title: Effective intravenous therapy of murine pulmonary metastases with an oncolytic herpes virus expressing interleukin 12.
abstract: OBJECTIVE
  There currently is no therapy that enhances the survival of patients with distantly metastatic squamous cell carcinoma (SCC). Engineered herpes oncolytic viruses are effective therapeutic agents when delivered directly to tumors in animal models, but their efficacy in treating disseminated disease is poorly defined.
  
  
  METHODS
  We treated disseminated pulmonary SCC in mice with an interleukin (IL)-12-expressing oncolytic herpes virus (NV1042) or with the parent oncolytic virus (NV1023, IL-12 deficient) by i.v. tail vein administration.
  
  
  RESULTS
  Lung IL-12 was 16.1 pg/mg and IFN-gamma was 4.3 pg/mg at day 1 after a single dose of NV1042 (5 x 10(7) plaque-forming units); levels of both were undetectable for NV1023. 5-Bromo-4-chloro-3-indolyl-beta-D-galactopyranoside histochemistry demonstrated viral infection of disseminated pulmonary tumor nodules by both vectors at day 1, with sparing of adjacent alveolar cells. NV1042-treated lungs showed no surface nodules at day 12, in contrast to NV1023-treated (92 +/- 27 surface nodules) and PBS-treated (225 +/- 9 surface nodules) lungs. Significantly enhanced survival was observed in NV1042-treated animals compared with NV1023- and PBS-treated animals (log rank < 0.05). In animals with a low tumor burden, 100% of NV1042-treated, 70% of NV1023-treated, and none of the control animals achieved long-term survival. NV1042 efficacy was similar to NV1023 efficacy in animals depleted of CD4/CD8 T lymphocytes, showing that IL-12 expression enhances oncolytic activity through immune effects. Histology showed no cytopathic effects in non-tumor-bearing lung, brain, spleen, liver, and pancreas after completion of viral therapy. No animals demonstrated any visible side effects attributable to viral therapy.
  
  
  CONCLUSIONS
  The i.v. delivery of an oncolytic herpes virus may achieve effective infection, oncolysis, and transgene expression at distant tumor sites. This approach to systemic therapy combining oncolysis with IL-12 immune stimulation led to significantly improved survival in animals with disseminated SCC.
authors.affiliation: Head and Neck Service, Laboratory of Epithelial Cancer Biology,Hepatobiliary Service, andDepartments of Surgery andPathology, Memorial Sloan-Kettering Cancer Center, New York, New York, andMediGene Inc., San Diego, California.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Wong
authors.affiliation: Head and Neck Service, Laboratory of Epithelial Cancer Biology,Hepatobiliary Service, andDepartments of Surgery andPathology, Memorial Sloan-Kettering Cancer Center, New York, New York, andMediGene Inc., San Diego, California.
authors.forename: Mei-Ki
authors.initials: MK
authors.lastname: Chan
authors.affiliation: Head and Neck Service, Laboratory of Epithelial Cancer Biology,Hepatobiliary Service, andDepartments of Surgery andPathology, Memorial Sloan-Kettering Cancer Center, New York, New York, andMediGene Inc., San Diego, California.
authors.forename: Zhenkun
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Head and Neck Service, Laboratory of Epithelial Cancer Biology,Hepatobiliary Service, andDepartments of Surgery andPathology, Memorial Sloan-Kettering Cancer Center, New York, New York, andMediGene Inc., San Diego, California.
authors.forename: Teresa H
authors.initials: TH
authors.lastname: Kim
authors.affiliation: Head and Neck Service, Laboratory of Epithelial Cancer Biology,Hepatobiliary Service, andDepartments of Surgery andPathology, Memorial Sloan-Kettering Cancer Center, New York, New York, andMediGene Inc., San Diego, California.
authors.forename: Amit
authors.initials: A
authors.lastname: Bhargava
authors.affiliation: Head and Neck Service, Laboratory of Epithelial Cancer Biology,Hepatobiliary Service, andDepartments of Surgery andPathology, Memorial Sloan-Kettering Cancer Center, New York, New York, andMediGene Inc., San Diego, California.
authors.forename: Brendon M
authors.initials: BM
authors.lastname: Stiles
authors.affiliation: Head and Neck Service, Laboratory of Epithelial Cancer Biology,Hepatobiliary Service, andDepartments of Surgery andPathology, Memorial Sloan-Kettering Cancer Center, New York, New York, andMediGene Inc., San Diego, California.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Horsburgh
authors.affiliation: Head and Neck Service, Laboratory of Epithelial Cancer Biology,Hepatobiliary Service, andDepartments of Surgery andPathology, Memorial Sloan-Kettering Cancer Center, New York, New York, andMediGene Inc., San Diego, California.
authors.forename: Jatin P
authors.initials: JP
authors.lastname: Shah
authors.affiliation: Head and Neck Service, Laboratory of Epithelial Cancer Biology,Hepatobiliary Service, andDepartments of Surgery andPathology, Memorial Sloan-Kettering Cancer Center, New York, New York, andMediGene Inc., San Diego, California.
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Ghossein
authors.affiliation: Head and Neck Service, Laboratory of Epithelial Cancer Biology,Hepatobiliary Service, andDepartments of Surgery andPathology, Memorial Sloan-Kettering Cancer Center, New York, New York, andMediGene Inc., San Diego, California.
authors.forename: Bhuvanesh
authors.initials: B
authors.lastname: Singh
authors.affiliation: Head and Neck Service, Laboratory of Epithelial Cancer Biology,Hepatobiliary Service, andDepartments of Surgery andPathology, Memorial Sloan-Kettering Cancer Center, New York, New York, andMediGene Inc., San Diego, California.
authors.forename: Yuman
authors.initials: Y
authors.lastname: Fong
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000556:secondary / Q000628:therapy*; D003673:Defective Viruses; D015316:Genetic Therapy; D018259:Herpesvirus 1, Human / Q000502:physiology*; D007275:Injections, Intravenous; D007371:Interferon-gamma / Q000494:pharmacology; D018664:Interleukin-12 / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary / Q000628:therapy*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D014779:Virus Replication
chemical_list: D018664:Interleukin-12; D007371:Interferon-gamma