Abstract
Malignant brain tumors remain refractory to adenovirus type 5 (Ad5)-based gene therapy, mostly due to the lack of the primary Ad5 receptor, the coxsackie and adenovirus receptor, on brain tumor cells. To bypass the dependence on coxsackie and adenovirus receptor for adenoviral entry and infectivity, we used a novel, double targeted Ad5 backbone-based vector carrying a chimeric Ad5/3 fiber with integrin-binding RGD motif incorporated in its Ad3 knob domain. We then tested the new virus in vitro and in vivo in the setting of malignant glioma. Ad5/3-RGD showed a 10-fold increase in gene expression in passaged cell lines and up to 75-fold increase in primary tumors obtained from patients relative to the control. These results were further corroborated in our in vivo human glioma xenograft model, where the Ad5/3-RGD vector showed a 1,000-fold increase in infectivity as compared with the control. Taken together, our findings indicate that Ad5/3-RGD may be a superior vector for applications in glioma gene therapy and therefore warrants further attention in the field of neuro-oncology.
Highlights
Malignant glioma, in particular glioblastoma multiforme, represents a devastating form of primary brain cancer
The use of adenovirus type 5 (Ad5) for cancer therapy is limited by the deficiency of its primary cell attachment receptor, or coxsackie and adenovirus receptor (CAR), on brain tumors cells (11 – 15)
Ad5 retargeting to alternate receptors through a fiber genetic modification can be used to circumvent CAR dependence of its natural tropism, and thereby achieve infectivity enhancement
Summary
In particular glioblastoma multiforme, represents a devastating form of primary brain cancer. Gene therapy is a novel strategy that can be used to treat glioblastoma multiforme. Because these tumors rarely metastasize outside of the central nervous system and recur in proximity to the original site, direct delivery of a highly therapeutic gene offers the potential to effectively target these tumors. A recent phase I trial using ONYX-015, a mutated oncolytic adenovirus, showed that injection of up to 1010 plaque-forming units was well tolerated in patients with malignant glioma (4). Whereas further research will be needed to ascertain the therapeutic value of this virus, studies such as this clearly provide the scientific rationale for further development of targeted adenoviral gene therapies for glioblastoma multiforme
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