Advances in Immunotherapy for Adult Glioblastoma.
Ontology highlight
ABSTRACT:
SUBMITTER: Chokshi CR
PROVIDER: S-EPMC8305609 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Survival for patients with glioblastoma, the most common high-grade primary CNS tumor, remains poor despite multiple therapeutic interventions including intensifying cytotoxic therapy, targeting dysregulated cell signaling pathways, and blocking angiogenesis. Exciting, durable clinical benefits have recently been demonstrated for a number of other challenging cancers using a variety of immunotherapeutic approaches. Much modern research confirms that the CNS is immunoactive rather than immunoprivileged. Preliminary results of clinical studies demonstrate that varied vaccine strategies have achieved encouraging evidence of clinical benefit for glioblastoma patients, although multiple variables will likely require systematic investigation before optimal outcomes are realized. Initial preclinical studies have also revealed promising results with other immunotherapies including cell-based approaches and immune checkpoint blockade. Clinical studies to evaluate a wide array of immune therapies for malignant glioma patients are being rapidly developed. Important considerations going forward include optimizing response assessment and identifiying correlative biomarkers for predict therapeutic benefit. Finally, the potential of complementary combinatorial immunotherapeutic regimens is highly exciting and warrants expedited investigation.
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Project description:Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults. Patients with GBM have poor outcomes, even with the current gold-standard first-line treatment: maximal safe resection combined with radiotherapy and temozolomide chemotherapy. Accumulating evidence suggests that advances in antigen-specific cancer vaccines and immune checkpoint blockade in other advanced tumors may provide an appealing promise for immunotherapy in glioma. The future of therapy for GBM will likely incorporate a combinatorial, personalized approach, including current conventional treatments, active immunotherapeutics, plus agents targeting immunosuppressive checkpoints.
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Project description:Purpose of reviewThis review seeks to inform oncology clinicians and researchers about the development of novel immunotherapies for the treatment of glioblastoma. An enumeration of ongoing and recently completed clinical trials will be discussed with special attention given to current technologies implemented to overcome central nervous system-specific challenges including barriers to the peripheral immune system, impaired antigen presentation, and T cell dysfunction.Recent findingsThe success of immunotherapy in other solid cancers has served as a catalyst to explore its application in glioblastoma, which has limited response to other treatments. Recent developments include multi-antigen vaccines that seek to overcome the heterogeneity of glioblastoma, as well as immune checkpoint inhibitors, which could amplify the adaptive immune response and may have promise in combinatorial approaches. Additionally, oncolytic and retroviruses have opened the door to a plethora of combinatorial approaches aiming to leverage their immunogenicity and/or ability to carry therapeutic transgenes. Treatment of glioblastoma remains a serious challenge both with regard to immune-based as well as other therapeutic strategies. The disease has proven to be highly resistant to treatment due to a combination of tumor heterogeneity, adaptive expansion of resistant cellular subclones, evasion of immune surveillance, and manipulation of various signaling pathways involved in tumor progression and immune response. Immunotherapeutics that are efficacious in other cancer types have unfortunately not enjoyed the same success in glioblastoma, illustrating the challenging and complex nature of this disease and demonstrating the need for development of multimodal treatment regimens utilizing the synergistic qualities of immune-mediated therapies.
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Project description:Glioblastoma, or glioblastoma multiforme (GBM, WHO Grade IV), is a highly aggressive adult glioma. Despite extensive efforts to improve treatment, the current standard-of-care (SOC) regimen, which consists of maximal resection, radiotherapy, and temozolomide (TMZ), achieves only a 12-15 month survival. The clinical improvements achieved through immunotherapy in several extracranial solid tumors, including non-small-cell lung cancer, melanoma, and non-Hodgkin lymphoma, inspired investigations to pursue various immunotherapeutic interventions in adult glioblastoma patients. Despite some encouraging reports from preclinical and early-stage clinical trials, none of the tested agents have been convincing in Phase III clinical trials. One, but not the only, factor that is accountable for the slow progress is the blood-brain barrier, which prevents most antitumor drugs from reaching the target in appreciable amounts. Herein, we review the current state of immunotherapy in glioblastoma and discuss the significant challenges that prevent advancement. We also provide thoughts on steps that may be taken to remediate these challenges, including the application of ultrasound technologies.
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Project description:Glioblastoma (GBM) is the most aggressive type of brain tumor. Despite the multimodal therapies, the effectiveness of traditional treatments is not much satisfying. In recent years, immunotherapy has become the focus of tumor treatment. Unlike traditional treatments that directly target tumor cells, immunotherapy uses the body's immune system to kill tumors. However, due to the severe immunosuppressive microenvironment of GBM, it generally has a poor response to immunotherapy. In addition, the existence of the blood-brain barrier (BBB) also compromises the immunotherapeutic efficacy. Therefore, effective immunotherapy of GBM requires the therapeutic agents to not only efficiently cross the BBB but also relieve the strong immunosuppression of the tumor microenvironment of GBM. In this review, we will first introduce the CNS immune system, immunosuppressive mechanism of GBM, and current GBM immunotherapy strategies. Then, we will discuss the development of nanomaterials for GBM immunotherapy based on different strategies, roughly divided into four parts: immune checkpoint therapy, targeting tumor-associated immune cells, activating immune cells through immunogenic cell death, and combination therapy, to provide new insights for future GBM immunotherapy.
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Project description:Outcome for glioma (GBM) remains dismal despite advances in therapeutic interventions including chemotherapy, radiotherapy and surgical resection. The overall survival benefit observed with immunotherapies in cancers such as melanoma and prostate cancer has fuelled research into evaluating immunotherapies for GBM.Preclinical studies have brought a wealth of information for improving the prognosis of GBM and multiple clinical studies are evaluating a wide array of immunotherapies for GBM patients. This review highlights advances in the development of immunotherapeutic approaches. We discuss the strategies and outcomes of active and passive immunotherapies for GBM including vaccination strategies, gene therapy, check point blockade and adoptive T cell therapies. We also focus on immunoediting and tumor neoantigens that can impact the efficacy of immunotherapies.Encouraging results have been observed with immunotherapeutic strategies; some clinical trials are reaching phase III. Significant progress has been made in unraveling the molecular and genetic heterogeneity of GBM and its implications to disease prognosis. There is now consensus related to the critical need to incorporate tumor heterogeneity into the design of therapeutic approaches. Recent data also indicates that an efficacious treatment strategy will need to be combinatorial and personalized to the tumor genetic signature.
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Project description:Glioblastoma (GBM) is an aggressive brain tumour, associated with extremely poor prognosis and although there have been therapeutic advances, treatment options remain limited. This review focuses on the use of immunotherapy, harnessing the power of the host's immune system to reject cancer cells. Key challenges in glioma specific immunotherapy as with many other cancers are the limited immunogenicity of the cancer cells and the immunosuppressive environment of the tumour. Although specific antigens have been identified in several cancers; brain tumours, such as GBM, are considered poorly immunogenic. However, as detailed in this review, strategies aimed at circumventing these challenges are showing promise for GBM treatment; including identification of glioma specific antigens and endogenous immune cell activation in an attempt to overcome the immunosuppressive environment which is associated with GBM tumours. An up-to-date summary of current Phase I/II and ongoing Phase III GBM immunotherapy clinical trials is provided in addition to insights into promising preclinical approaches which are focused predominantly on increased induction of Type 1 helper T cell (Th1) immune responses within patients.
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Project description:Glioblastoma (GBM) stands out as the most common, aggressive form of primary malignant brain tumor conferring a devastatingly poor prognosis. Despite aggressive standard-of-care in surgical resection and chemoradiation with temozolomide, the median overall survival of patients still remains no longer than 15 months, due to significant tumor heterogeneity, immunosuppression induced by the tumor immune microenvironment and low mutational burden. Advances in immunotherapeutic approaches have revolutionized the treatment of various cancer types and become conceptually attractive for glioblastoma. In this review, we provide an overview of the basic knowledge underlying immune targeting and promising immunotherapeutic strategies including CAR T cells, oncolytic viruses, cancer vaccines, and checkpoint blockade inhibitors that have been recently investigated in glioblastoma. Current clinical trials and previous clinical trial findings are discussed, shedding light on novel strategies to overcome various limitations and challenges.
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Project description:In recent years, the introduction and Federal Drug Administration approval of immune checkpoint inhibitor antibodies has dramatically improved the clinical outcomes for patients with advanced melanoma. These antagonist monoclonal antibodies are capable of unleashing dormant or exhausted antitumor immunity, which has led to durable complete and partial responses in a large number of patients. Ipilimumab targets the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) receptor. Nivolumab and pembrolizumab target programmed cell death protein 1 (PD-1) receptors and have proven to be superior to ipilimumab alone. The combination of ipilimumab and nivolumab has yielded higher response rates, greater tumor shrinkage, and longer progression-free survival than either monotherapy alone. As other promising immunotherapies for melanoma proceed through clinical trials, future goals include defining the role of immune checkpoint inhibitors as adjuvant therapy, identifying optimal combination strategies, and developing reliable predictive biomarkers to guide treatment selection for individual patients.
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Project description:Paolo A Ascierto obtained his MD from the University of Naples, Italy, where he earned board certification in oncology. He is currently Director at the Unit of Melanoma, Cancer Immunotherapy and Innovative Therapy Unit, National Tumor Institute 'Fondazione G. Pascale', Naples, Italy. Before his present position, he served consecutive positions there as a postdoctoral fellow and then as Vice Director of the Department of Clinical Immunology. His major research interests have included genetics and proteomics research of melanoma, apoptosis and cell death in human cancer and the assessment of molecular markers for tumor progression in melanoma, as well as the management of targeted therapies for melanoma, vaccination treatments and biochemical and immunological monitoring. He has served as a principal investigator in numerous clinical trials and has been widely published in peer-reviewed journals on topics related to his interests. Ascierto has been an invited speaker at more than 200 national and international meetings and is an active member of the Italian Society of Medical Oncology (AIOM), the American Society of Clinical Oncology (ASCO), the European Society of Medical Oncology (ESMO), the European Organisation for Research and Treatment of Cancer (EORTC) and the International Society for Biological Therapy of Cancer (iSBTc). He is also the Editor-in-Chief of the Combination Strategies section of the Journal of Translational Medicine and serves as a scientific reviewer for several journals. James Larkin is a consultant medical oncologist specializing in the treatment of patients with cancer of the kidney and cancers of the skin, including melanoma. Larkin obtained a first-class degree in Natural Sciences from Cambridge University and undertook clinical training at Oxford University, qualifying in 1996. He underwent general medical training in London and, in 2001, won a Medical Research Council Fellowship for a Clinician, carrying out laboratory research at the Institute of Cancer Research (ICR), which led to the awarding of his PhD. He completed specialist training at The Royal Marsden Hospital and was appointed as a consultant in 2008. His research interests include the individualization of patient treatment in renal cancer and melanoma and the combination of novel targeted therapies for the treatment these diseases. He is the UK Chief Investigator for a number of clinical trials in melanoma and kidney cancer and has been awarded research grants from bodies including Cancer Research UK, the Wellcome Trust and the European Framework Programme 7. He is a member of the National Cancer Research Institute (NCRI) Melanoma Clinical Studies Group and Chair of both the NCRI Renal Cancer Clinical Studies Group and The Royal Marsden/ICR Committee for Clinical Research.
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