Effective Intravenous Therapy of Murine Pulmonary Metastases with an Oncolytic Herpes Virus Expressing Interleukin 12

Richard J. Wong, Mei Ki Chan, Zhenkun Yu, Teresa H. Kim, Amit Bhargava, Brendon M. Stiles, Brian C. Horsburgh, Jatin P. Shah, Ronald A. Ghossein, Bhuvanesh Singh, Yuman Fong

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Abstract

Purpose: 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. Experimental Design: 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-γ was 4.3 pg/mg at day 1 after a single dose of NV1042 (5 × 107 plaque-forming units); levels of both were undetectable for NV1023.5-Bromo-4-chloro-3-indolyl-β-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.

Original languageEnglish (US)
Pages (from-to)251-259
Number of pages9
JournalClinical Cancer Research
Volume10
Issue number1 I
DOIs
StatePublished - Jan 1 2004

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Oncolytic Viruses
Interleukin-12
Neoplasm Metastasis
Lung
Squamous Cell Carcinoma
Therapeutics
Survival
Alveolar Epithelial Cells
Neoplasms
Virus Diseases
Tumor Burden
Transgenes
Galactose
Tail
Pancreas
Veins
Histology
Research Design
Spleen
Animal Models

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Effective Intravenous Therapy of Murine Pulmonary Metastases with an Oncolytic Herpes Virus Expressing Interleukin 12. / Wong, Richard J.; Chan, Mei Ki; Yu, Zhenkun; Kim, Teresa H.; Bhargava, Amit; Stiles, Brendon M.; Horsburgh, Brian C.; Shah, Jatin P.; Ghossein, Ronald A.; Singh, Bhuvanesh; Fong, Yuman.

In: Clinical Cancer Research, Vol. 10, No. 1 I, 01.01.2004, p. 251-259.

Research output: Contribution to journalArticle

Wong, RJ, Chan, MK, Yu, Z, Kim, TH, Bhargava, A, Stiles, BM, Horsburgh, BC, Shah, JP, Ghossein, RA, Singh, B & Fong, Y 2004, 'Effective Intravenous Therapy of Murine Pulmonary Metastases with an Oncolytic Herpes Virus Expressing Interleukin 12', Clinical Cancer Research, vol. 10, no. 1 I, pp. 251-259. https://doi.org/10.1158/1078-0432.CCR-0197-3
Wong, Richard J. ; Chan, Mei Ki ; Yu, Zhenkun ; Kim, Teresa H. ; Bhargava, Amit ; Stiles, Brendon M. ; Horsburgh, Brian C. ; Shah, Jatin P. ; Ghossein, Ronald A. ; Singh, Bhuvanesh ; Fong, Yuman. / Effective Intravenous Therapy of Murine Pulmonary Metastases with an Oncolytic Herpes Virus Expressing Interleukin 12. In: Clinical Cancer Research. 2004 ; Vol. 10, No. 1 I. pp. 251-259.
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abstract = "Purpose: 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. Experimental Design: 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-γ was 4.3 pg/mg at day 1 after a single dose of NV1042 (5 × 107 plaque-forming units); levels of both were undetectable for NV1023.5-Bromo-4-chloro-3-indolyl-β-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.",
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AU - Chan, Mei Ki

AU - Yu, Zhenkun

AU - Kim, Teresa H.

AU - Bhargava, Amit

AU - Stiles, Brendon M.

AU - Horsburgh, Brian C.

AU - Shah, Jatin P.

AU - Ghossein, Ronald A.

AU - Singh, Bhuvanesh

AU - Fong, Yuman

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N2 - Purpose: 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. Experimental Design: 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-γ was 4.3 pg/mg at day 1 after a single dose of NV1042 (5 × 107 plaque-forming units); levels of both were undetectable for NV1023.5-Bromo-4-chloro-3-indolyl-β-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.

AB - Purpose: 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. Experimental Design: 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-γ was 4.3 pg/mg at day 1 after a single dose of NV1042 (5 × 107 plaque-forming units); levels of both were undetectable for NV1023.5-Bromo-4-chloro-3-indolyl-β-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.

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