title: Evaluation of cancer virotherapy with attenuated replicative Semliki forest virus in different rodent tumor models.
abstract: Semliki Forest virus (SFV) is one of the latest candidates for a virotherapeutic agent against cancer, and recent studies have demonstrated its efficacy in tumor models. In the present study, we examined the antitumor efficacy of an avirulent SFV strain A7(74) and its derivative, a replication-competent SFV vector VA7-EGFP, in a partially immunodeficient mouse tumor model (subcutaneous A549 human lung adenocarcinoma in NMRI nu/nu mouse) and in an immunocompetent rat tumor model (intracranial BT4C glioma in BDIX rat). When subcutaneous mouse tumors were injected 3 times with VA7-EGFP, intratumorally treated animals showed almost complete inhibition of tumor growth, while systemically treated mice displayed only delayed tumor growth (intravenous injection) or no response at all (intraperitoneal injection). This was at least partially due to a strong type I interferon (IFN) response in the tumors. The animals did not display any signs of abnormal behavior or encephalitis, even though SFV-positive foci were detected in the brain after the initial blood viremia. Intracranial rat tumors were injected directly with SFV A7(74) virus and monitored with magnetic resonance imaging. Tumor growth was significantly reduced (p < 0.05) with one virus injection, but the tumor size continued to increase after a lag period and none of the treated animals survived. Three virus injections or T-cell suppression with dexamethasone did not significantly improve treatment efficacy. It appeared that the local virotherapy induced extensive production of neutralizing anti-SFV antibodies that most likely contributed to the insufficient treatment efficacy. In conclusion, we show here that SFV A7(74) is a potential oncolytic agent for cancer virotherapy, but major immunological hurdles may need to be overcome before the virus can be clinically tested.
authors: Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute, University of Kuopio, Kuopio, Finland.
authors: Ann-Marie
authors: AM
authors: Määttä
authors: Timo
authors: T
authors: Liimatainen
authors: Tiina
authors: T
authors: Wahlfors
authors: Thomas
authors: T
authors: Wirth
authors: Markus
authors: M
authors: Vähä-Koskela
authors: Linda
authors: L
authors: Jansson
authors: Piia
authors: P
authors: Valonen
authors: Katja
authors: K
authors: Häkkinen
authors: Outi
authors: O
authors: Rautsi
authors: Riikka
authors: R
authors: Pellinen
authors: Kimmo
authors: K
authors: Mäkinen
authors: Juhana
authors: J
authors: Hakumäki
authors: Ari
authors: A
authors: Hinkkanen
authors: Jarmo
authors: J
authors: Wahlfors
mesh_terms: D000230:Adenocarcinoma / Q000628:therapy* / Q000821:virology; D000818:Animals; D001932:Brain Neoplasms / Q000628:therapy* / Q000821:virology; D045744:Cell Line, Tumor; D005822:Genetic Vectors; D005910:Glioma / Q000628:therapy* / Q000821:virology; D006801:Humans; D008175:Lung Neoplasms / Q000628:therapy* / Q000821:virology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D050130:Oncolytic Virotherapy; D051381:Rats; D012672:Semliki forest virus / Q000235:genetics*; D015996:Survival Rate; D014162:Transfection; D014183:Transplantation, Heterologous; D014779:Virus Replication