Cytokine-secreting herpes viral mutants effectively treat tumor in a murine metastatic colorectal liver model by oncolytic and T-cell-dependent mechanisms Journal Article

  

Authors:	DeRubertis, B. G.; Stiles, B. M.; Bhargava, A.; Gusani, N. J.; Hezel, M.; D'Angelica, M.; Fong, Y.
Article Title:	Cytokine-secreting herpes viral mutants effectively treat tumor in a murine metastatic colorectal liver model by oncolytic and T-cell-dependent mechanisms
Abstract:	In this model of hepatic micrometastases, the antitumor efficacy and role of the T-cell and natural killer (NK) cell populations were studied for oncolytic herpes simplex virus type-1 (HSV-1) viral mutants containing the granulocyte-monocyte colony stimulating factor (GM-CSF (NV1034)) or interluken-12 (IL-12 (NV1042)) cytokine genes. These were compared to saline and control virus (NV1023) in vitro and in vivo. HSV-1 mutants were assessed for cytotoxicity, replication and cytokine expression in CT-26 cells. A syngeneic micrometastatic liver model was then established in naive and immune cell-depleted animals to assess the antitumor efficacy of these viruses. In vitro cytotoxicity and viral replication were similar for each virus, resulting in greater than 80 and 98% cytotoxicity at multiplicity of infection of 1 and 10, respectively. Peak viral titers were 25- to 50-fold higher than initial titer and were not significantly different between viruses. In vivo, all three viruses reduced metastases relative to control, but cytokine-secreting viruses did so with greater efficacy compared to NV1023. This effect was abrogated by T-cell depletion, but not NK-cell depletion. Single-agent therapy with oncolytic viral agents containing GM-CSF or IL-12 is effective in a murine model of liver metastases and likely involves direct viral oncolysis and actions of specific immune effector cells. © 2007 Nature Publishing Group All rights reserved.
Keywords:	controlled study; protein expression; treatment outcome; nonhuman; comparative study; t-lymphocytes; animal cell; mouse; animals; mice; granulocyte macrophage colony stimulating factor; animal experiment; animal model; antineoplastic activity; cytotoxicity; cell population; animalia; genetic vectors; colorectal neoplasms; models, animal; liver metastasis; cytokine; liver; cytokines; t-lymphocytes, regulatory; gene therapy; murinae; simplexvirus; oncolytic virotherapy; cell culture techniques; natural killer cell; liver cancer; virus replication; metastases; t cell depletion; virus strain; herpes simplex virus 1; herpes; sodium chloride; t lymphocyte activation; interleukin 12; murine model; lymphocyte function; virus titration; human herpesvirus 1; oncolytic viral therapy; cytokine gene therapy; hsv; herpesvirus vector
Journal Title:	Cancer Gene Therapy
Volume:	14
Issue:	6
ISSN:	0929-1903
Publisher:	Nature Publishing Group
Date Published:	2007-06-01
Start Page:	590
End Page:	597
Language:	English
DOI:	10.1038/sj.cgt.7701053
PUBMED:	17431402
PROVIDER:	scopus
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-34249086265&partnerID=40&md5=99e91456d296d6a9e4dc86a96c46d491
Notes:	--- - "Cited By (since 1996): 9" - "Export Date: 17 November 2011" - "CODEN: CGTHE" - "Source: Scopus"

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