Exploiting Radiation Therapy to Restore Immune Reactivity of Glioblastoma.
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ABSTRACT:
SUBMITTER: De Martino M
PROVIDER: S-EPMC8173136 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Glioblastoma multiforme (GBM) is the most common primary brain cancer. Even with aggressive combination therapy, the median life expectancy for patients with GBM remains approximately 14 months. In order to improve the outcomes of patients with GBM, the development of newer treatments is critical. The concept of using the immune system as a therapeutic option has been suggested for several decades; by harnessing the body's adaptive immune mechanisms, immunotherapy could provide a durable and targeted treatment against cancer. However, many cancers, including GBM, have developed mechanisms that protect tumor cells from being recognized and eliminated by the immune system. For new immunotherapeutic regimens to be successful, overcoming immunosuppression via immune checkpoint signaling should be taken into consideration.
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Project description:Radiation oncology modalities such as intensity-modulated and image-guided radiation therapy can reduce the high dose to normal tissue and deliver a heterogeneous dose to tumors, focusing on areas deemed at highest risk for tumor persistence. Clinical radiation oncology produces daily doses ranging from 1 to 20 Gy, with tissues being exposed to 30 or more daily fractions. Hypothesizing the cells that survive fractionated radiation therapy have a substantially different phenotype than the untreated cells, which might be exploitable for targeting with molecular therapeutics or immunotherapy, three prostate cancer cell lines (PC3, DU145, and LNCaP) and normal endothelial cells were studied to understand the biology of differential effects of multifraction (MF) radiation of 0.5, 1, and/or 2 Gy fraction to 10 Gy total dose, and a single dose of 5 and 10 Gy. The resulting changes in mRNA, miRNA, and phosphoproteome were analyzed. Significant differences were observed in the MF radiation exposures including those from the 0.5 Gy MF that produces little cell killing. As expected, p53 function played a major role in response. Pathways modified by MF include immune response, DNA damage, cell-cycle arrest, TGF-?, survival, and apoptotic signal transduction. The radiation-induced stress response will set forth a unique platform for exploiting the effects of radiation therapy as "focused biology" for cancer treatment in conjunction with molecular targeted or immunologically directed therapy. Given that more normal tissue is treated, albeit to lower doses with these newer techniques, the response of the normal tissue may also influence long-term treatment outcome.
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Project description:In contrast to the conventional radiotherapy/chemoradiotherapy paradigms used in the treatment of majority of cancer types, this review will describe two areas of radiobiology, hyperfractionated and hypofractionated radiation therapy, for cancer treatment focusing on application of novel concepts underlying these treatment modalities. The initial part of the review discusses the phenomenon of hyper-radiation sensitivity (HRS) at lower doses (0.1 to 0.6 Gy), describing the underlying mechanisms and how this could enhance the effects of chemotherapy, particularly, in hyperfractionated settings. The second part examines the radiobiological/physiological mechanisms underlying the effects of high-dose hypofractionated radiation therapy that can be exploited for tumor cure. These include abscopal/bystander effects, activation of immune system, endothelial cell death and effect of hypoxia with re-oxygenation. These biological properties along with targeted dose delivery and distribution to reduce normal tissue toxicity may make high-dose hypofractionation more effective than conventional radiation therapy for treatment of advanced cancers. The novel radiation physics based methods that take into consideration the tumor volume to be irradiated and normal tissue avoidance/tolerance can further improve treatment outcome and post-treatment quality of life. In conclusion, there is enough evidence to further explore novel avenues to exploit biological mechanisms from hyper-fractionation by enhancing the efficacy of chemotherapy and hypo-fractionated radiation therapy that could enhance tumor control and use imaging and technological advances to reduce toxicity.
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Project description:BackgroundPulsed radiation therapy (PRT) has shown effective tumor control and superior normal-tissue sparing ability compared with standard radiotherapy (SRT) in preclinical models and retrospective clinical series. This is the first prospective trial to investigate PRT in the treatment of patients with newly diagnosed glioblastoma (GBM).MethodsThis is a single-arm, prospective study. Patients with newly diagnosed GBM underwent surgery, followed by 60 Gy of PRT with concurrent temozolomide (TMZ). Each day, a 2-Gy fraction was divided into ten 0.2-Gy pulses, separated by 3-minute intervals. Patients received maintenance TMZ. Neurocognitive function (NCF) and quality of life (QoL) were monitored for 2 years using the Hopkins Verbal Learning Test‒Revised and the European Organisation for Research and Treatment of Cancer QLQ-C30 QoL questionnaire. Change in NCF was evaluated based on a minimal clinically important difference (MCID) threshold of 0.5 standard deviation.ResultsTwenty patients were enrolled with a median follow-up of 21 months. Median age was 60 years. Forty percent underwent subtotal resection, and 60% underwent gross total resection. One patient had an isocitrate dehydrogenase (IDH)-mutated tumor. Median progression-free survival (PFS) and overall survival (OS) were 10.7 and 20.9 months, respectively. In a post-hoc comparison, median OS for the prospective cohort was longer, compared with a matched cohort receiving SRT (20.9 vs 14 mo, P = 0.042). There was no decline in QoL, and changes in NCF scores did not meet the threshold of an MCID.ConclusionsTreatment of newly diagnosed GBM with PRT is feasible and produces promising effectiveness while maintaining neurocognitive function and QoL. Validation of our results in a larger prospective trial warrants consideration.
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Project description:Purpose: Immune checkpoint inhibitors designed to revert tumor-induced immunosuppression have emerged as potent anticancer therapies. Tryptophan metabolism represents an immune checkpoint, and targeting this pathway's rate-limiting enzyme IDO1 is actively being investigated clinically. Here, we studied the intermediary metabolism of tryptophan metabolism in glioblastoma and evaluated the activity of the IDO1 inhibitor GDC-0919, both alone and in combination with radiation (RT).Experimental Design: LC/GC-MS and expression profiling was performed for metabolomic and genomic analyses of patient-derived glioma. Immunocompetent mice were injected orthotopically with genetically engineered murine glioma cells and treated with GDC-0919 alone or combined with RT. Flow cytometry was performed on isolated tumors to determine immune consequences of individual treatments.Results: Integrated cross-platform analyses coupling global metabolomic and gene expression profiling identified aberrant tryptophan metabolism as a metabolic node specific to the mesenchymal and classical subtypes of glioblastoma. GDC-0919 demonstrated potent inhibition of this node and effectively crossed the blood-brain barrier. Although GDC-0919 as a single agent did not demonstrate antitumor activity, it had a strong potential for enhancing RT response in glioblastoma, which was further augmented with a hypofractionated regimen. RT response in glioblastoma involves immune stimulation, reflected by increases in activated and cytotoxic T cells, which was balanced by immune checkpoint reactivation, reflected by an increase in IDO1 expression and regulatory T cells (Treg). GDC-0919 mitigated RT-induced Tregs and enhanced T-cell activation.Conclusions: Tryptophan metabolism represents a metabolic node in glioblastoma, and combining RT with IDO1 inhibition enhances therapeutic response by mitigating RT-induced immunosuppression. Clin Cancer Res; 24(15); 3632-43. ©2018 AACR.
| S-EPMC6591719 | biostudies-literature
Project description:Glioblastoma is in need of innovative treatment approaches. Immune therapy for cancer refers to the use of the body's immune system to target malignant cells in the body. Such immune therapeutics have recently been very successful in treating a diverse group of cancerous lesions. As a result, many new immune therapies have gained Food and Drug Administration approval for the treatment of cancer, and there has been an explosion in the study of immune therapeutics for cancer treatment over the past few years. However, the immune suppression of glioblastoma and the unique immune microenvironment of the brain make immune therapeutics more challenging to apply to the brain than to other systemic cancers. Here, we discuss the existing barriers to successful immune therapy for glioblastoma and the ongoing development of immune therapeutics. We will discuss the discovery and classification of immune suppressive factors in the glioblastoma microenvironment; the development of vaccine-based therapies; the use of convection-enhanced delivery to introduce tumoricidal viruses into the tumor microenvironment, leading to secondary immune responses; the emerging use of adoptive cell therapy in the treatment of glioblastoma; and future frontiers, such as the use of cerebral microdialysis for immune monitoring and the use of sequencing to develop patient-specific therapeutics. Armed with a better understanding of the challenges inherent in immune therapy for glioblastoma, we may soon see more successes in immune-based clinical trials for this deadly disease.
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Project description:Glioblastoma (GBM) is the most malignant form of astrocytoma with short survival and a high recurrence rate and remains a global problem. Currently, surgery, chemotherapy, radiotherapy, and other comprehensive treatments are the main treatment modalities, but patients still have a poor prognosis mainly due to the infiltrative growth of GBM and the protective effect of the blood-brain barrier on tumor cells. Therefore, immunotherapy is expected to be a good option for GBM. In the immune system, different cells play varying roles in the treatment of GBM, so understanding the roles played by various immune cells in treating GBM and considering how to combine these effects to maximize the efficacy of these cells is important for the selection of comprehensive and optimal treatment plans and improving GBM prognosis. Therefore, this study reviews the latest research progress on the role of various types of immune cells in the treatment of GBM.
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Project description:Glioblastoma (GBM), one of the most aggressive forms of brain cancer, has limited treatment options. Recent years have witnessed the remarkable success of checkpoint inhibitor immunotherapy across various cancer types. Against this backdrop, several clinical trials investigating checkpoint inhibitors for GBM are underway in multiple countries. Furthermore, the integration of immunotherapy with traditional treatment approaches is now emerging as a highly promising strategy. This review summarizes the latest advancements in checkpoint inhibitor immunotherapy for GBM treatment. We provide a concise yet comprehensive overview of current GBM immunotherapy options. Additionally, this review underscores combination strategies and potential biomarkers for predicting response and resistance in GBM immunotherapies.
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Project description:The only available option to treat radiation-induced hematopoietic syndrome is allogeneic hematopoietic cell transplantation, a therapy unavailable to many patients undergoing treatment for malignancy, which would also be infeasible in a radiological disaster. Stromal cells serve as critical components of the hematopoietic stem cell niche and are thought to protect hematopoietic cells under stress. Prior studies that have transplanted mesenchymal stromal cells (MSCs) without co-administration of a hematopoietic graft have shown underwhelming rescue of endogenous hematopoiesis and have delivered the cells within 24 h of radiation exposure. Herein, we examine the efficacy of a human bone marrow-derived MSC therapy delivered at 3 h or 30 h in ameliorating radiation-induced hematopoietic syndrome and show that pancytopenia persists despite MSC therapy. Animals exposed to radiation had poorer survival and experienced loss of leukocytes, platelets, and red blood cells. Importantly, mice that received a therapeutic dose of MSCs were significantly less likely to die but experienced equivalent collapse of the hematopoietic system. The cause of the improved survival was unclear, as complete blood counts, splenic and marrow cellularity, numbers and function of hematopoietic stem and progenitor cells, and frequency of niche cells were not significantly improved by MSC therapy. Moreover, human MSCs were not detected in the bone marrow. MSC therapy reduced crypt dropout in the small intestine and promoted elevated expression of growth factors with established roles in gut development and regeneration, including PDGF-A, IGFBP-3, IGFBP-2, and IGF-1. We conclude that MSC therapy improves survival not through overt hematopoietic rescue but by positive impact on other radiosensitive tissues, such as the intestinal mucosa. Collectively, these data reveal that MSCs could be an effective countermeasure in cancer patients and victims of nuclear accidents but that MSCs alone do not significantly accelerate or contribute to recovery of the blood system.
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Project description:Glioblastoma is the most aggressive primary brain tumor in adults. Limited treatment options and the intense nature of therapy make determining the appropriate treatment course for each patient difficult. The appearance of transient worsening of imaging findings, known as treatment effect, after chemoradiation further complicates clinical decision-making. Accurately differentiating treatment effects from true progression is critical as subsequent treatment decisions are based largely on radiographic evidence of tumor progression. As chemoradiation can cause worsening of imaging findings, it is possible that the use of new treatments and modified chemoradiation regimens may alter the presentation of treatment effect. Therefore, physicians should be aware that atypical presentations of treatment effects can occur, and may be more likely, when treatment regimens are modified. Here, we present the case of a patient with isocitrate dehydrogenase 1 wild type, O-6-methylguanine-DNA methyltransferase-methylated glioblastoma who underwent dose-escalation radiation therapy (to 75 Gy) and exhibited worsened imaging findings at 8 months post-radiation.
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