Effective intravenous therapy of murine pulmonary metastases with an oncolytic herpes virus expressing interleukin 12.
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.
Wong
Richard J
RJ
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.
Chan
Mei-Ki
MK
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.
Yu
Zhenkun
Z
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.
Kim
Teresa H
TH
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.
Bhargava
Amit
A
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.
Stiles
Brendon M
BM
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.
Horsburgh
Brian C
BC
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.
Shah
Jatin P
JP
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.
Ghossein
Ronald A
RA
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.
Singh
Bhuvanesh
B
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.
Fong
Yuman
Y
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.
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
D018664:Interleukin-12; D007371:Interferon-gamma