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PD-1/PD-L1 immune checkpoint inhibitors in glioblastoma: clinical studies, challenges and potential.

ABSTRACT: Immune checkpoint inhibitors (CIs) have changed the landscape of tumor immunotherapy. Glioblastoma (GBM) remains the most common primary malignant brain tumor in adults and has a very poor prognosis. Due to the high invasiveness and aggressiveness of GBM, there is considerable interest in programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) treatment. However, the immunosuppressive and immune-privileged characteristics of GBM limit the efficacy of CIs. While clinical studies of CI monotherapies have shown unsatisfactory survival benefits, new treatment strategies have received attention. Multiple clinical studies have focused on combination of standard therapy (temozolomide, radiotherapy), targeted therapy and other immunotherapies, and some have reported results. Here, we reviewed recent clinical trials of anti-PD-1/PD-L1 monotherapy, studies with neoadjuvant strategies, and preclinical and clinical studies of combination immunotherapies for GBM. The preliminary clinical reports in certain subsets of patients with hypermutated or mismatch repair system deficiency GBM are also discussed.

SUBMITTER: Yang T

PROVIDER: S-EPMC7899692 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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PD-1/PD-L1 immune checkpoint inhibitors in glioblastoma: clinical studies, challenges and potential.

Yang Tianrui T Kong Ziren Z Ma Wenbin W

Human vaccines & immunotherapeutics 20200709 2

Immune checkpoint inhibitors (CIs) have changed the landscape of tumor immunotherapy. Glioblastoma (GBM) remains the most common primary malignant brain tumor in adults and has a very poor prognosis. Due to the high invasiveness and aggressiveness of GBM, there is considerable interest in programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) treatment. However, the immunosuppressive and immune-privileged characteristics of GBM limit the efficacy of CIs. While clinical studies of ...[more]

PMID: 32643507

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Project description:PurposeBlocking the interaction between the programmed cell death (PD)-1 protein and one of its ligands, PD-L1, has been reported to have impressive antitumor responses. Therapeutics targeting this pathway are currently in clinical trials. Pembrolizumab and nivolumab are the first of this anti-PD-1 pathway family of checkpoint inhibitors to gain accelerated approval from the US Food and Drug Administration (FDA) for the treatment of ipilimumab-refractory melanoma. Nivolumab has been associated with improved overall survival compared with dacarbazine in patients with previously untreated wild-type serine/threonine-protein kinase B-raf proto-oncogene BRAF melanoma. Although the most mature data are in the treatment of melanoma, the FDA has granted approval of nivolumab for squamous cell lung cancer and the breakthrough therapy designation to immune- checkpoint inhibitors for use in other cancers: nivolumab, an anti-PD-1 monoclonal antibody, for Hodgkin lymphoma, and MPDL-3280A, an anti-PD-L1 monoclonal antibody, for bladder cancer and non-small cell lung cancer. Here we review the literature on PD-1 and PD-L1 blockade and focus on the reported clinical studies that have included patients with melanoma.MethodsPubMed was searched to identify relevant clinical studies of PD-1/PD-L1-targeted therapies in melanoma. A review of data from the current trials on clinicaltrial.gov was incorporated, as well as data presented in abstracts at the 2014 annual meeting of the American Society of Clinical Oncology, given the limited number of published clinical trials on this topic.FindingsThe anti-PD-1 and anti-PD-L1 agents have been reported to have impressive antitumor effects in several malignancies, including melanoma. The greatest clinical activity in unselected patients has been seen in melanoma. Tumor expression of PD-L1 is a suggestive, but inadequate, biomarker predictive of response to immune-checkpoint blockade. However, tumors expressing little or no PD-L1 are less likely to respond to PD-1 pathway blockade. Combination checkpoint blockade with PD-1 plus cytotoxic T-lymphocyte antigen (CTLA)-4 blockade appears to improve response rates in patients who are less likely to respond to single-checkpoint blockade. Toxicity with PD-1 blocking agents is less than the toxicity with previous immunotherapies (eg, interleukin 2, CTLA-4 blockade). Certain adverse events can be severe and potentially life threatening, but most can be prevented or reversed with close monitoring and appropriate management.ImplicationsThis family of immune-checkpoint inhibitors benefits not only patients with metastatic melanoma but also those with historically less responsive tumor types. Although a subset of patients responds to single-agent blockade, the initial trial of checkpoint-inhibitor combinations has reported a potential to improve response rates. Combination therapies appear to be a means of increasing response rates, albeit with increased immune-related adverse events. As these treatments become available to patients, education regarding the recognition and management of immune-related effects of immune-checkpoint blockade will be essential for maximizing clinical benefit.

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PD-1/PD-L1 immune checkpoint inhibitors in glioblastoma: clinical studies, challenges and potential.

Publications

PD-1/PD-L1 immune checkpoint inhibitors in glioblastoma: clinical studies, challenges and potential.

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