Immunotherapy For High-grade Glioma Research Articles

Benefits and Prospects of VEGF-targeted Anti-angiogenic Therapy and Immunotherapy for High-grade Glioma

Elucidation of the ecological characteristics of malignant tumors has shown that angiogenesis and an immunosuppressive status in the tumor microenvironment are important for resolving treatment resistance and poor prognosis. Vascular endothelial growth factor(VEGF) and components of related signaling pathway can be targeted by anti-angiogenic therapy. Suppression of abundant angiogenesis using anti-angiogenic agents in high-grade gliomas inhibits rapid neurological deterioration in patients. Additionally, as VEGF promotes the formation of an immunosuppressive tumor microenvironment, anti-angiogenic therapy is expected to contribute to improving the immune status in the tumor microenvironment. In this review, we discuss the role of VEGF-targeted therapy and immunotherapy targeting immune checkpoint inhibitors and macrophages in high-grade gliomas. The authors also discuss the possibility of using these as combination therapies.

Immunotherapy and radiation for high-grade glioma: a narrative review.

Glioblastoma and other high-grade gliomas (HGGs) are the most common and deadly primary brain tumors. Due to recent advances in immunotherapy and improved clinical outcomes in other disease sites, the study of immunotherapy in HGG has increased significantly. Herein, we summarize and evaluate existing evidence and ongoing clinical trials investigating the use of immunotherapy in the treatment of HGG, including therapeutic vaccination, immune checkpoint inhibition, adoptive lymphocyte transfer, and combinatorial approaches utilizing radiation and multiple modalities of immunotherapy. Special attention is given to the mechanisms by which radiation may improve immunogenicity in HGG, why this motivates the study of radiation in combination with immunotherapy, and how to determine optimal dosing and scheduling of radiation. Though larger randomized controlled trials have not consistently shown improvements in clinical outcomes, this area of research is still in its early stages and a number of important lessons can be taken away from the studies that have been completed to date. Many studies found a subset of patients who experienced durable responses, and analysis of their immune cells and tumor cells can be used to identify biomarkers that predict therapeutic response, as well as additional glioma-specific targets that can enhance therapeutic efficacy in a challenging tumor type.

Clinical decision making in the era of immunotherapy for high grade-glioma: report of four cases

BackgroundImmune checkpoint inhibitors (ICPIs) are being investigated in clinical trials for patients with glioblastoma. While these therapies hold great promise, management of the patients receiving such treatment can be complicated due to the challenges in recognizing immune-related adverse events caused by checkpoint inhibitor treatment. Brain imaging changes that are the consequence of an inflammatory response may be misinterpreted as disease progression leading to inappropriate premature cessation of treatment. The aim of this study was to, by way of a series of cases, underscore the challenges in determining the nature of contrast-enhancing masses that develop during the treatment of patients with glioblastoma treated with ICPIs.Case presentationWe reviewed the clinical course and management of 4 patients on ICPIs who developed signs of tumor progression on imaging. These findings were examined in the context of Immunotherapy Response Assessment in Neuro-Oncology (iRANO) guidelines. Although all 4 patients had very similar imaging findings, 2 of the 4 patients were later found to have intense inflammatory changes (pseudoprogression) by pathologic examination.ConclusionsA high index of suspicion for pseudoprogression needs to be maintained when a patient with brain tumor on immunotherapy presents with worsening in an area of a pre-existing tumor or a new lesion in brain. Our findings strongly suggest that pathological diagnosis remains the gold standard for distinguishing tumor progression from pseudoprogression in patients receiving immunotherapy. There is a large unmet need to develop reliable non-invasive imaging diagnostic techniques.Trial registrationClinicalTrials.gov NCT02311920. Registered 8 December 2014.

Immunotherapy for high-grade glioma.

4th Quadrennial Meeting of the World Federation of Neuro-Oncology in conjunction with the 18th Annual Meeting of the Society for Neuro-Oncology, San Francisco, CA, USA, 21-24 November 2013. Aside from temozolomide, there has been no major breakthrough for decades to improve outcome for high-grade glioma. Bevacizumab failed to show a survival advantage in two large studies - AVaglio and RTOG-0825 - and no other novel chemotherapy agents seem to be appearing on the horizon for this universally fatal disease. Consequently, the neuro-oncology fraternity is turning to immunotherapy. This became apparent in this meeting, considering a number of delegates focused their attention to presentations on immunotherapy. The ReACT study demonstrated the safety and efficacy of the combination of a promising peptide vaccine, rindopepimut, and bevacizumab with longer survival seen in patients with a higher antibody titer. Several presentations reassured that dendritic cell-based immunotherapy is safe and can generate a lasting immune response. Employing gene therapy, increased intratumor 5-fluorouracil chemotherapy concentration can be achieved using TOCA 511, and temozolomide-resistant transgenic lymphocytes could be produced through retroviral coding. Blocking immune checkpoints PDL-01, CTLA-4 and indoleamine 2,3-dioxygenase through monoclonal antibodies appears promising.

Immunotherapy for High-Grade Glioma: How to Go Beyond Phase I/II Clinical Trials

Evaluation of: Lasky JL 3rd, Panosyan EH, Plant A et al. Autologous tumor lysate-pulsed dendritic cell immunotherapy for pediatric patients with newly diagnosed or recurrent high-grade gliomas. Anticancer Res. 33, 2047-2056 (2013). Immunotherapy for children and adults with high-grade glioma (HGG) is an emerging innovative treatment approach, which aims at stimulating the body's own immune system against HGG by using autologous dendritic cells pulsed with autologous tumor lysate as a therapeutic vaccine. This is the third report on immunotherapy for HGG in children, bringing additional knowledge and experience to the scientific community. However, at the same time, this and other manuscripts urge for the next step in treatment development.

Immunotherapy for high grade glioma: current clinical practice for patients with (relapsed) GBM

Immunotherapy for high grade glioma: current clinical practice for patients with (relapsed) GBM

Cellular Immunotherapy for High Grade Gliomas: Mathematical Analysis Deriving Efficacious Infusion Rates Based on Patient Requirements

To date, no effective cure has been found for high grade malignant glioma (HGG), current median survival for HGG patients under treatment ranging from 18 months (grade IV) to 5 years (grade III). Recently, T cell therapy for HGG has been suggested as a promising avenue for treating such resistant tumors, but clinical outcome has not been conclusive. For studying this new therapy option, a mathematical model for tumor–T cell interactions was developed, where tumor immune response was modeled by six coupled ordinary differential equations describing tumor cells, T cells, and their respective secreted cytokines and immune mediating receptors. Here we mathematically analyze the model in an untreated case and under T cell immunotherapy. For both settings we classify steady states, determine stability properties, and explore the global behavior of the model. Analysis suggests that in untreated patients, the system always converges to a steady state of a large tumor mass. An increase in the patient's pro-inflamm...

Targeted downregulation of TGF-beta2 as immunotherapy for high-grade glioma: A phase IIb study

1537 Background: High-grade (malignant) glioma are highly aggressive tumors showing marked overexpression of transforming growth factor-beta2 (TGF-beta2). TGF-beta plays a key role in malignant progression by inducing proliferation, invasion and metastasis, angiogenesis and immunosuppression and is responsible for the immunodeficient state of malignant glioma patients. AP 12009, a phosphorothioate antisense oligodeoxynucleotide specific for the human TGF-beta2 mRNA, has been developed as a targeted anti-tumor therapy. AP 12009 has already proven safety and shown anti-tumor activity in phase I/II clinical studies as therapy for recurrent high-grade glioma after intratumoral infusion. Methods: Based on the successful phase I/II studies with AP 12009 a phase IIb multinational study in adult patients with recurrent high-grade glioma, i.e. Anaplastic Astrocytoma (AA), WHO grade III, and Glioblastoma Multiforme (GBM), WHO grade IV, is currently ongoing. Patients are randomized into 3 treatment groups to receive either one of two doses of AP 12009 or standard chemotherapy, i.e. temozolomide, or the combination Procarbazine/CCNU/Vincristine (PCV). The primary objectives of this open label, phase IIb study are response rate (RR), progression free survival (PFS) and overall survival at different time points. AP 12009 is administered intratumorally as continuous high-flow microperfusion for 7 days every other week for up to 11 cycles. Both, efficacy and safety will be used as criteria for evaluation. Results and Conclusion: In the previous phase I/II studies the median overall survival time was longer than the one reported in the recent literature (Yung et al, 2000, Theodosopoulus et al, 2001, Chang et al, 2004) on standard chemotherapy. Data on anti-tumor activity in phase I/II studies with 24 patients included several patients with stabilizations and two patients with complete tumor remissions, both of them long-lasting without recurrence. In the current phase IIb study more than 120 patients have been enrolled. Based on the clinical data in malignant glioma and very encouraging preclinical results in pancreatic carcinoma AP 12009 is now in phase I/II studies in pancreatic carcinoma as its second tumor indication. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Antisense Pharma GmbH Antisense Pharma GmbH Antisense Pharma, Antisense Pharma GmbH

Results of a Phase I Clinical Trial of Adoptive Immunotherapy for High Grade Gliomas Using Ex- Vivo Activated, Vaccine-Draining Lymph Node (LN) T Cells

Results of a Phase I Clinical Trial of Adoptive Immunotherapy for High Grade Gliomas Using Ex- Vivo Activated, Vaccine-Draining Lymph Node (LN) T Cells

Results of a Phase I Clinical Trial of Adoptive Immunotherapy for High Grade Gliomas Using Ex-Vivo Activated, Vaccine-Draining Lymph Node (LN) T Cells

Results of a Phase I Clinical Trial of Adoptive Immunotherapy for High Grade Gliomas Using Ex-Vivo Activated, Vaccine-Draining Lymph Node (LN) T Cells