Adenoviral vector-mediated gene therapy for gliomas: coming of age

Abstract

Introduction Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults; it carries a dismal prognosis. Adenoviral vector (Ad)-mediated gene transfer is being developed as a promising therapeutic strategy for GBM. Preclinical studies have demonstrated safety and efficacy of adenovirus administration into the brain and tumor mass in rodents and into the non-human primates’ brain. Importantly Ads have been safely administered within the tumor resection cavity in humans. Areas Covered Background on GBM and Ad vectors; we describe gene therapy strategies for GBM and discuss the value of combination approaches. Finally we discuss the results of the human clinical trials for GBM that have used adenoviral vectors. Expert Opinion The transduction characteristics of Ad vectors, and their safety profile, added to their capacity to achieve high levels of transgene expression have made them powerful vectors for the treatment of GBM. Recent gene therapy successes in the treatment of retinal diseases and systemic brain metabolic diseases, encourages the development of gene therapy for malignant glioma. Exciting clinical trials are currently recruiting patients; although it is large randomized phase III controlled clinical trials that will provide the final decision on the success of gene therapy for the treatment of GBM.

Recent advances and future of immunotherapy for glioblastoma

“…Gene therapy initially developed to restore the function of defective or absent genes, and has gained popularity for the treatment of glioblastoma, due in part to the failure of other treatment options and to the successful design of many vectors able to safely deliver therapeutic genes into the tumor, such as viruses (adeno- and adeno-associated, retroviruses, herpes simplex virus, measles, reovirus, poliovirus), stem cells (neural, mesenchymal or embryonic), liposomes and nanoparticles 17, 83 . Current gene therapeutic approaches for glioma can be classified in four categories: suicide gene therapy, oncolytic virotherapy, tumor suppressor gene therapy and immuno-stimulatory therapy 84 .…”

Novel delivery approaches for cancer therapeutics

“…(a) Adenovirus (Ads) are non-enveloped viruses that possess linear ds (double stranded) DNA [72]. Ads can cause transduction safely along with high transgene expression, which makes it a very powerful vector to treat glioblastoma multiforme (GBM) [72].…”

“…Ads can cause transduction safely along with high transgene expression, which makes it a very powerful vector to treat glioblastoma multiforme (GBM) [72]. However, the application of Ads in gene therapy is limited by the low therapeutic efficacy after systemic administration and severe toxicity [73].…”

Preclinical Efficacy and Safety Profile of Allometrically Scaled Doses of Doxycycline Used to Turn “On” Therapeutic Transgene Expression from High-Capacity Adenoviral Vectors in a Glioma Model

“…[2][3][4] Replication-deficient first-generation adenoviral vectors (Ads) lacking the E1 gene, while effective at eliciting transgene expression, maintain low levels of viral gene expres-sion. The result is an adaptive immune response against the vector leading to transient transgene expression.…”