Immunotherapy and radiation for high-grade glioma: a narrative review
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ABSTRACT:
SUBMITTER: Fakhoury K
PROVIDER: S-EPMC8797698 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background:High-grade gliomas (HGGs) are a heterogeneous disease group, with variable prognosis, inevitably causing deterioration of the quality of life. The estimated 2-year overall survival is 20%, despite the best trimodality treatment consisting of surgery, chemotherapy, and radiotherapy. Aim:To evaluate long-term survival outcomes and factors influencing the survival of patients with high-grade gliomas treated with radiotherapy. Materials and methods:Data from 47 patients diagnosed with high-grade gliomas between 2009 and 2014 and treated with three-dimensional radiotherapy (3DRT) or intensity-modulated radiotherapy (IMRT) were analyzed retrospectively. Results:Median survival was 16.6 months; 29 patients (62%) died before the time of analysis. IMRT was employed in 68% of cases. The mean duration of radiotherapy was 56 days, and the mean delay to the start of radiotherapy was 61.7 days (range, 27-123 days). There were no statistically significant effects of duration of radiotherapy or delay to the start of radiotherapy on patient outcomes. Conclusions:Age, total amount of gross resection, histological type, and use of adjuvant temozolomide influenced survival rate (p < 0.05). The estimated overall survival was 18 months (Kaplan-Meier estimator). Our results corroborated those reported in the literature.
| S-EPMC6187089 | biostudies-literature
Project description:IntroductionChildren with high-grade gliomas (pHGGs) represent a clinical population in substantial need of new therapeutic options given the inefficacy and toxicity of current standard-of-care modalities. Although immunotherapy has emerged as a promising modality, it has yet to elicit a significant survival benefit for pHGG patients. While preclinical studies address a variety of underlying challenges, translational clinical trial design and management also need to reflect the most updated progress and lessons from the field.Areas coveredThe authors will focus our discussion on the design of clinical trials, the management of potential toxicities, immune monitoring, and novel biomarkers. Clinical trial design should integrate appropriate patient populations, novel, and preclinically optimized trial design, and logical treatment combinations, particularly those which synergize with standard of care modalities. However, there are caveats due to the nature of immunotherapy trials, such as patient selection bias, evidenced by the frequent exclusion of patients on high-dose corticosteroids. Robust immune-modulating effects of modern immunotherapy can have toxicities. As such, it is important to understand and manage these, especially in pHGG patients.Expert opinionAdequate integration of these considerations should allow us to effectively gain insights on biological activity, safety, and biomarkers associated with benefits for patients.
| S-EPMC7880880 | biostudies-literature
Project description:Radiation-induced high-grade gliomas (RIGs) are an incurable late complication of cranial radiation therapy. We performed DNA methylation profiling, RNA-seq, and DNA sequencing on 32 RIG tumors and an in vitro drug screen in two RIG cell lines. We report that based on DNA methylation, RIGs cluster primarily with the pediatric receptor tyrosine kinase I high-grade glioma subtype. Common copy-number alterations include Chromosome (Ch.) 1p loss/1q gain, and Ch. 13q and Ch. 14q loss; focal alterations include PDGFRA and CDK4 gain and CDKN2A and BCOR loss. Transcriptomically, RIGs comprise a stem-like subgroup with lesser mutation burden and Ch. 1p loss and a pro-inflammatory subgroup with greater mutation burden and depleted DNA repair gene expression. Chromothripsis in several RIG samples is associated with extrachromosomal circular DNA-mediated amplification of PDGFRA and CDK4. Drug screening suggests microtubule inhibitors/stabilizers, DNA-damaging agents, MEK inhibition, and, in the inflammatory subgroup, proteasome inhibitors, as potentially effective therapies.
| S-EPMC8452624 | biostudies-literature
Project description:Despite advances in chemotherapy, radiation, and surgery, prognosis in gastroesophageal cancers (GEC) remains poor. Recent studies have demonstrated that immune checkpoint inhibitors specific to the PD-1/PD-L1 axis can improve survival with dramatic durability for a subset of patients with GEC. Radiation therapy (RT) has been shown to enhance priming and anti-tumor immunogenicity. The combination of these two treatments has shown promising results acting synergistically in pre-clinical and clinical models. Much of this synergy appears linked to in-field radiation responses, but also the abscopal response where out-of-field tumors demonstrate regression. In this review, we summarize the current role of immunotherapy and radiation in GEC. We also highlight progress from preclinical studies and translational biomarker analyses that provide rationale for ongoing efforts combining immune checkpoint inhibition and radiotherapy specifically in GECs. Questions that remain unanswered in the clinic are the optimal radiation dosing, timing, and fractionation strategies to augment abscopal immune responses. Increasing recognition of the heterogeneity of immunosuppressive mechanisms that can arise in response to radiation indicates the need for novel immune checkpoint inhibitors that target beyond the PD-1/PD-L1 axis. Smartly designed prospective trials incorporating these two approaches with ongoing translational analyses will be critical in increasing the success of combinatorial radiation and immunotherapy strategies in this disease.
| S-EPMC8798391 | biostudies-literature
Project description:Lung cancer remains the leading cause of cancer morbidity and mortality worldwide among both men and women. While surgical resection remains the standard of care for early stage NSCLC, chemoradiation has been a mainstay of treatment for locally advanced non-small-cell lung cancer (LA-NSCLC) patients for decades. Consolidation immunotherapy has improved survival in this subset of patients after conventional chemoradiation, and has emerged as the new standard. The synergy between immunotherapy and radiation, as well as ongoing research on the effects of radiation on the immune system, allows for the exploration of new avenues in the treatment of LA-NSCLC. In addition to the use of durvalumab as consolidative systemic therapy after concurrent chemoradiotherapy for Stage III NSCLC, other combination regimens have been shown to be effective in various disease stages in preclinical and clinical studies. These regimens include CTLA-4 and PD/PDL-1 checkpoint inhibitors combined with radiation treatment. While these combined regimens have demonstrated efficacy, they are not without toxicity, and require additional evaluation when combined with radiation. In this review, we have summarized the immunostimulatory and immunosuppressive effects of radiation therapy. We also evaluate the current evidence and ongoing research supporting the combination of radiotherapy and immunotherapy across early to LA-NSCLC.
| S-EPMC7842553 | biostudies-literature
Project description:Stereotactic radiotherapy (SRT) has become an attractive treatment modality in full bloom in recent years by presenting itself as a safe, noninvasive alternative to surgery to control primary or secondary malignancies. Although the focus has been on local tumor control as the therapeutic goal of stereotactic radiotherapy, rare but intriguing observations of abscopal (or out-of-field) effects have highlighted the exciting possibility of activating antitumor immunity using high-dose radiation. Furthermore, immunotherapy has revolutionized the treatment of several types of cancers in recent years. However, resistance to immunotherapy often develops. These observations have led researchers to combine immunotherapy with SRT in an attempt to improve outcomes. The benefits of this combination would come from the stimulation and suppression of various immune pathways. Thus, in this review, we will first discuss the immunomodulation induced by SRT with the promising results of preclinical studies on the changes in the immune balance observed after SRT. Then, we will discuss the opportunities and risks of the combination of SRT and immunotherapy with the preclinical and clinical data available in the literature. Furthermore, we will see that many perspectives are conceivable to potentiate the synergistic effects of this combination with the need for prospective studies to confirm the encouraging data.
| S-EPMC9219862 | biostudies-literature
Project description:High-grade (WHO grades III-IV) glioma remains one of the most lethal human cancers. Adoptive transfer of tumor-targeting chimeric antigen receptor (CAR)-redirected T cells for high-grade glioma has revealed promising indications of anti-tumor activity, but objective clinical responses remain elusive for most patients. A significant challenge to effective immunotherapy is the highly heterogeneous structure of these tumors, including large variations in the magnitudes and distributions of target antigen expression, observed both within individual tumors and between patients. To obtain a more detailed understanding of immunotherapy target antigens within patient tumors, we immunochemically mapped at single cell resolution three clinically-relevant targets, IL13Rα2, HER2 and EGFR, on tumor samples drawn from a 43-patient cohort. We observed that within individual tumor samples, expression of these antigens was neither random nor uniform, but rather that they mapped into local neighborhoods - phenotypically similar cells within regions of cellular tumor - reflecting not well understood properties of tumor cells and their milieu. Notably, tumor cell neighborhoods of high antigen expression were not arranged independently within regions. For example, in cellular tumor regions, neighborhoods of high IL13Rα2 and HER2 expression appeared to be reciprocal to those of EGFR, while in areas of pseudopalisading necrosis, expression of IL13Rα2 and HER2, but not EGFR, appeared to reflect the radial organization of tumor cells around hypoxic cores. Other structural features affecting expression of immunotherapy target antigens remain to be elucidated. This structured but heterogeneous organization of antigen expression in high grade glioma is highly permissive for antigen escape, and combinatorial antigen targeting is a commonly suggested potential mitigating strategy. Deeper understanding of antigen expression within and between patient tumors will enhance optimization of combination immunotherapies, the most immediate clinical application of the observations presented here being the importance of including (wild-type) EGFR as a target antigen.
| S-EPMC9108993 | biostudies-literature
Project description:Radiation-induced high-grade gliomas (RIGs) are an incurable late complication of cranial radiation therapy. We performed DNA methylation profiling, RNA-seq, and DNA sequencing on 32 RIG tumors and an in vitro drug screen in two RIG cell lines. We report that based on DNA methylation, RIGs cluster primarily with the pediatric receptor tyrosine kinase I high-grade glioma subtype. Common copy-number alterations include Chromosome (Ch.) 1p loss/1q gain, and Ch. 13q and Ch. 14q loss; focal alterations include PDGFRA and CDK4 gain and CDKN2A and BCOR loss. Transcriptomically, RIGs comprise a stem-like subgroup with lesser mutation burden and Ch. 1p loss and a pro-inflammatory subgroup with greater mutation burden and depleted DNA repair gene expression. Chromothripsis in several RIG samples is associated with extrachromosomal circular DNA-mediated amplification of PDGFRA and CDK4. Drug screening suggests microtubule inhibitors/stabilizers, DNA-damaging agents, MEK inhibition, and, in the inflammatory subgroup, proteasome inhibitors as potentially effective therapies.
2021-05-27 | GSE175543 | GEO
Project description:BackgroundThe addition of procarbazine, lomustine, vincristine (PCV) chemotherapy to radiotherapy (RT) for patients with high-risk (?40 y old or subtotally resected) low-grade glioma (LGG) results in an absolute median survival benefit of over 5 years. We evaluated the cost-effectiveness of this treatment strategy.MethodsA decision tree with an integrated 3-state Markov model was created to follow patients with high-risk LGG after surgery treated with RT versus RT+PCV. Patients existed in one of 3 health states: stable, progressive, or dead. Survival and freedom from progression were modeled to reflect the results of RTOG 9802 using time-dependent transition probabilities. Health utility values and costs of care were derived from the literature and national registry databases. Analysis was conducted from the health care perspective. Deterministic and probabilistic sensitivity analysis explored uncertainty in model parameters.ResultsModeled outcomes demonstrated agreement with clinical data in expected benefit of addition of PCV to RT. The addition of PCV to RT yielded an incremental benefit of 4.77 quality-adjusted life-years (QALYs) (9.94 for RT+PCV vs 5.17 for RT alone) at an incremental cost of $48635 ($188234 for RT+PCV vs $139598 for RT alone), resulting in an incremental cost-effectiveness ratio of $10186 per QALY gained. Probabilistic sensitivity analysis demonstrates that within modeled distributions of parameters, RT+PCV has 99.96% probability of being cost-effectiveness at a willingness-to-pay threshold of $100000 per QALY.ConclusionThe addition of PCV to RT is a cost-effective treatment strategy for patients with high-risk LGG.
| S-EPMC5716167 | biostudies-literature
Project description:Despite decreasing smoking rates, lung cancer remains the leading cause of death from cancer in the United States. Radiation therapy has been established as an effective locoregional therapy for both early stage and locally advanced disease and is known to stimulate local immune response. Past treatment paradigms have established the role of combining cytotoxic chemotherapy regimens and radiation therapy to help address the local and systemic nature of lung cancer. However, these regimens have limitations in their tolerability due to toxicity. Additionally, cytotoxic chemotherapy has limited efficacy in preventing systemic spread of lung cancer. Newer systemic agents such as immune checkpoint inhibitors have shown improved survival in metastatic and locally advanced lung cancer and have the advantage of more limited toxicity profiles compared to cytotoxic chemotherapy. Furthermore, improved overall response rates and systemic tumor responses have been observed with the combination of radiation therapy and immunotherapy, leading to numerous active clinical trials evaluating the combination of immune checkpoint inhibition with radiotherapy. This comprehensive review discusses the current clinical data and ongoing studies evaluating the combination of radiation therapy and immunotherapy in both non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC).
| S-EPMC8797746 | biostudies-literature