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Evaluation of cancer virotherapy with attenuated replicative Semliki forest virus in different rodent tumor models
Author(s) -
Määttä AnnMarie,
Liimatainen Timo,
Wahlfors Tiina,
Wirth Thomas,
VähäKoskela Markus,
Jansson Linda,
Valonen Piia,
Häkkinen Katja,
Rautsi Outi,
Pellinen Riikka,
Mäkinen Kimmo,
Hakumäki Juhana,
Hinkkanen Ari,
Wahlfors Jarmo
Publication year - 2007
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.22758
Subject(s) - semliki forest virus , oncolytic virus , virotherapy , alphavirus , virus , virology , biology , glioma , cancer research , immunology , medicine , rna , biochemistry , gene
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. © 2007 Wiley‐Liss, Inc.