The Safety of available immunotherapy for the treatment of glioblastoma.
ABSTRACT: Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Current standard of care involves maximal surgical resection combined with adjuvant chemoradiation. Growing support exists for a role of immunotherapy in treating these tumors with the goal of targeted cytotoxicity. Here we review data on the safety for current immunotherapies being tested in GBM. Areas covered: Safety data from published clinical trials, including ongoing clinical trials were reviewed. Immunotherapeutic classes currently under investigation in GBM include various vaccination strategies, adoptive T cell immunotherapy, immune checkpoint blockade, monoclonal antibodies, and cytokine therapies. Trials include children, adolescents, and adults with either primary or recurrent GBM. Expert opinion: Based on the reviewed clinical trials, the current immunotherapies targeting GBM are safe and well-tolerated with minimal toxicities which should be noted. However, the gains in patient survival have been modest. A safe and well-tolerated combinatory immunotherapeutic approach may be essential for optimal efficacy towards GBM.
Project description:Brain tumors comprise different types of malignancies, most of which are originated from glial cells. Glioblastoma multiforme (GBM) is the most aggressive type of brain tumor with a poor response to conventional therapies and dismal survival rates (15 months) despite multimodal therapies. The development of immunotherapeutic strategies seems to be necessary to enhance the overall survival of GBM patients. So far, the immunotherapies applied in GBM had promising results in the primary phases of clinical trials but failed to continue their beneficial effects in later phases. GBM-microenvironment (GME) is a heterogenic and rigorously immunosuppressive milieu wrapping by an impenetrable blood-brain barrier. Hence, in-depth knowledge about the dominant immunosuppressive mechanisms in the GME could foster GBM immunotherapy. Recently, the adenosinergic pathway (AP) is found to be a major player in the suppression of antitumor immune responses in the GME. Tumor cells evolve to metabolize pro-inflammatory ATP to anti-inflammatory adenosine. Adenosine can suppress immune responses through the signaling of adenosine receptors on immune cells. The preclinical results targeting AP in GBM showed promising results in reinvigorating antitumor responses, overriding chemoresistance, and increasing survival. We reviewed the current GBM immunotherapies and elaborated on the role of AP in the immunopathogenesis, treatment, and even prognosis of GBM. We suggest that future clinical studies should consider this pathway in their combination therapies along with other immunotherapeutic approaches.
Project description:Glioblastoma is the most common adult primary brain tumor and carries a dismal prognosis. Radiation is a standard first-line therapy, typically deployed following maximal safe surgical debulking, when possible, in combination with cytotoxic chemotherapy. For other systemic cancers, standard of care is being transformed by immunotherapies, including checkpoint-blocking antibodies targeting CTLA-4 and PD-1/PD-L1, with potential for long-term remission. Ongoing studies are evaluating the role of immunotherapies for GBM. Despite dramatic responses in some cases, randomized trials to date have not met primary outcomes. Challenges have been attributed in part to the immunologically "cold" nature of glioblastoma relative to other malignancies successfully treated with immunotherapy. Radiation may serve as a mechanism to improve tumor immunogenicity. In this review, we critically evaluate current evidence regarding radiation as a synergistic facilitator of immunotherapies through modulation of both the innate and adaptive immune milieu. Although current preclinical data encourage efforts to harness synergistic biology between radiation and immunotherapy, several practical and scientific challenges remain. Moreover, insights from radiation biology may unveil additional novel opportunities to help mobilize immunity against GBM.
Project description:The current standard of care for glioblastoma (GBM) is maximal surgical resection with adjuvant radiotherapy and temozolomide (TMZ). As the 5-year survival with GBM remains at a dismal <10%, novel therapies are needed. Immunotherapies such as the dendritic cell (DC) vaccine, heat shock protein vaccines, and epidermal growth factor receptor (EGFRvIII) vaccines have shown encouraging results in clinical trials, and have demonstrated synergistic effects with conventional therapeutics resulting in ongoing phase III trials. Chemoradiation has been shown to have synergistic effects when used in combination with immunotherapy. Cytotoxic ionizing radiation is known to trigger pro-inflammatory signaling cascades and immune activation secondary to cell death, which can then be exploited by immunotherapies. The future of GBM therapeutics will involve finding the place for immunotherapy in the current treatment regimen with a focus on developing strategies. Here, we review current GBM therapy and the evidence for combination of immune checkpoint inhibitors, DC and peptide vaccines with the current standard of care.
Project description:IMPORTANCE OF THE FIELD:Although most children with cancer are cured, there remain significant limitations of standard treatment, most notably chemotherapy resistance and non-specific toxicities. Novel immune-based therapies that target pediatric malignancies offer attractive adjuncts and/or alternatives to commonly employed cytotoxic regimens of chemotherapy or radiotherapy. Elucidation of the principles of tumor biology and the development of novel laboratory technologies over the last decade have led to substantial progress in bringing immunotherapies to the bedside. AREAS COVERED IN THIS REVIEW:Current immunotherapeutic clinical trials in pediatric oncology and the science behind their development are reviewed. WHAT THE READER WILL GAIN:Most of the immune-based therapies studied to date have been well tolerated, and some have shown promise in the setting of refractory or high-risk malignancies, demonstrating that immunotherapy has the potential to overcome resistance to conventional chemotherapy. TAKE HOME MESSAGE:Some immune-based therapies, such as ch14.18 and MTP-PE, have already been proven effective in phase III randomized trials. Further studies are needed to optimize and integrate other therapies into standard regimens, and to test them in randomized trials for patients with childhood cancer.
Project description:Malignant gliomas, including glioblastoma (GBM) as the most aggressive type of adult CNS tumors, are notoriously resistant to current standard of care treatments, including surgery, systemic chemotherapy, and radiation therapy (RT). This lack of effective treatment options highlights the urgent need for novel therapies, including immunotherapies. The overarching goal of immunotherapy is to stimulate and activate the patient's immune system in a targeted manner to kill tumor cells. The success of immunotherapeutic interventions in other cancer types has led to interest in and evaluation of various experimental immunotherapies in patients with malignant gliomas. However, these primary malignant brain tumors present a challenge because they exist in a vital and sensitive organ with a unique immune environment. The challenges and current status of experimental immunotherapeutic approaches, including vaccines, immune-checkpoint blockade, chimeric antigen receptor T-cell therapy, and oncolytic viruses will be discussed, as well as the potential for combinatorial therapies.
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.
Project description:Glioblastoma multiforme (GBM) is the most frequently occurring primary brain tumor and has a very poor prognosis, with only around 5% of patients surviving for a period of 5 years or more after diagnosis. Despite aggressive multimodal therapy, consisting mostly of a combination of surgery, radiotherapy, and temozolomide chemotherapy, tumors nearly always recur close to the site of resection. For the past 15 years, very little progress has been made with regards to improving patient survival. Although immunotherapy represents an attractive therapy modality due to the promising pre-clinical results observed, many of these potential immunotherapeutic approaches fail during clinical trials, and to date no immunotherapeutic treatments for GBM have been approved. As for many other difficult to treat cancers, GBM combines a lack of immunogenicity with few mutations and a highly immunosuppressive tumor microenvironment (TME). Unfortunately, both tumor and immune cells have been shown to contribute towards this immunosuppressive phenotype. In addition, current therapeutics also exacerbate this immunosuppression which might explain the failure of immunotherapy-based clinical trials in the GBM setting. Understanding how these mechanisms interact with one another, as well as how one can increase the anti-tumor immune response by addressing local immunosuppression will lead to better clinical results for immune-based therapeutics. Improving therapeutic delivery across the blood brain barrier also presents a challenge for immunotherapy and future therapies will need to consider this. This review highlights the immunosuppressive mechanisms employed by GBM cancers and examines potential immunotherapeutic treatments that can overcome these significant immunosuppressive hurdles.
Project description:Outcome for glioblastoma (GBM), the most common primary CNS malignancy, remains poor. The overall survival benefit recently achieved with immunotherapeutics for melanoma and prostate cancer support evaluation of immunotherapies for other challenging cancers, including GBM. Much historical dogma depicting the CNS as immunoprivileged has been replaced by data demonstrating CNS immunocompetence and active interaction with the peripheral immune system. Several glioma antigens have been identified for potential immunotherapeutic exploitation. Active immunotherapy studies for GBM, supported by preclinical data, have focused on tumor lysate and synthetic antigen vaccination strategies. Results to date confirm consistent safety, including a lack of autoimmune reactivity; however, modest efficacy and variable immunogenicity have been observed. These findings underscore the need to optimize vaccination variables and to address challenges posed by systemic and local immunosuppression inherent to GBM tumors. Additional immunotherapy strategies are also in development for GBM. Future studies may consider combinatorial immunotherapy strategies with complimentary actions.
Project description:Glioblastoma multiforme (GBM) is the most common and lethal primary malignant brain tumor. The traditional treatments for GBM, including surgery, radiation, and chemotherapy, only modestly improve patient survival. Therefore, immunotherapy has emerged as a novel therapeutic modality. Immunotherapeutic strategies exploit the immune system's ability to recognize and mount a specific response against tumor cells, but not normal cells. Current immunotherapeutic approaches for glioma can be divided into 3 categories: immune priming (active immunotherapy), immunomodulation (passive immunotherapy), and adoptive immunotherapy. Immune priming sensitizes the patient's immune cells to tumor antigens using various vaccination protocols. In the case of immunomodulation, strategies are aimed at reducing suppressive cytokines in the tumor microenvironment or using immune molecules to specifically target tumor cells. Adoptive immunotherapy involves harvesting the patient's immune cells, followed by ex vivo activation and expansion before reinfusion. This article provides an overview of the interactions between the central nervous system and the immune system, and discusses the challenges facing current immunotherapeutic strategies.