Single-cycle viral gene expression, rather than progressive replication and oncolysis, is required for VSV therapy of B16 melanoma

被引:64
作者
Galivo, F.
Diaz, R. M. [2 ]
Wongthida, P.
Thompson, J.
Kottke, T.
Barber, G. [3 ,4 ]
Melcher, A. [5 ]
Vile, R. [1 ,2 ,5 ]
机构
[1] Mayo Clin, Mol Med Program Guggenheim 1842C, Dept Mol Med, Rochester, MN 55905 USA
[2] Mayo Clin, Dept Immunol, Rochester, MN 55905 USA
[3] Univ Miami, Sch Med, Dept Microbiol & Immunol, Miami, FL USA
[4] Univ Miami, Sch Med, Sylvester Comprehens Canc Ctr, Miami, FL USA
[5] Univ Leeds, Inst Mol Med, Leeds, W Yorkshire, England
关键词
oncolytic viruses; experimental melanoma; interferon type I; virus replication; rhabdovirus; VESICULAR STOMATITIS-VIRUS; T-CELL THERAPY; HEPATOCELLULAR-CARCINOMA; COMPETENT VECTOR; DENDRITIC CELLS; CANCER; RESPONSES; TUMORS; VIROTHERAPY; INTERFERON;
D O I
10.1038/gt.2009.161
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
A fully intact immune system would be expected to hinder the efficacy of oncolytic virotherapy by inhibiting viral replication. Simultaneously, however, it may also enhance antitumor therapy through initiation of proinflammatory, antiviral cytokine responses at the tumor site. The aim of this study was to investigate the role of a fully intact immune system on the antitumor efficacy of an oncolytic virus. In this respect, injection of oncolytic vesicular stomatitis virus (VSV) into subcutaneous B16ova melanomas in C57Bl/6 mice leads to tumor regression, but it is not associated with viral replicative burst in the tumor. In contrast, intratumoral delivery of VSV induces an acute proinflammatory reaction, which quickly resolves concomitantly with virus clearance. Consistent with the hypothesis that therapy may not be dependent on the ability of VSV to undergo progressive rounds of replication, a single-cycle VSV is equally effective as a fully replication-competent VSV, whereas inactivated viruses do not generate therapy. Even though therapy is dependent on host CD8+ and natural killer cells, these effects are not associated with interferon-g-dependent responses against either the virus or tumor. There is, however, a strong correlation between viral gene expression, induction of proinflammatory reaction in the tumor and in vivo therapy. Overall, our results suggest that acute innate antiviral immune response, which rapidly clears VSV from B16ova tumors, is associated with the therapy observed in this model. Therefore, the antiviral immune response to an oncolytic virus mediates an intricate balance between safety, restriction of oncolysis and, potentially, significant immune-mediated antitumor therapy. Gene Therapy (2010) 17, 158-170; doi: 10.1038/gt.2009.161; published online 17 December 2009
引用
收藏
页码:158 / 170
页数:13
相关论文
共 40 条
[1]   Exponential enhancement of oncolytic vesicular stomatitis virus potency by vector-mediated suppression of inflammatory responses in vivo [J].
Altomonte, Jennifer ;
Wu, Lan ;
Chen, Li ;
Meseck, Marcia ;
Ebert, Oliver ;
Garcia-Sastre, Adolfo ;
Fallon, John ;
Woo, Savio L. C. .
MOLECULAR THERAPY, 2008, 16 (01) :146-153
[2]   FORMALIN INACTIVATION OF VESICULAR STOMATITIS-VIRUS IMPAIRS T-CELL- BUT NOT T-HELP-INDEPENDENT B-CELL RESPONSES [J].
BACHMANN, MF ;
KUNDIG, TM ;
KALBERER, CP ;
HENGARTNER, H ;
ZINKERNAGEL, RM .
JOURNAL OF VIROLOGY, 1993, 67 (07) :3917-3922
[3]   Oncolytic activity of vesicular stomatitis virus is effective against tumors exhibiting aberrant p53, Ras, or Myc function and involves the induction of apoptosis [J].
Balachandran, S ;
Porosnicu, M ;
Barber, GN .
JOURNAL OF VIROLOGY, 2001, 75 (07) :3474-3479
[4]   Vesicular stomatitis virus (VSV) therapy of tumors [J].
Balachandran, S ;
Barber, GN .
IUBMB LIFE, 2000, 50 (02) :135-138
[5]   IFN-γ mediates CD4+ T-cell loss and impairs secondary antitumor responses after successful initial immunotherapy [J].
Berner, Vanessa ;
Liu, Haiyan ;
Zhou, Qing ;
Alderson, Kory L. ;
Sun, Kai ;
Weiss, Jonathan M. ;
Back, Timothy C. ;
Longo, Dan L. ;
Blazar, Bruce R. ;
Wiltrout, Robert H. ;
Welniak, Lisbeth A. ;
Redelman, Doug ;
Murphy, William J. .
NATURE MEDICINE, 2007, 13 (03) :354-360
[6]   Replication-competent rhabdoviruses with human immunodeficiency virus type 1 coats and green fluorescent protein: Entry by a pH-independent pathway [J].
Boritz, E ;
Gerlach, J ;
Johnson, JE ;
Rose, JK .
JOURNAL OF VIROLOGY, 1999, 73 (08) :6937-6945
[7]   Oncolytic viruses [J].
Chiocca, EA .
NATURE REVIEWS CANCER, 2002, 2 (12) :938-950
[8]   Oncolytic immunovirotherapy for melanoma using vesicular stomatitis virus [J].
Diaz, Rosa Maria ;
Galivo, Feorillo ;
Kottke, Timothy ;
Wongthida, Phonphimon ;
Qiao, Jian ;
Thompson, Jill ;
Valdes, Mikael ;
Barber, Glen ;
Vile, Richard G. .
CANCER RESEARCH, 2007, 67 (06) :2840-2848
[9]   Systemic therapy of experimental breast cancer metastases by mutant vesicular stomatitis virus in immune-competent mice [J].
Ebert, O ;
Harbaran, S ;
Shinozaki, K ;
Woo, SLC .
CANCER GENE THERAPY, 2005, 12 (04) :350-358
[10]  
Ebert O, 2003, CANCER RES, V63, P3605