Current Approaches for Glioma Gene Therapy and Virotherapy

Abstract

Glioblastoma (GBM) is the most common and aggressive primary brain tumor in the adult population and it carries a dismal prognosis. Inefficient drug delivery across the blood brain barrier (BBB), an immunosuppressive tumor microenvironment (TME) and development of drug resistance are key barriers to successful glioma treatment. Since gliomas occur through sequential acquisition of genetic alterations, gene therapy, which enables to modification of the genetic make-up of target cells, appears to be a promising approach to overcome the obstacles encountered by current therapeutic strategies. Gene therapy is a rapidly evolving field with the ultimate goal of achieving specific delivery of therapeutic molecules using either viral or non-viral delivery vehicles. Gene therapy can also be used to enhance immune responses to tumor antigens, reprogram the TME aiming at blocking glioma-mediated immunosuppression and normalize angiogenesis. Nano-particles-mediated gene therapy is currently being developed to overcome the BBB for glioma treatment. Another approach to enhance the anti-glioma efficacy is the implementation of viro-immunotherapy using oncolytic viruses, which are immunogenic. Oncolytic viruses kill tumor cells due to cancer cell-specific viral replication, and can also initiate an anti-tumor immunity. However, concerns still remain related to off target effects, and therapeutic and transduction efficiency. In this review, we describe the rationale and strategies as well as advantages and disadvantages of current gene therapy approaches against gliomas in clinical and preclinical studies. This includes different delivery systems comprising of viral, and non-viral delivery platforms along with suicide/prodrug, oncolytic, cytokine, and tumor suppressor-mediated gene therapy approaches. In addition, advances in glioma treatment through BBB-disruptive gene therapy and anti-EGFRvIII/VEGFR gene therapy are also discussed. Finally, we discuss the results of gene therapy-mediated human clinical trials for gliomas. In summary, we highlight the progress, prospects and remaining challenges of gene therapies aiming at broadening our understanding and highlighting the therapeutic arsenal for GBM.

Current Immunotherapeutic Approaches for Malignant Gliomas

“…Cytokines such as IL2, IL4, IL12, and IFN-γ can induce robust immune responses to glioma cells, and virus-mediated cytokine therapy has been shown to be effective in treating gliomas [ 118 119 ]. Intratumoral injection of a combination of adenoviral (Ad) vector expressing Flt3L (Ad-Flt3L) and an Ad vector expressing herpes simplex virus type 1–thymidine kinase (Ad-TK) showed tumor regression and long-term survival in animal models of glioblastoma [ 120 121 ].…”

Glioblastoma pharmacotherapy: A multifaceted perspective of conventional and emerging treatments (Review)

“…Therefore, gene or nucleic acid carriers that are able to successfully penetrate into the tumour tissue have been extensively studied. Although several clinical trials have evaluated the use of viral vectors for GBM gene therapy, none achieved FDA approval, mainly due to inefficient viral delivery, lack of tumour penetration and insufficient efficacy (138,139). However, a number of non-viral vectors have shown promising results in pre-clinical trials and have entered clinical trial testing (140).…”

Role of RAGE and Its Ligands on Inflammatory Responses to Brain Tumors

“…Most patients with gliomas undergo surgical resection of the tumor, followed by radiation and chemotherapy ( Davis, 2016 ; Banerjee et al, 2021 ). The goal of the surgery is to remove most of tumor without damaging the surrounding normal brain tissue.…”

“…For low-grade gliomas, the extent of resection has been associated with better overall survival ( Young et al, 2015 ; Morshed et al, 2019 ); but for higher-grade gliomas, survival benefit from aggressive surgery is modest ( Young et al, 2015 ). Following surgery, patients are then treated with radiation and chemotherapy (typically temozolomide) as an adjuvant treatment ( Banerjee et al, 2021 ; Singh et al, 2021 ). While advancements in these therapies have marginally extended the overall survival for patients with glioblastoma, tumor relapse is inevitable.…”