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glioblastoma immunotherapy

S Sengupta, G Mao, Z S Gokaslan, P Sampath
Glioblastoma (GBM) is by far the most common and the most aggressive of all the primary brain malignancies. No curative therapy exists, and median life expectancy hovers at around 1 year after diagnosis, with a minute fraction surviving beyond 5 years. The difficulty in treating GBM lies in the cancer's protected niche within the blood-brain barrier and the heterogeneity of the cancer cells, which possess varying degrees of susceptibility to various common modalities of treatment. Over time, it is the tumor heterogeneity of GBM and the ability of the cancer stem cells to evolve in response treatment that renders the cancer refractory to conventional treatment...
October 21, 2016: Cancer Gene Therapy
Shigeo Ohba, Yuichi Hirose
Glioblastomas are the most aggressive of all gliomas and have the worst prognosis, with 5-year survival rates of less than 10%. Temozolomide (TMZ) is a DNA-methylating agent. Now that TMZ is available, the standard treatment is to resect as much of the tumor as possible without inducing unacceptable neurologic deficits, followed by treatment with radiation and TMZ. TMZ has also been used for maintenance therapy. Recently, bevacizumab, which is a monoclonal antibody to vascular endothelial growth factor, has been used for the initial treatment of glioblastomas and for the treatment of recurrent glioblastomas...
October 14, 2016: Current Medicinal Chemistry
Kara W Moyes, Nicole Ap Lieberman, Shannon A Kreuser, Harrison Chinn, Conrad Winter, Gail Deutsch, Virginia Hoglund, Reid Watson, Courtney A Crane
In spite of their successes against hematologic malignancies, immunotherapeutic interventions for the treatment of patients with glioblastoma (GBM) have thus far been unsuccessful. This is in part due to the presence of a tumor microenvironment that fosters neoplastic growth and protects the tumor from destruction by the immune system. We have developed a novel genetically engineered macrophage-based platform with the potential to minimize the effects of the suppressive tumor microenvironment and improve innate and adaptive anti-tumor immune responses...
October 19, 2016: Human Gene Therapy
Sanne Duinkerken, Yvette van Kooyk, Juan J Garcia-Vallejo
Glioblastoma multiforme (GBM) is the most aggressive brain tumor and median survival time with current therapies is only 14.6 mo. Although multiple immunotherapeutic strategies are being explored, efficacy remains poor. In order to improve immunotherapy for GBM, we propose to combine currently used endogenous with human cytomegalovirus (HCMV) specific antigens expressed on cancer cells.
2016: Oncoimmunology
Linsen Mu, Yongzhi Wang, Yonggang Wang, Hongbo Zhang, Dewei Shang, Fuqiang Tan, Yan Li, Xuzhu Chen
INTRODUCTION: Toll-like receptor 9(TLR9) is a key immunotherapy target for glioblastoma (GBM). This study explored the correlation of TLR9 expression with tumor location and survival outcomes in patients with supratentorial GBM. METHODS: We retrospectively identified 46 patients with supratentorial GBMs and divided them into those with high (TRL9(High)) and low TLR9 (TRL9(Low)) levels. The two groups were compared by patients' ages, sex, preoperative Karnofsky Performance Score (KPS), resection extent, tumor location, progression-free survival (PFS) and overall survival (OS)...
October 12, 2016: World Neurosurgery
C Gzell, M Back, H Wheeler, D Bailey, M Foote
The aim of this review is to explore the changing utility of radiotherapy in the treatment of patients with glioblastoma over the past 60 years. Together with surgery, radiotherapy has always been the cornerstone of treatment of glioblastoma, but techniques have significantly advanced over this time. The exploration of early two-dimensional techniques, investigation of dose escalation, concomitant chemotherapy and modern techniques, including intensity-modulated radiotherapy, image-guided radiotherapy, and volumetric-modulated arc therapy will be covered...
October 13, 2016: Clinical Oncology: a Journal of the Royal College of Radiologists
Amanda Tivnan, Tatjana Heilinger, Ed C Lavelle, Jochen H M Prehn
Glioblastoma (GBM) is an aggressive brain tumour, associated with extremely poor prognosis and although there have been therapeutic advances, treatment options remain limited. This review focuses on the use of immunotherapy, harnessing the power of the host's immune system to reject cancer cells. Key challenges in glioma specific immunotherapy as with many other cancers are the limited immunogenicity of the cancer cells and the immunosuppressive environment of the tumour. Although specific antigens have been identified in several cancers; brain tumours, such as GBM, are considered poorly immunogenic...
October 14, 2016: Journal of Neuro-oncology
Isabel Mérida, Pedro Torres-Ayuso, Antonia Ávila-Flores, Javier Arranz-Nicolás, Elena Andrada, María Tello-Lafoz, Rosa Liébana, Raquel Arcos
Diacylglycerol kinases (DGK) are a family of enzymes that catalyze the transformation of diacylglycerol into phosphatidic acid. In T lymphocytes, DGKα and ζ limit the activation of the PLCγ/Ras/ERK axis, providing a critical checkpoint to inhibit T cell responses. Upregulation of these isoforms limits Ras activation, leading to hypo-responsive, anergic states similar to those caused by tumors. Recent studies have identified DGKα upregulation in tumor lymphocyte infiltrates, and cells from DGKα and ζ deficient mice show enhanced antitumor activity, suggesting that limitation of DAG based signals by DGK is used by tumors to evade immune attack...
September 23, 2016: Advances in Biological Regulation
Doo-Sik Kong, Do-Hyun Nam, Shin-Hyuk Kang, Jae Won Lee, Jong-Hee Chang, Jeong-Hoon Kim, Young-Jin Lim, Young-Cho Koh, Yong-Gu Chung, Jae-Min Kim, Choong-Hyun Kim
PURPOSE: Adoptive cell immunotherapy involves an ex vivo expansion of autologous cytokine-induced killer (CIK) cells before their reinfusion into the host. We evaluated the efficacy and safety of CIK cell immunotherapy with radiotherapy-temozolomide (TMZ) for the treatment of newly diagnosed glioblastomas. EXPERIMENTAL DESIGN: In this multi-center, open-label, phase 3 study, we randomly assigned patients with newly diagnosed glioblastoma to receive CIK cell immunotherapy combined with standard TMZ chemoradiotherapy (CIK immunotherapy group) or standard TMZ chemoradiotherapy alone (control group)...
September 27, 2016: Oncotarget
Yasuharu Akasaki, Tetsuro Kikuchi, Sadamu Homma, Shigeo Koido, Toshifumi Ohkusa, Tetsunori Tasaki, Kazumi Hayashi, Hideo Komita, Nobuyuki Watanabe, Yuta Suzuki, Yohei Yamamoto, Ryosuke Mori, Takao Arai, Toshihide Tanaka, Tatsuhiro Joki, Takaaki Yanagisawa, Yuichi Murayama
BACKGROUND: This trial was designed to evaluate the safety and clinical responses to a combination of temozolomide (TMZ) chemotherapy and immunotherapy with fusions of DCs and glioma cells in patients with glioblastoma (GBM). METHOD: GBM patients were assigned to two groups: a group of recurrent GBMs after failing TMZ-chemotherapy against the initially diagnosed glioma (Group-R) or a group of newly diagnosed GBMs (Group-N). Autologous cultured glioma cells obtained from surgical specimens were fused with autologous DCs using polyethylene glycol...
September 29, 2016: Cancer Immunology, Immunotherapy: CII
Tanner M Johanns, Christopher A Miller, Ian G Dorward, Christina Tsien, Edward Chang, Arie Perry, Ravindra Uppaluri, Cole Ferguson, Robert E Schmidt, Sonika Dahiya, George Ansstas, Elaine R Mardis, Gavin P Dunn
We present the case of a patient with a left frontal glioblastoma with PNET features and hypermutated genotype in the setting of a POLE germline alteration. During standard-of-care chemoradiation, the patient developed a cervical spine metastasis and was subsequently treated with Pembrolizumab. Shortly thereafter, the patient developed an additional metastatic spinal lesion. Using whole exome DNA sequencing and clonal analysis, we report changes in the subclonal architecture throughout treatment. Furthermore, a persistently high neoantigen load was observed within all tumors...
September 28, 2016: Cancer Discovery
Mary Elizabeth Davis
BACKGROUND: Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults. Current treatment options at diagnosis are multimodal and include surgical resection, radiation, and chemotherapy. Significant advances in the understanding of the molecular pathology of GBM and associated cell signaling pathways have opened opportunities for new therapies for recurrent and newly diagnosed disease. Innovative treatments, such as tumor-treating fields (TTFields) and immunotherapy, give hope for enhanced survival...
October 1, 2016: Clinical Journal of Oncology Nursing
Mohanraj Ramachandran, Di Yu, Matheus Dyczynski, Sathishkumar Baskaran, Lei Zhang, Sirle Saul, Aleksei Lulla, Valeria Lulla, Sven Nelander, Anna Dimberg, Andres Merits, Justyna Leja-Jarblad, Magnus Essand
PURPOSE: Glioblastoma multiforme (GBM) and high-risk neuroblastoma are cancers with poor outcome. Immunotherapy in the form of neurotropic oncolytic viruses is a promising therapeutic strategy for these malignancies. Here we evaluate the oncolytic potential of the neurovirulent and partly interferon (IFN)-β-resistant Semliki Forest virus (SFV)-4 in GBMs and neuroblastomas. To reduce neurovirulence we constructed SFV4miRT, which is attenuated in normal CNS cells through insertion of microRNA target sequences for miR124, miR125, miR134 Experimental Design:Oncolytic activity of SFV4miRT was examined in mouse neuroblastoma and GBM cell lines and in patient-derived human glioblastoma cell cultures (HGCC)...
September 16, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Leiming Zhang, Junlin Ren, Hangyu Zhang, Gang Cheng, Yanming Xu, Shuangwu Yang, Chao Dong, Dandong Fang, Jianning Zhang, Angang Yang
Glioblastoma multiforme (GBM), which is associated with a high rate of morbidity and mortality, is among the most malignant and treatment-refractory neoplasms in human adults. As GBM is highly resistant to conventional therapies, immunotherapies are a promising treatment candidate. HER2 is an attractive target for GBM immunotherapy, as its expression is highly associated with various types of GBM. We previously reported that a novel HER2-targeted recombinant protein e23sFv-Fdt-casp6 has an antitumor effect on HER2-positive gastric cancer cells...
September 12, 2016: Oncology Reports
Ted K Yanagihara, Heva J Saadatmand, Tony J C Wang
Countless therapeutic strategies have been explored over many decades to prevent or slow the progression of glioblastoma. Despite radical changes in radiation management in other malignancies, there have been no major advances in the radiotherapeutic approach to glioblastoma in over 30 years. Past hopes to overcome inherent radioresistance with escalating doses have been met with frustration. However, prior clinical trials were performed before temozolomide, a radiosensitizer, altered the standard of care and this has renewed interest in dose escalation...
September 8, 2016: Journal of Neuro-oncology
Christopher D Corso, Ranjit S Bindra
Glioblastoma multiforme (GBM) is an aggressive intracranial tumor characterized by local and distant brain relapse despite aggressive therapy. Current standard treatment includes surgical resection followed by radiation with concurrent and adjuvant temozolomide as part of a combined modality approach. In this review, the historical basis for the current standard treatment is discussed as well as other recent combined modality successes and failures. An overview of emerging combined modality therapies for GBM is presented including immunotherapy, and rationally designed radiosensitizers...
October 2016: Seminars in Radiation Oncology
Cristina Riccadonna, Céline Yacoub Maroun, Romain Vuillefroy de Silly, Margaux Boehler, Marta Calvo Tardón, Simone Jueliger, Pietro Taverna, Leticia Barba, Eliana Marinari, Serena Pellegatta, Esen Yonca Bassoy, Denis Martinvalet, Pierre-Yves Dietrich, Paul R Walker
Malignant gliomas are aggressive brain tumours with very poor prognosis. The majority of glioma cells are differentiated (glioma-differentiated cells: GDCs), whereas the smaller population (glioma-initiating cells, GICs) is undifferentiated and resistant to conventional therapies. Therefore, to better target this pool of heterogeneous cells, a combination of diverse therapeutic approaches is envisaged. Here we investigated whether the immunosensitising properties of the hypomethylating agent decitabine can be extended to GICs...
2016: PloS One
Layale Yaghi, Isabelle Poras, Renata T Simoes, Eduardo A Donadi, Jörg Tost, Antoine Daunay, Bibiana Sgorla de Almeida, Edgardo D Carosella, Philippe Moreau
HLA-G is an immune checkpoint molecule with specific relevance in cancer immunotherapy. It was first identified in cytotrophoblasts, protecting the fetus from maternal rejection. HLA-G tissue expression is very restricted but induced in numerous malignant tumors such as glioblastoma, contributing to their immune escape. Hypoxia occurs during placenta and tumor development and was shown to activate HLA-G. We aimed to elucidate the mechanisms of HLA-G activation under conditions combining hypoxia-mimicking treatment and 5-aza-2'deoxycytidine, a DNA demethylating agent used in anti-cancer therapy which also induces HLA-G...
August 26, 2016: Oncotarget
Rekha Jain, Apurva Atak, Avani Yeola, Sanjeeva Srivastava
: Glioblastoma multiforme is Grade IV brain tumor associated with high mortality and limited therapeutics. Signal Transducer and Activator of Transcription 3 (STAT3) is persistently active in several cancers including gliomas, and plays a major role in disease progression and survival of glioma patients, thus being a potential therapeutic target for treatment. S3I201 and its analogs inhibit the transcriptional functions of STAT3 and reduce growth of tumor tissues. Here we have studied proteomic alteration associated with S3I201 treated U87 cells using 2-DE and Isobaric tags for relative and absolute quantitation coupled with mass spectrometry...
August 23, 2016: Journal of Proteomics
Marinos Tsiatas, Giannis Mountzios, Giuseppe Curigliano
The advent of immunotherapy has transformed the treatment paradigm of several solid tumors and is expected to influence the therapeutic algorithm even more in the future following the results of numerous ongoing clinical trials in a wide range of malignancies. Exploiting the anti-cancer effect of the immune system with the use of vaccines, viral vectors, and more lately with immune check-point inhibitors and chimeric antigen receptor modification, has been proven a successful therapeutic strategy in a broad spectrum of tumors...
July 2016: Annals of Translational Medicine
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