Current Status of Gene Therapy for Brain Tumors∗

Abstract

Glioblastoma (GBM) is the most common and deadliest primary brain tumor in adults, with current treatments having limited impact on disease progression. Therefore the development of alternative treatment options is greatly needed. Gene therapy is a treatment strategy that relies on the delivery of genetic material, usually transgenes or viruses, into cells for therapeutic purposes, and has been applied to GBM with increasing promise. We have included selectively replicationcompetent oncolytic viruses within this strategy, although the virus acts directly as a complex biologic anti-tumor agent rather than as a classic gene delivery vehicle. GBM is a good candidate for gene therapy because tumors remain locally within the brain and only rarely metastasize to other tissues; the majority of cells in the brain are post-mitotic, which allows for specific targeting of dividing tumor cells; and tumors can often be accessed neurosurgically for administration of therapy. Delivery vehicles used for brain tumors include nonreplicating viral vectors, normal adult stem/progenitor cells, and oncolytic viruses. The therapeutic transgenes or viruses are typically cytotoxic or express prodrug activating suicide genes to kill glioma cells, immunostimulatory to induce or amplify anti-tumor immune responses, and/or modify the tumor microenvironment such as blocking angiogenesis. This review describes current preclinical and clinical gene therapy strategies for the treatment of glioma.Treating malignant gliomas, of which glioblastoma (GBM) is the most common and least curable, remains a daunting challenge even after substantial efforts to develop alternative therapies. The current standard of care is maximal surgical resection followed by radiation and temozolomide chemotherapy; however, the median survival still remains less than 15 months. 1,2 This poor survival is due to the aggressive and invasive nature of the tumor cells, resistance to treatment, and the challenges of delivering therapeutics into the brain. 3 GBM is thought to be derived from a small population of glioblastoma stem cells (GSCs), so-called because of their stem cell-like properties of self-renewal and multilineage differentiation while being highly tumorigenic. [4][5][6] GSCs have become an important model for studying GBM because their xenografts mimic the heterogeneous histopathology of the patient's tumor from which they were derived 7,8 and they remain genotypically similar to the patient's tumor, in contrast to serum-cultured cell lines. 9 These cells have provided insights into the origin of tumor-initiating cells and new targets for therapy. Other GBM animal models include established glioma cell lines (human and rodent) implanted intracranially into immunodeficient or immunocompetent animals, and genetically engineered mice that spontaneously develop brain tumors or are induced with viral vectors. 10 GENE DELIVERY VEHICLES FOR GLIOBLASTOMAMost gene therapies for GBM use biologic vectors such as viruses or cells. Replicationdefective or non-repli...

Oncolytic virus-based suicide gene therapy for cancer treatment: a perspective of the clinical trials conducted at Henry Ford Health

“…The immune system is also activated due to the viral infection, leading to unmasking of tumor antigens, aiding the immune system in recognizing and attacking neoplasms [ 57 ]. Thus, oncolytic viruses can be used not only as a vector but also as an active cytotoxic and inflammatory agent [ 59 ].

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Efficacy of Oncolytic Herpes Simplex Virus T-VEC Combined with BET Inhibitors as an Innovative Therapy Approach for NUT Carcinoma

“…Furthermore, this process, called oncolysis, leads to the release of tumor-specific antigens in a highly inflamed tumor microenvironment, thus enabling a profound systemic anti-tumoral immune reaction, which is considered the key success factor of this biological cancer therapy [ 17 ]. Selectivity of OVs for cancer cells is due to defects found in many cancers, such as the loss of tumor suppressors, defective apoptosis pathways, activation of oncogenic signaling pathways, and most importantly, the loss of antiviral defense mechanisms [ 18 ]. Hence, oncolytic immunovirotherapy represents a promising therapeutic approach and also a potential combination partner for BET inhibitors for the treatment of NC.…”