Cohort A is also required, but with a 6 week DLT observation period. Study Status: All cohorts opened to enrollment in March 2015 with Cohorts A and C currently limited by the subject safety run-in period. As of 10 June 2015, the numbers of subjects enrolled by cohort are: Cohort A = 2, Cohort B = 26, Cohort C = 3. No DLTs have been reported, and clinical efficacy and safety data collection are ongoing. Citation Format: David A. Reardon, Jorg Dietrich, Thomas Kaley, Hui Gan, Gavin P. Dunn, Timothy Cloughesy, Michael Lim, Jennifer Clarke, Andrew Park, Linda Pan, Domenic W. Lai, Joyson Karakunnel, Paul Robbins, Rajesh Narwal, Ralph Venhaus. Phase 2 study to evaluate the clinical efficacy and safety of MEDI4736 in patients with glioblastoma (GBM). [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A046.

Immunosuppressive mechanisms in glioblastoma.

Despite maximal surgical and medical therapy, the treatment of glioblastoma remains a seriously vexing problem, with median survival well under 2 years and few long-term survivors. Targeted therapy has yet to produce significant advances in treatment of these lesions in spite of advanced molecular characterization of glioblastoma and glioblastoma cancer stem cells. Recently, immunotherapy has emerged as a promising mode for some of the hardest to treat tumors, including metastatic melanoma. Although immunotherapy has been evaluated in glioblastoma in the past with limited success, better understanding of the failures of these therapies could lead to more successful treatments in the future. Furthermore, there is a persistent challenge for the use of immune therapy to treat glioblastoma secondary to the existence of redundant mechanisms of tumor-mediated immune suppression. Here we will address these mechanisms of immunosuppression in glioblastoma and therapeutic approaches.

ME-15 * INTERACTION BETWEEN CANCER STEM CELLS AND MYELOID DERIVED SUPPRESSOR CELLS DRIVES IMMUNOSUPPRESSION AND GLIOBLASTOMA GROWTH

Cellular and molecular regulation of the immune system is exquisitely controlled in the brain and disrupted in neoplasia. Glioblastoma (GBM) has an immunosuppressive phenotype, and despite the accumulation of immune cells in the tumor microenvironment, tumor growth persists. Myeloid derived suppressor cells (MDSCs) are a class of immature immune cells that mitigate cytotoxic T cell responses and promote immunosuppression in a variety of cancers. MDSCs are increased in the peripheral blood of GBM patients, but their role in the GBM microenvironment is undefined. We observed co-localization between arginase (Arg1) producing immunosuppressive MDSCs and cancer stem cells (CSCs) in GBM patient specimens and xenografts, leading to the hypothesis that CSCs stimulate MDSCs to promote immunosuppression. Intracranial injections of CSCs into mice led to GBM formation, expansion of the Arg1-producing MDSCs within the marrow of GBM-bearing mice, and increased levels of MDSCs within the GBM microenvironment. CSC conditioned media increased Arg1 production of murine marrow MDSCs which were then able to modulate cytotoxic T cell responses in co-culture models. Screening of conditioned media revealed cytokines secreted selectively by CSCs that activated MDSCs suppression. Removal of CSC-secreted factors decreased MDSCs in the GBM microenvironment, increased cytotoxic T cell infiltration, and had a pronounced survival benefit. Peripheral targeting of MDSCs through a sub-therapeutic dose of 5-fluorouracil (5-FU) in an immunocompetent syngeneic mouse model led to a similar phenotype to CSC-secreted factor removal in the GBM microenvironment, and an even greater survival benefit. Taken together, our results suggest a critical role of MDSC-mediated immunosuppression in GBM, a novel paradigm of immunomodulation by CSCs, and demonstrate that peripheral removal of MDSCs leads to increased T cell infiltration into GBM, and consequently suggest a novel chemotherapeutic strategy that is not generally toxic to bone marrow and that is not dependent on agents crossing the blood brain barrier.

Highlights of This Issue

Immunosuppression in glioblastoma is a critical barrier to effective immunotherapy. Wainwright and colleagues found that overexpression of indoleamine 2,3 dioxygenase (IDO) in glioma was associated with a decreased lifespan in patients. Using orthotopic and transgenic models of glioma, as well as shRNA-mediated knockdown, they then showed that glioma-derived IDO expression led to increased tumor-infiltrating regulatory T cells (Treg) and decreased overall survival. In contrast, IDO inhibition led to decreased Treg levels and increased longterm survival. This study provides a strong rationale for further analysis of IDO in the context of malignant glioma, with a new focus on therapeutic inhibition.The vast majority of human surgical samples are stored as formalin-fixed, paraffin-embedded (FFPE) blocks, with more than 20 million archived annually in the United States. Although this represents a tremendous resource for disease research, RNA degradation has limited their use for transcriptional profiling. Waldron and colleagues analyzed gene expression in more than 1,000 FFPE samples from long-term multicenter studies of breast and colorectal cancer, together with a meta-analysis including 12 additional datasets. They introduce quality control protocols that improve discovery of reproducible biomarkers, an essential step forward in realizing the potential of clinical FFPE tissues for genomic analysis.The miRNA regulatory network is emerging as a novel target for the treatment of human cancer. To explore the potential of miR-34a against human multiple myeloma, Di Martino and colleagues evaluated the therapeutic activity triggered by miR-34a mimics. The translational relevance of the study resides in the finding that systemic delivery of novel lipidic-formulated miR-34a exerts antimyeloma activity in different clinically relevant murine models of human multiple myeloma, without toxicity. The specificity of miR-34a activity was shown by downregulation of canonical targets BCL2 and CDK6. These findings provide a framework for clinical development of formulated miR-34a mimics in multiple myeloma.The treatment of cancer with oncolytic viruses primarily depends on the selective viral replication in cancer cells. However, a replication-incompetent Sendai virus (HVJ) envelope (HVJ-E) showed effective oncolytic activities without producing toxic effects in nonmalignant cells. Matsushima-Miyagi and colleagues elucidated the mechanism for cancer cell–selective apoptosis induced by HVJ-E. The viral RNA fragments derived from HVJ-E upregulated TRAIL and Noxa selectively in cancer cells, but not in noncancerous cells, through the RIG-I/MAVS signaling pathway. The orthotopic prostate cancers were dramatically eradicated in immunodeficient NOD–SCID mice injected with HVJ-E. Thus, the RIG-I/MAVS signaling pathway represents an attractive target for cancer therapy.

Abstract 5303: Systemic immunosuppression in glioblastoma: the interplay between lymphopenia, CD14+HLA-DRlo/neg monocytes, tumor factors, and dexamethasone

Abstract Patients with glioblastoma (GBM) exhibit profound systemic immune defects that affect the success of traditional and immune-based treatments. A better understanding of the contribution of the tumor and therapy on systemic and local immune suppression is necessary to improve immune based therapies and monitor the effects of conventional and novel therapies. To identify possible sources of immunosuppression, we measured the constituents of circulating immunity in newly diagnosed and recurrent GBM patients with or without dexamethasone treatment. We identified dexamethasone dependent and independent changes in systemic immunity associated with GBM. Of note, we identified a profound lymphopenia associated with dexamethasone treatement that manifested itself in the T cell compartment with targeted effects on the CD4+ T cells. In addition, we identified tumor and dexamethasone dependent altered monocyte phenotypes. The major population of altered monocytes (CD14+HLA-DRlo/neg) inhibited T cell proliferation, was unable to fully differentiate into mature dendritic cells, was associated with dexamethasone-mediated changes in CCL2 levels, and could be re-created in vitro using tumor supernatants. Interestingly, CD14+HLA-DRlo/neg monocytes were elevated similarly in newly diagnosed and recurrent patients. These data demonstrate that both tumor and steroids contribute to systemic immunosuppression. We provide evidence that tumors express high levels of the monocyte recruitment chemokine CCL2, can contain high numbers of CD14+ cells, that tumor supernatants can transform CD14+HLA-DR+ cells into CD14+HLA-DRlo/neg immune suppressors, and that dexamethasone reduces CCL2 in vitro and is correlated with reduction of CCL2 in vivo. Consequently, we have developed a model for tumor mediated systemic immune suppression via recruitment and transformation of CD14+ cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5303.