Replication competent Semliki Forest virus prolongs survival in experimental lung cancer

Abstract

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...

High efficiency of alphaviral gene transfer in combination with 5-fluorouracil in a mouse mammary tumor model

“…Due to the rapid induction of apoptosis in infected cells, treatment with natural oncolytic alphaviral vectors results in tumor regression [12-15]. Administration of replication-deficient vectors encoding reporter or immunomodulator genes, such as cytokines or growth factors, has also been demonstrated.…”

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).…”

Oncolytic Alphaviruses in Cancer Immunotherapy

“…The natural tumor targeting of SIN [60] and the recent discovery of the naturally oncolytic M1 alphavirus [83] represent potential assets for enhanced cancer immunotherapy applications. Several studies have been conducted with the attenuated SFV VA7 vector [70,71,72,75,76] resulting in therapeutic effect in immunized mice. Clearly, a stronger impact was obtained after intratumoral injections than systemic administration.…”

“…In another study, locally administered SFV VA7-EGFP increased the survival rate in mice with implanted A549 lung adenocarcinoma cells [75]. However, the systemic delivery did not elicit significant anti-tumor responses, which might be related to the route of administration, immunological barriers and IFN responsiveness.…”