We evaluated the therapeutic potential of the replication competent vector VA7-EGFP, which is based on the avirulent Semliki Forest virus (SFV) strain A7 (74) carrying the EGFP marker gene in an orthotopic lung cancer tumor model in nude mice. We have previously shown that this oncolytic vector destroys tumor cells efficiently in vitro and in vivo (in subcutaneous tumor model). Tumor growth in animals with orthotopically implanted adenocarcinoma cells (A549) were monitored during the study with small animal CT. We show that locally administered virotherapy with VA7-EGFP increased survival rate in experimental lung cancer significantly (p < 0.001) comparable to results obtained with the second generation conditionally replicating adenoviral vector Ad5-D24TK-GFP, used for comparison. The limited efficacy in systemically administered oncolytic viruses is the essential problem in oncolytic virotherapy and also in this study we were not able to elicit significant response with systemic administration route. Despite the fact that tumor microenvironment in orthotopic lung cancer is more optimal, viruses failed to home to the tumors and were unable to initiate efficient intratumoral replication. Clearly, the efficacy of virotherapy is influenced by many factors such as the route of virus administration, immunological and physiological barriers and cancer cell-specific features (IFNresponsiveness). ' 2008 Wiley-Liss, Inc.Key words: SFV; CRAd; oncolytic; orthotopic tumor model; NSCLC The most common cancer and the most common cause of cancer death throughout the world is lung cancer. There were an estimated 1.35 million new lung cancer cases and 1.18 million deaths in 2002. 1 Based on differences in biological behavior and clinical course, lung cancer is classified into two main groups: non-small cell lung cancer (NSCLC) and small cell lung cancer. The tree major subtypes of NSCLCs are squamous cell carcinoma (epidermoid carcinoma), adenocarcinoma and large cell carcinoma. These cancer types account for nearly 80 % of all lung cancer cases. 2,3 For lung cancer, radical surgical resection is the only clinically relevant option for long-term survival. Unfortunately, at the time of diagnosis only 20-30% of the patients are eligible for radical resection. [4][5][6] Moreover, the conventional treatment modalities (radiotherapy and chemotherapy) remain mostly palliative (UICC Manual of Clinical Oncology, 2004). The failure to treat lung cancer successfully with conventional treatments highlights the need to develop new and innovative treatment modalities, such as gene therapy and oncolytic virotherapy.Oncolytic virotherapy induces tumor cell destruction through lysis of the malignant cells, caused by vigorous replication of the virus. This promising approach to specifically destroy the tumor tissue via genetically manipulated or natural viruses has been widely tested in experimental settings, 7,8 and a few promising regimens have reached the clinical phase. [9][10][11] Semliki Forest virus (SFV) (family: Togaviridae, genus: al...
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.
Sindbis vectors have shown remarkable antitumor efficacy and tumor-targeting capacity in animal models and hold promise for cancer therapy. Different packaging systems are used to produce propagation-incompetent Sindbis vectors. However, the vectors produced using either DH-BB single helper RNA or split helper RNA can spread in permissive cell cultures. We investigated the mechanisms of vector spreading and show, here, that recombination occurs between the replicon and DH-BB helper RNA, leading to formation of the full-length virus genome. Split helper RNA may not completely prevent wild-type reversion, although the frequency is greatly reduced. Contrary to propagation of Sindbis DH-BB vectors, Sindbis split helper vectors were frequently able to spread without cytopathic effect (CPE), a feature that was linked to wild-type reversion. Our results support the hypothesis that the non-cytopathic local spreading constantly observed with Sindbis split helper vector results from unspecific packaging of helper RNAs into vector particles and co-infection with particles containing replicon and helper RNAs. Several malignant cell lines with defective interferon responses were found to be permissive for non-cytopathic spreading of the Sindbis split helper vector. Interferon-α suppressed the spreading providing a possible option to control the vector.
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