A Capsid-Modified, Conditionally Replicating Oncolytic Adenovirus Vector Expressing TRAIL Leads to Enhanced Cancer Cell Killing in Human Glioblastoma Models

Abstract

Glioblastoma multiforme (GBM) is the most aggressive brain tumor, and patients rarely survive for more than 2 years. Gene therapy may offer new treatment options and improve the prognosis for patients with GBM. Adenovirus-mediated gene therapy strategies for brain tumors have been limited by inefficient gene transfer due to low expression of the adenovirus serotype 5 (Ad5) receptor. We have used an adenovirus vector that specifically replicates in tumor cells and uses an Ad5 capsid and the adenovirus serotype (Ad35) fiber for efficient infection of malignant tumor cells. This vector also expresses adenovirus E1A and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in a tumor-specific manner. Here, we show that this oncolytic vector (Ad5/Ad35.IR-E1A/TRAIL) efficiently infects the GBM tumor cell lines SF767, T98G, and U-87 MG. Tumor cell killing was markedly enhanced with Ad5/Ad35.IR-E1A/TRAIL compared with wildtype Ad5 and Ad35 virus or Ad5/Ad35.IR-E1A-vectors without TRAIL expression in vitro. In vivo experiments using s.c. xenografted U-87 MG cells in NOD/SCID mice showed a significant growth delay of tumors after i.t. injection of Ad5/Ad35.IR-E1A/TRAIL, whereas adenovirus wild-type injections showed only marginal or no effect. Our findings indicate that the use of a capsid-modified adenoviral vector, in combination with TRAIL expression, is a promising novel approach for gene therapy of glioblastoma. [Cancer Res 2007;67(18):8783-90]

Clinical development directions in oncolytic viral therapy

“…Physical shielding to enhance delivery and reduce viral clearance is being tested [170][171][172][173][174][175] (plus Rehman 2001). Currently, liposome encapsulated, polymer coated, and cell carrier modes of oncolytic virus delivery are being developed for preclinical testing.…”

“…The liposome and polymer coated methods can be coated with tumorspecific antibodies, peptides or small molecules to further enhance tumor-specific uptake and delivery. [176][177][178][179][180][181][182][183][184] Plasmapheresis rotation of viral serotype [170][171][172][173][174][175] and B-cell suppression have had limited testing as methods to reduce normal immune reactivity against administered viral particles. Restoration of the E3 region of the viral genome or E3 protein activity, in an effort to limit effects of tumor necrosis factor-a through combination with soluble tumor necrosis factor-a receptors, demonstrates positive effect.…”

“…administration without further replication or spread. Consequently, new approaches which enhance viral replication and cell to cell spread are under investigation, 174,186,187 while at the same time attempts are underway to identify more highly replicative viruses. Improving development of tumor-specific promoters to limit viral replication in malignant tissue may enable greater confidence in the utilization of replication aggressive viruses.…”

Viruses, gene therapy and stem cells for the treatment of human glioma

“…18 Thus, use of a capsid-modified adenoviral vector, in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression, increased the infectivity and cell death of glioma cells compared with unmodified virus. 19 Adenoviral vectors encoding either the extracellular domain of vascular endothelial growth factor receptor-2-Fc fusion protein (Ad-VEGFR2-Fc) alone, soluble endostatin alone or a combination of both were injected in mice bearing U87 intracranial gliomas. The results suggested that systemic delivery and sustained production of endostatin and soluble VEGFR2 could slow by 60-70% intracranial glial tumor growth by both reducing cell proliferation and increasing tumor apoptosis.…”

Augmentation of adenovirus 5 vector-mediated gene transduction under physiological pH conditions by a chitosan/NaHCO3 solution

“…3 As some cells express CAR at low to no levels, some important gene therapy target cells, such as hematopoietic cells, endothelial cells, skeletal and smooth muscle cells, and certain cancer cells are refractive to rAdv infection. [4][5][6][7][8][9][10] Therefore, improvement of rAdv-mediated transduction (AMGT) to cells that do not contain CAR or express it only at low-levels can advance the practice of rAdv-based gene therapy.…”