Programmed death ligand 1 expression and tumor-infiltrating lymphocytes in glioblastoma

Berghoff, Anna Sophie; Kiesel, Barbara; Widhalm, Georg; Rajky, Orsolya; Ricken, Gerda; Wöhrer, Adelheid; Dieckmann, Karin; Filipits, Martin; Brandstetter, Anita; Weller, Michael; Kurscheid, Sebastian; Hegi, Monika E.; Zielinski, Christoph; Marosi, Christine; Hainfellner, Johannes A.; Wick, Wolfgang

doi:10.1093/neuonc/nou307

Cited by 487 publications

(525 citation statements)

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“…Furthermore, PD-L1 expression level in the tumor tissue was positively associated with the likelihood of clinical benefit with PD-1 inhibitor in nonsmall-cell lung cancer as well as other tumor types (132,133). A recent study showed robust and diffuse expression of PD-L1 assessed by immunohistochemistry in newlydiagnosed as well as recurrent GBM (88% vs. 72.2%, respectively), which is a relatively high percentage compared to other cancer types such as melanoma (134). Higher expression of PD-L1 in tumor tissue correlated with worse outcome in another study with 94 patients with GBM (135).…”

Section: The Role Of Immune Checkpoint Inhibitors In Glioblastoma Immmentioning

confidence: 99%

Advances in Experimental Targeted Therapy and Immunotherapy for Patients with Glioblastoma Multiforme

et al. 2017

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Abstract. Glioblastoma multiforme (GBM) represents the most malignant primary brain tumor in adults with generally dismal prognosis, early clinical deterioration and high mortality. GBM is extremely invasive, characterized by intense and aberrant vascularization and high resistance to multimodal treatment. Standard therapy (surgery, radiotherapy and chemotherapy with temozolomide) has very limited effectiveness, with median overall survival of patients no longer than 15 months. Progress in genetics and epigenetics of GBM over the past decade has revealed various aberrations in cellular signaling pathways, the tumor microenvironment, and pathological angiogenesis. A number of targeted anticancer drugs, such as small-molecule kinase inhibitors and monoclonal antibodies, have been evaluated in clinical trials with newly-diagnosed, as well as recurrent GBM. Unfortunately, to date, only a single antiangiogenic agent, bevacizumab, has been approved for the treatment of recurrent GBM in the USA and Canada. The novel possibilities of cancer immunotherapy, especially immune checkpoint inhibitors, are being evaluated in clinical trials of patients with GBM. The most recent clinical experiences with targeted therapy as well as immunotherapy of GBM are given in this review. The relative lack of success of some of these approaches recently revealed in well-designed randomized clinical trials is also discussed.Glioblastoma multiforme (GBM) belongs to the largest group of primary central nervous system (CNS) tumors, so-called gliomas, which are formed from supporting glial cells in the brain parenchyma (1, 2). GBM represents the most common and most malignant tumor in this class, with an incidence of 3-4/100,000/year (3, 4). GBM is an extremely invasive and difficult to treat tumor, characterized by intense and aberrant vascularization and high resistance to radiotherapy (RT) and chemotherapy (CHT). The current standard of care for patients with newly-diagnosed GBM comprises of neurosurgery and subsequent concomitant chemoradiotherapy by fractionated external-beam RT and systemic temozolomide followed by systemic temozolomide in the adjuvant setting (5). There are only very limited possibilities for the treatment of subsequent recurrences, generally with minimal clinical efficacy (6). Despite intensive multimodal treatment strategies, the median survival of patients with GBM is still 12.1-14.6 months and only 3-5% of patients survive longer than 3 years (7).Enormous progress has been made in the genetics and epigenetics of GBM during the past decade. The Cancer 21Τhis article is freely accessible online.Correspondence to: Jiri Polivka, Department of Neurology, Faculty Hospital Plzen, alej Svobody 80, 304 60, Plzen, Czech Republic. E-mail: polivka@fnplzen.cz Key Words: Glioblastoma multiforme, GBM, targeted therapy, immunotherapy, immune checkpoint inhibitors, PD1 inhibition, CTLA4 inhibition, clinical trials, personalized medicine, review. ANTICANCER RESEARCH 37: 21-34 (2017) [8][9][10][11][12]. The most important genetic...

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Section: The Role Of Immune Checkpoint Inhibitors In Glioblastoma Immmentioning

confidence: 99%

Advances in Experimental Targeted Therapy and Immunotherapy for Patients with Glioblastoma Multiforme

et al. 2017

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“…18,19 Gliomas have been shown to employ a variety of mechanisms to suppress the immune system, such as downregulation of MHC class I molecules, production of transforming growth factor-b (TGF-b), vascular endothelial growth factor (VEGF), prostaglandin E2, and IL-10, expression of ligands of checkpoint receptors, such as PD-1, and accumulation of immunosuppressive cells, such as myeloidderived suppressor cells (MDSCs), regulatory T cells (Tregs), and tumor-associated macrophages (TAMs). [23][24][25][26][27][28][29][30] It has been previously shown in human samples and experimental GBM models that MDSCs are powerful inhibitors of anti-tumor immune responses. 30,31 Through a variety of mechanisms that inhibit T cell activation and expansion, including the production of arginase and inducible nitric oxide synthase (iNOS), reactive oxygen species and/or reactive nitrogen species (ROS and/or RNS), release of IL-10, expansion of regulatory T cells (Tregs), and inhibition of T cell migration, MDSCs have been shown to promote immunosuppression and tumor progression.…”

Section: Malignant Brain Tumors (Gliomasmentioning

confidence: 99%

“…Circulating monocytes from GBM patients express high levels of PDL1 ( Figure 6A). 23,51 Since our data showed that MDSC depletion enhanced the quantity and quality of anti-GBM T cell response, we assessed whether MDSCs from GBM-bearing mice expressed the ligands for CTLA-4 and PD-1. We analyzed the expression of PDL1 and CD80 on tumor-infiltrating and splenic MDSCs.…”

Section: Depletion Of Mdscs Enhances the Tk/flt3l-induced Anti-gbm CDmentioning

confidence: 99%

Immunosuppressive Myeloid Cells’ Blockade in the Glioma Microenvironment Enhances the Efficacy of Immune-Stimulatory Gene Therapy

et al. 2017

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Survival of glioma (GBM) patients treated with the current standard of care remains dismal. Immunotherapeutic approaches that harness the cytotoxic and memory potential of the host immune system have shown great benefit in other cancers. GBMs have developed multiple strategies, including the accumulation of myeloid-derived suppressor cells (MDSCs) to induce immunosuppression. It is therefore imperative to develop multipronged approaches when aiming to generate a robust anti-tumor immune response. Herein, we tested whether combining MDSC depletion or checkpoint blockade would augment the efficacy of immune-stimulatory herpes simplex type-I thymidine kinase (TK) plus Fms-like tyrosine kinase ligand (Flt3L)-mediated immune stimulatory gene therapy. Our results show that MDSCs constitute >40% of the tumorinfiltrating immune cells. These cells express IL-4Ra, inducible nitric oxide synthase (iNOS), arginase, programmed death ligand 1 (PDL1), and CD80, molecules that are critically involved in antigen-specific T cell suppression. Depletion of MDSCs strongly enhanced the TK/Flt3L gene therapy-induced tumor-specific CD8 T cell response, which lead to increased median survival and percentage of long-term survivors. Also, combining PDL1 or CTLA-4 immune checkpoint blockade greatly improved the efficacy of TK/Flt3L gene therapy. Our results, therefore, indicate that blocking MDSC-mediated immunosuppression holds great promise for increasing the efficacy of gene therapy-mediated immunotherapies for GBM.

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“…A non-randomized Phase II trial investigated the efficacy of Pembrolizumab for patients with untreated melanoma or non-small cell lung cancer (NSCLC) brain metastasis revealed durable responses in 4 of 18 patients with melanoma and 6 of 18 patients with NSCLC [136]. Given recent data demonstrating PD-1 expression upon tumor-infiltrating lymphocytes, recent clinical trials determining the efficacy of anti-PD-1 or anti-PD-L1 therapy in primary brain tumors are under investigation [137,138]. A phase III trial comparing Nivolumab with bevacizumab and Nivolumab with or without Ipilimumab is currently recruiting patients although a small safety lead-in revealed an overall survival at 6 months of 70% (NCT02017717; Checkmate 143).…”

Section: Immune Checkpoint Therapymentioning

confidence: 99%

Immunotherapy for Glioblastoma

Theodros¹,

Moran²,

Garzón-Muvdi³

et al. 2016

J Clin Cell Immunol

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Glioblastoma (GBM) is the most common primary malignant brain cancer with a dismal prognosis in spite of aggressive treatment options. Although once thought to be an "immune-privileged" site, recent advances have begun to highlight the complex interaction between the immune system and the central nervous system. Thus, great interest has emerged in the ability of immunotherapy to potentially prolong the survival of patients suffering from GBM. Indeed, numerous clinical trials have demonstrated durable responses in late stage disease, as well as, among patients with brain metastasis. A variety of approaches to modulating the immune system exist and their efficacy are currently being investigated in various clinical trials. Here we provide a brief overview of neuroimmunology and explore the various approaches towards priming the immune system against GBM.

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Programmed death ligand 1 expression and tumor-infiltrating lymphocytes in glioblastoma

Abstract: TILs and PD-L1 expression are detectable in the majority of glioblastoma samples but are not related to outcome. Because the target is present, a clinical study with specific immune checkpoint inhibitors seems to be warranted in glioblastoma.

Cited by 487 publications

References 50 publications

Advances in Experimental Targeted Therapy and Immunotherapy for Patients with Glioblastoma Multiforme

Advances in Experimental Targeted Therapy and Immunotherapy for Patients with Glioblastoma Multiforme

Immunosuppressive Myeloid Cells’ Blockade in the Glioma Microenvironment Enhances the Efficacy of Immune-Stimulatory Gene Therapy

Immunotherapy for Glioblastoma

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