Oncolytic Semliki Forest Virus Vector as a Novel Candidate against Unresectable Osteosarcoma

Abstract

Oncolytic viruses are a promising tool for treatment of cancer. We studied an oncolytic Semliki Forest virus (SFV) vector, VA7, carrying the enhanced green fluorescent protein gene (EGFP), as a novel virotherapy candidate against unresectable osteosarcoma. The efficiency and characteristics of the VA7-EGFP treatment were compared with a widely studied oncolytic adenovirus, Ad5#24, both in vitro and in vivo. VA7-EGFP resulted in more rapid oncolysis and was more efficient at low multiplicities of infection (MOI) when compared with Ad5#24 in vitro. Yet, in MG-63 cells, a subpopulation resistant to the VA7-EGFP vector emerged. In subcutaneous human osteosarcoma xenografts in nude mice treatment with either vector reduced tumor size, whereas tumors in control mice expanded quickly. The VA7-EGFP-treated tumors were either completely abolished or regressed to pinpoint size. The efficacy of VA7-EGFP vector was studied also in an orthotopic osteosarcoma nude mouse model characterized by highly aggressive tumor growth. Treatment with oncolytic SFV extended survival of the animals significantly (P < 0.01), yet none of the animals were finally cured. Sera from SFV-treated mice contained neutralizing antibodies, and as nude mice are not able to establish IgG response, the result points out the role of IgM class antibodies in clearance of virus from peripheral tumors. Furthermore, biodistribution analysis at the survival end point verified the presence of virus in some of the brain samples, which is in line with previous studies demonstrating that IgG is required for clearance of SFV from central nervous system.

Attenuation of Semliki Forest Virus Neurovirulence by MicroRNA-Mediated Detargeting

“…Replication-competent SFV vectors based on A7(74) have been considered promising tools for cancer virotherapy (17)(18)(19). Since SFV is neurotropic, infecting cells of the CNS, it has been of particular interest in virotherapy of brain tumors (see references 20 and 21).…”

Safe and Effective Treatment of Experimental Neuroblastoma and Glioblastoma Using Systemically Delivered Triple MicroRNA-Detargeted Oncolytic Semliki Forest Virus

“…The SFV A7/74 strain has been successfully tested safe for use as an oncolytic agent in several preclinical models for glioblastoma multiforme and other cancer types (8,31,32). However, type-I IFN responsive gliomas are resistant to A7/74 virotherapy in murine models (14).…”

“…It is an enveloped, positive strand RNA virus, having high replication efficacy and ability to kill a variety of tumor cells (7)(8)(9)(10). It has a natural neurotropism (11), making it an attractive candidate for use as an oncolytic immunotherapy agent to treat neuroblastoma and glioblastoma multiforme.…”

Alphavirus Vectors for Therapy of Neurological Disorders

“…Interestingly, the expression was highly glial cell specific at 37°C, but at 31°C the GFP expression was similar to the wild type phenotype demonstrating neuron-specific (up to 94%) expression. Further development has included using oncolytic SFV vectors against lung cancer [26] and osteosarcoma [27] in mouse models. Recently, intravenous administration of oncolytic SFV-A7 provided therapeutic efficacy in nude mice with human glioma xenografts [28].…”