Emerging immunotherapies for malignant glioma: from immunogenomics to cell therapy.
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ABSTRACT:
SUBMITTER: Dunn GP
PROVIDER: S-EPMC7686464 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Glioblastoma multiforme (GBM) is a highly malignant primary brain cancer with a dreadful overall survival and for which treatment options are limited. Recent breakthroughs in novel immune-related treatment strategies for cancer have spurred interests in usurping the power of the patient's immune system to recognize and eliminate GBM. Here, we discuss the unique properties of GBM's tumor microenvironment, the effects of GBM standard on care therapy on tumor-associated immune cells, and review several approaches aimed at therapeutically targeting the immune system for GBM treatment. We believe that a comprehensive understanding of the intricate micro-environmental landscape of GBM will abound into the development of novel immunotherapy strategies for GBM patients.
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Project description:Glioblastoma multiforme (GBM) is the most frequent and devastating primary brain tumor in adults. Despite current treatment modalities, such as surgical resection followed by chemotherapy and radiotherapy, only modest improvements in median survival have been achieved. Frequent recurrence and invasiveness of GBM are likely due to the resistance of glioma stem cells to conventional treatments; therefore, novel alternative treatment strategies are desperately needed. Recent advancements in molecular biology and gene technology have provided attractive novel treatment possibilities for patients with GBM. Gene therapy is defined as a technology that aims to modify the genetic complement of cells to obtain therapeutic benefit. To date, gene therapy for the treatment of GBM has demonstrated anti-tumor efficacy in pre-clinical studies and promising safety profiles in clinical studies. However, while this approach is obviously promising, concerns still exist regarding issues associated with transduction efficiency, viral delivery, the pathologic response of the brain, and treatment efficacy. Tumor development and progression involve alterations in a wide spectrum of genes, therefore a variety of gene therapy approaches for GBM have been proposed. Improved viral vectors are being evaluated, and the potential use of gene therapy alone or in synergy with other treatments against GBM are being studied. In this review, we will discuss the most commonly studied gene therapy approaches for the treatment of GBM in preclinical and clinical studies including: prodrug/suicide gene therapy; oncolytic gene therapy; cytokine mediated gene therapy; and tumor suppressor gene therapy. In addition, we review the principles and mechanisms of current gene therapy strategies as well as advantages and disadvantages of each.
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Project description:Diffuse midline glioma (DMG) is an incurable malignancy with the highest mortality rate among pediatric brain tumors. While radiotherapy and chemotherapy are the most common treatments, these modalities have limited promise. Due to their diffuse nature in critical areas of the brain, the prognosis of DMG remains dismal. DMGs are characterized by unique phenotypic heterogeneity and histological features. Mutations of H3K27M, TP53, and ACVR1 drive DMG tumorigenesis. Histological artifacts include pseudopalisading necrosis and vascular endothelial proliferation. Mouse models that recapitulate human DMG have been used to study key driver mutations and the tumor microenvironment. DMG consists of a largely immunologically cold tumor microenvironment that lacks immune cell infiltration, immunosuppressive factors, and immune surveillance. While tumor-associated macrophages are the most abundant immune cell population, there is reduced T lymphocyte infiltration. Immunotherapies can stimulate the immune system to find, attack, and eliminate cancer cells. However, it is critical to understand the immune microenvironment of DMG before designing immunotherapies since differences in the microenvironment influence treatment efficacy. To this end, our review aims to overview the immune microenvironment of DMG, discuss emerging insights about the immune landscape that drives disease pathophysiology, and present recent findings and new opportunities for therapeutic discovery.
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Project description:IntroductionImmunotherapy for brain cancer has evolved dramatically over the past decade, owed in part to our improved understanding of how the immune system interacts with tumors residing within the central nervous system (CNS). Glioblastoma (GBM), the most common primary malignant brain tumor in adults, carries a poor prognosis (<15 months) and only few advances have been made since the FDA's approval of temozolomide (TMZ) in 2005. Importantly, several immunotherapies have now entered patient trials based on promising preclinical data, and recent studies have shed light on how GBM employs a slew of immunosuppressive mechanisms that may be targeted for therapeutic gain. Altogether, accumulating evidence suggests immunotherapy may soon earn its keep as a mainstay of clinical management for GBM.Areas coveredHere, we review cancer vaccines, checkpoint inhibitors, adoptive T-cell immunotherapy, and oncolytic virotherapy.Expert opinionCheckpoint blockade induces antitumor activity by preventing negative regulation of T-cell activation. This platform, however, depends on an existing frequency of tumor-reactive T cells. GBM tumors are exceptionally equipped to prevent this, occupying low levels of antigen expression and elaborate mechanisms of immunosuppression. Therefore, checkpoint blockade may be most effective when used in combination with a DC vaccine or adoptively transferred tumor-specific T cells generated ex vivo. Both approaches have been shown to induce endogenous immune responses against tumor antigens, providing a rationale for use with checkpoint blockade where both primary and secondary responses may be potentiated.
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Project description:Although new passive and active immunotherapy methods are emerging, unconjugated monoclonal antibodies remain the only kind of biological preparations approved for high-grade glioma therapy in clinical practice. In this review, we combine clinical and experimental data discussion. As antiangiogenic therapy is the standard of care for recurrent glioblastoma multiforme (GBM), we analyze major clinical trials and possible therapeutic combinations of bevacizumab, the most common monoclonal antibody to vascular endothelial growth factor (VEGF). Another humanized antibody to gain recognition in GBM is epidermal growth factor (EGFR) antagonist nimotuzumab. Other antigens (VEGF receptor, platelet-derived growth factor receptor, hepatocyte growth factor and c-Met system) showed significance in gliomas and were used to create monoclonal antibodies applied in different malignant tumors. We assess the role of genetic markers (isocitrate dehydrogenase, O6-methylguanine-DNA methyltransnsferase) in GBM treatment outcome prediction. Besides antibodies studied in clinical trials, we focus on perspective targets and briefly list other means of passive immunotherapy.
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Project description:Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, is characterized by a high mortality rate and poor prognosis. Current treatments for PDAC, are ineffective due to a prominent immunosuppressive PDAC tumor microenvironment (TME). Although B lymphocytes are highly infiltrated into PDAC, the importance of B lymphocytes in tumorigenesis is largely neglected. B cells play a dual role in the PDAC tumor microenvironment, acting as either anti-tumorigenic or pro-tumorigenic depending on where they are localized. Tumor-infiltrating B cells, which reside in ectopic lymph nodes, namely tertiary lymphoid structures (TLS), produce anti-tumor antibodies and present tumor antigens to T cells to contribute to cancer immunosurveillance. Alternatively, regulatory B cells (Bregs), dispersed inside the TME, contribute to the dampening of anti-tumor immune responses by secreting anti-inflammatory cytokines (IL-10 and IL-35), which promote tumor growth and metastasis. Determining the role of Bregs in the PDAC microenvironment is thus becoming increasingly attractive for developing novel immunotherapeutic approaches. In this minireview, we shed light on the emerging role of B cells in PDAC development and progression, with an emphasis on regulatory B cells (Bregs). Furthermore, we discussed the potential link of Bregs to immunotherapies in PDAC. These current findings will help us in understanding the full potential of B cells in immunotherapy.
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Project description:Purpose of review: Inhibition of immune escape mechanisms, such as the programed death-ligand 1 pathway, has demonstrated rapid, durable responses in multiple tumor types, including advanced urothelial carcinoma. This review discusses emerging immunotherapies for urothelial carcinoma in various stages of clinical development.Recent findings: Urothelial carcinoma has a high mutational burden, which may increase the number of tumor antigens and potentially enhance the ability of the immune system to recognize tumor cells as foreign. However, urothelial carcinoma can evade the immune system by downregulating tumor-antigen presentation, upregulating various immune checkpoints, and inactivating cytotoxic T cells. Immunotherapies for urothelial carcinoma target each of these steps to restore immune-mediated cytotoxicity. Many of these agents are in clinical trials for urothelial carcinoma.Summary: Immunotherapies are active in urothelial carcinoma, but only in a fraction of patients, implying the presence of persistent immune escape. Identifying the mechanisms of immune escape and developing rational combinatorial regimens may make the benefit of immunotherapy accessible to a broader population.
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Project description:Novel treatments in development for rheumatoid arthritis target 3 broad areas: cytokines, cells, and signaling pathways. Therapies from each domain share common advantages (for example previously demonstrated efficacy, potential long-term immunomodulation, and oral administration respectively) that have stimulated research in each area but also common obstacles to their development. In this review recent progress in each area will be discussed alongside the factors that have impeded their path to clinical use.
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Project description:Symptomatic treatment options for Parkinson disease have steadily improved, and individualized therapeutic approaches are becoming established for every stage of the disease. However, disease-modifying therapy with a causal approach is still unavailable. The central causative role of alpha-synuclein pathology, including its progressive spread to most areas of the CNS, has been widely recognized, and a strong involvement of immune responses has recently been discovered. New immunologic technologies have been shown to effectively prevent the progression of alpha-synuclein pathology in animal models. These approaches have recently been translated into the first human clinical trials, representing a novel starting point for the causal therapy of Parkinson disease. In this review, the pathomechanistic role of alpha-synuclein and its influence on the surrounding cellular environment are analyzed with a strong focus on immune responses and neuroinflammation. The potential of novel immunotherapeutic approaches that reduce the burden of alpha-synuclein pathology in the CNS is critically evaluated, and currently ongoing human clinical trials are presented. The clinical development of these new immunotherapies is progressing rapidly and gives reason to hope that a causal therapy of Parkinson disease could be possible in the foreseeable future.
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Project description:Glioma is the most frequent and aggressive type of brain neoplasm, being anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM), its most malignant forms. The survival rate in patients with these neoplasms is 15 months after diagnosis, despite a diversity of treatments, including surgery, radiation, chemotherapy, and immunotherapy. The resistance of GBM to various therapies is due to a highly mutated genome; these genetic changes induce a de-regulation of several signaling pathways and result in higher cell proliferation rates, angiogenesis, invasion, and a marked resistance to apoptosis; this latter trait is a hallmark of highly invasive tumor cells, such as glioma cells. Due to a defective apoptosis in gliomas, induced autophagic death can be an alternative to remove tumor cells. Paradoxically, however, autophagy in cancer can promote either a cell death or survival. Modulating the autophagic pathway as a death mechanism for cancer cells has prompted the use of both inhibitors and autophagy inducers. The autophagic process, either as a cancer suppressing or inducing mechanism in high-grade gliomas is discussed in this review, along with therapeutic approaches to inhibit or induce autophagy in pre-clinical and clinical studies, aiming to increase the efficiency of conventional treatments to remove glioma neoplastic cells.
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