Immunotherapy and Epigenetic Pathway Modulation in Glioblastoma Multiforme

Abstract

Glioblastoma Multiforme (GBM) is the most common malignant primary brain tumor. Despite aggressive multimodality treatment it remains one of the most challenging and intractable cancers (1]. While current standard of care treatment for GBM is maximal safe surgical resection, systemic chemotherapy with Temozolimide (TMZ), and radiation therapy, the current prognosis of GBM patients remains poor, with a median overall survival of 12–15 months (2, 3). Therefore, other treatments are needed to provide better outcomes for GBM patients. Immunotherapy is one of the most promising new cancer treatment approaches. Immunotherapy drugs have obtained regulatory approval in a variety of cancers including melanoma (4), Hodgkin lymphoma (5), and non-small cell lung cancer (6). The basis of immunotherapy in cancer treatment is linked to stimulating the immune system to recognize cancer cells as foreign, thereby leading to the eventual elimination of the tumor. One form of immunotherapy utilizes vaccines that target tumor antigens (7), while other approaches utilize T-cells in patients to stimulate them to attack tumor cells (8). Despite intensive efforts all approaches have not been overtly successful (9), suggesting that we need to better understand the underlying biology of tumor cells and their environment as they respond to immunotherapy. Recent studies have elucidated epigenetic pathway regulation of GBM tumor expansion (10), suggesting that combined epigenetic pathway inhibition with immunotherapy may be feasible. In this review, we discuss current GBM clinical trials and how immune system interactions with epigenetic pathways and signaling nodes can be delineated to uncover potential combination therapies for this incurable disease.

Physiological Imaging Methods for Evaluating Response to Immunotherapies in Glioblastomas

“…Several promising novel immunotherapeutic approaches are being actively investigated in clinical trials for GBM treatment ( Figure 1 ) [ 7 , 8 , 9 , 10 , 11 ]. These include inhibitors of immune checkpoint regulators, antitumor vaccinations, adoptive transfer of genetically modified and cytotoxic T-lymphocytes, and generation of genetically engineered oncolytic viruses.…”

“…In the quest for an effective treatment, several immunotherapeutic approaches have been introduced in recent years that have been designed to harness patient’s immune response to fight and eliminate tumor cells. Broadly, these novel strategies can be divided into four major classes: immunomodulators, active immunotherapy, adoptive immunotherapy, and oncolytic viral therapy [ 5 , 6 , 7 , 8 , 9 , 10 , 11 ]. Although immunotherapy has yet to be established for providing consistent clinical benefits in GBM, several immunotherapy trials have reported acceptable safety profiles and survival benefits in small cohorts of patients [ 12 , 13 , 14 , 15 ].…”

Polysaccharide-based nanomedicines for cancer immunotherapy: A review

“…Since Th1 is one of main anti-tumor functioning T lymphocytes and the induction of Tregs is one of the mechanisms for immunosuppression and immune evasion of tumor cells [ [183] , [184] , [185] ], these siRNA-loaded PEG-chitosan-lactate nanomedicines could effectively stimulate anti-tumor immune responses selectively at the tumor sites without systemic injection of A2AR antagonists that may cause unwanted side effects through induction of Th1 and suppression of Tregs. As the induction of antitumor immune responses requires activation or inhibition of different receptors or signaling pathways, administration of multi-type nucleic acids targeting at different pathways may have the potential to further enhance the efficacy of cancer immunotherapy [ 186 , 187 ]. However, how to achieve co-delivery of different nucleic acids to targeting sites and simultaneously maintain their inherent bioactivity, is still a great challenge.…”

Coding of Glioblastoma Progression and Therapy Resistance through Long Noncoding RNAs

“…Immunotherapy alone and in combination with radiation and chemotherapy is currently explored as a method for glioblastoma treatment [119], but it still needs to prove its clinical importance. The importance of lncRNAs in immune regulation of glioblastomas is also being examined.…”