PD-L1 expression and prognostic impact in glioblastoma

Nduom, Edjah K.; Wei, Jun; Yaghi, Nasser K.; Huang, Neal; Kong, Ling Yuan; Gabrusiewicz, Konrad; Ling, Xiaoyang; Zhou, Shouhao; Ivan, Cristina; Chen, Jie Qing; Burks, Jared K.; Fuller, Gregory N.; Calin, George A.; Conrad, Charles A.; Creasy, Caitlin; Ritthipichai, Krit; Radvanyi, Laszlo G.; Heimberger, Amy B.

doi:10.1093/neuonc/nov172

Cited by 483 publications

(418 citation statements)

References 44 publications

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“…A recent smaller study of 94 GB tumors showed PD-L1 positive staining in greater than 60 % of tumors, but most with a small percentage of cell surface expression. Expression of PD1 and PD-L1 in this study was found to be a negative prognostic factor for survival [28].…”

Section: Clinical Datasupporting

confidence: 53%

Pembrolizumab: first experience with recurrent primary central nervous system (CNS) tumors

et al. 2016

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Patients with progressive primary brain tumors (PBT) are attracted to promising new treatments, even prior to convincing data. Anti-PD1 immunotherapies have been in the spotlight since publication of groundbreaking results for metastatic melanoma with pembrolizumab (PBL). Our objective was to report on the response and toxicity of PBL in patients with advanced PBT. We retrospectively reviewed the charts of 22 patients (17 adults and 5 children) with recurrent central nervous system tumors treated with PBL. We analyzed prior antineoplastic therapies, steroid usage, and outcomes. Patients received a median of two neoplastic therapies prior to PBL, and a median of three infusions of PBL in adults and four in children. Twelve patients (9 adults and 3 children) started PBL on steroids (median dose in adults 4 mg; range 2-8, and in children 1.5 mg, range 0.5-4) and five patients received steroids later during PBL treatment. Twelve patients (10 adults and 2 children) received concomitant bevacizumab with PBL. Side effects were minimal. All patients showed progressive tumor growth during therapy. Median OS from the start of PBL was 2.6 months in adults and 3.2 months in children. Two GB patients underwent tumor resection following treatment with PBL. Tumor-lymphocytic response in these cases was unremarkable, and PD-L1 immuno-staining was negative. In this series of 22 patients with recurrent primary brain tumors, PBL showed no clinical or histologic efficacy. We do not recommend further use of PBL for recurrent PBT unless convincing prospective clinical trial data are published.

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Section: Clinical Datasupporting

confidence: 53%

Pembrolizumab: first experience with recurrent primary central nervous system (CNS) tumors

et al. 2016

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“…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). Because of the promising pre-clinical experiments, proven activity in the CNS and the presence of targets in GBM tumor tissue, clinical trials with specific immune checkpoint inhibitors are warranted in patients with GBM in newly diagnosed as well as recurrent settings.…”

Section: The Role Of Immune Checkpoint Inhibitors In Glioblastoma Immmentioning

confidence: 94%

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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“…Drugs targeting PD-1 or PD-L1 are now also being investigated in the context of primary brain tumors, mainly glioblastoma, in which these molecules are frequently expressed [44,45]. A phase III trial comparing the PD-1 antibody nivolumab with bevacizumab in patients with recurrent glioblastoma has completed accrual (NCT02017717).…”

Section: Immune Checkpoint Inhibitorsmentioning

confidence: 99%

Immunotherapy of Brain Cancer

2016

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The brain has long been considered an immune-privileged site precluding potent immune responses. Nevertheless, because of the failure of conventional anti-cancer treatments to achieve sustained control of intracranial neoplasms, immunotherapy has been considered as a promising strategy for decades. However, several efforts aimed at exploiting the immune system as a therapeutic weapon were largely unsuccessful. The situation only changed with the introduction of the checkpoint inhibitors, which target immune cell receptors that interfere with the activation of immune effector cells. Following the observation of striking effects of drugs that target CTLA-4 or PD-1 against melanoma and other tumor entities, it was recognized that these drugs may also be active against metastatic tumor lesions in the brain. Their therapeutic activity against primary brain tumors is currently being investigated within clinical trials. In parallel, other immunotherapeutics such as peptide vaccines are at an advanced stage of clinical development. Further immunotherapeutic strategies currently under investigation comprise adoptive immune cell transfer as well as inhibitors of metabolic pathways involved in the local immunosuppression frequently found in brain tumors. Thus, the ongoing implementation of immunotherapeutic concepts into clinical routine may represent a powerful addition to the therapeutic arsenal against various brain tumors.

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PD-L1 expression and prognostic impact in glioblastoma

Abstract: The incidence of PD-L1 expression in GBM patients is frequent but is confined to a minority subpopulation, similar to other malignancies that have been profiled for PD-L1 expression. Higher expression of PD-L1 is correlated with worse outcome.

Cited by 483 publications

References 44 publications

Pembrolizumab: first experience with recurrent primary central nervous system (CNS) tumors

Pembrolizumab: first experience with recurrent primary central nervous system (CNS) tumors

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

Immunotherapy of Brain Cancer

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