Combination vascular delivery of herpes simplex oncolytic viruses and amplicon mediated cytokine gene transfer is effective therapy for experimental liver cancer Journal Article


Authors: Zager, J. S.; Delman, K. A.; Malhotra, S.; Ebright, M. I.; Bennett, J. J.; Kates, T.; Halterman, M.; Federoff, H.; Fong, Y.
Article Title: Combination vascular delivery of herpes simplex oncolytic viruses and amplicon mediated cytokine gene transfer is effective therapy for experimental liver cancer
Abstract: Background: Herpes simplex type I (HSV)-based vectors have been used experimentally for suicide gene therapy, immunomodulatory gene delivery, and direct oncolytic therapy. The current study utilizes the novel concept of regional delivery of an oncolytic virus in combination with or serving as the helper virus for packaging herpes-based amplicon vectors carrying a cytokine transgene, with the goal of identifying if this combination is more efficacious than either modality alone. Materials and Methods: A replication competent oncolytic HSV (G207) and a replication incompetent HSV amplicon carrying the gene for the immunomodulatory cytokine IL-2 (HSV-IL2) were tested in murine syngeneic colorectal carcinoma and in rat hepatocellular carcinoma models. Liver tumors were treated with vascular delivery of (1) phosphate-buffered saline (PBS), (2) G207, (3) HSV-IL2, (4) G207 and HSV-IL2 mixed in combination (mG207/HSV- IL2), and (5) G207 as the helper virus for packaging the construct HSV-IL2 (pG207/HSV-IL2). Results: Tumor burden was significantly reduced in all treatment groups in both rats and mice treated with high- dose G207, HSV-IL2, or both (p < 0.02). When a low dose of virus was used in mice, anti-tumor efficacy was improved by use of G207 and HSV-IL2 in combination or with HSV-IL2 packaged by G207 (p < 0.001). This improvement was abolished when CD4+ and CDS+ lymphocytes were depleted, implying that the enhanced anti-tumor response to low-dose combined therapy is immune mediated. Conclusions: Vascular regional delivery of oncolytic and amplicon HSV vectors can be used to induce improved anti-tumor efficacy by combining oncolytic and immunostimulatory strategies.
Keywords: genetics; cd8+ t lymphocyte; cd8-positive t-lymphocytes; mouse; animal; metabolism; animals; mice; cell survival; interleukin 2; pathology; tumor cells, cultured; mice, inbred balb c; physiology; gene transfer; disease model; immunology; bagg albino mouse; cell culture; liver tumor; cd4+ t lymphocyte; cd4-positive t-lymphocytes; rat; gene therapy; herpesvirus 1, human; rats; neoplasm transplantation; randomization; disease models, animal; herpes simplex virus 1; interleukin-2; random allocation; gene transfer techniques; cancer transplantation; liver neoplasms, experimental; male; article; buffalo rat; rats, inbred buf
Journal Title: Molecular Medicine
Volume: 7
Issue: 8
ISSN: 1076-1551
Publisher: The Feinstein Institute for Medical Research  
Date Published: 2001-08-01
Start Page: 561
End Page: 568
Language: English
PUBMED: 11591892
PROVIDER: scopus
PMCID: PMC1950059
DOI/URL:
Notes: Export Date: 21 May 2015 -- Source: Scopus
Citation Impact
MSK Authors
  1. Keith Delman
    19 Delman
  2. Jonathan Zager
    15 Zager
  3. Michael Irwin Ebright
    13 Ebright
  4. Joseph J Bennett
    19 Bennett
  5. Yuman Fong
    775 Fong
  6. Tara J Kates
    3 Kates