A phase I trial of hyperthermia-induced interleukin-12 gene therapy in spontaneously arising feline soft tissue sarcomas

Farzan Siddiqui, Chuan Yuan Li, Susan M. LaRue, Jean M. Poulson, Paul R. Avery, Amy F. Pruitt, Xiuwu Zhang, Robert L. Ullrich, Donald E. Thrall, Mark W. Dewhirst, Marlene L. Hauck

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Interleukin-12 (IL-12), a proinflammatory cytokine, shows anticancer properties. Systemically administered IL-12 causes dose-dependent toxicity. To achieve localized intratumoral gene expression, an adenoviral gene therapy vector with IL-12 controlled by a heat-inducible promoter (heat shock promoter 70B) was developed and tested in a phase I clinical trial in cats with spontaneously arising soft tissue sarcoma. A feasibility study was done in 16 cats with soft tissue sarcoma using murine IL-12 and/or enhanced green fluorescent protein adenoviral vectors under cytomegalovirus or heat shock promoter 70 control. Subsequently, we conducted a phase I clinical trial using an adenoviral feline IL-12 construct in 13 cats with soft tissue sarcoma. The soft tissue sarcomas were irradiated (48 Gy/16 fractions) followed by intratumoral injection of adenovirus. Twenty-four hours postinjection, tumors were heated (41 °C, 60 min). Tumor expression of feline IL-12 and IFN-γ was determined. Cats were monitored for systemic toxicity. For the murine IL-12 construct, an association was noted between viral dose and murine IL-12 levels within tumor, whereas serum levels were minimal. Mild toxicity was noted at 1011 plaque-forming units (pfu). With the feline IL-12 construct, high levels of feline IL-12 mRNA were detected in tumor biopsies with low or absent IFN-γ mRNA following gene therapy. Hematologic and hepatic toxicities were noted at the highest viral doses and were associated with detection of IFN-γ mRNA in tumor. It is possible to localize gene expression and limit systemic toxicity of IL-12 using the hyperthermia-induced gene therapy approach. The maximum tolerated dose of the feline IL-12 adenoviral vector was 1010 pfu/tumor as dose-limiting toxicities were noted at the 4 x 1010 pfu dose.

Original languageEnglish (US)
Pages (from-to)380-391
Number of pages12
JournalMolecular Cancer Therapeutics
Volume6
Issue number1
DOIs
StatePublished - Jan 2007
Externally publishedYes

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Induced Hyperthermia
Felidae
Interleukin-12
Sarcoma
Genetic Therapy
Cats
Neoplasms
Clinical Trials, Phase I
Hot Temperature
Messenger RNA
Shock
Gene Expression
Maximum Tolerated Dose
Feasibility Studies
Cytomegalovirus
Adenoviridae

ASJC Scopus subject areas

  • Oncology
  • Drug Discovery
  • Pharmacology

Cite this

A phase I trial of hyperthermia-induced interleukin-12 gene therapy in spontaneously arising feline soft tissue sarcomas. / Siddiqui, Farzan; Li, Chuan Yuan; LaRue, Susan M.; Poulson, Jean M.; Avery, Paul R.; Pruitt, Amy F.; Zhang, Xiuwu; Ullrich, Robert L.; Thrall, Donald E.; Dewhirst, Mark W.; Hauck, Marlene L.

In: Molecular Cancer Therapeutics, Vol. 6, No. 1, 01.2007, p. 380-391.

Research output: Contribution to journalArticle

Siddiqui, F, Li, CY, LaRue, SM, Poulson, JM, Avery, PR, Pruitt, AF, Zhang, X, Ullrich, RL, Thrall, DE, Dewhirst, MW & Hauck, ML 2007, 'A phase I trial of hyperthermia-induced interleukin-12 gene therapy in spontaneously arising feline soft tissue sarcomas', Molecular Cancer Therapeutics, vol. 6, no. 1, pp. 380-391. https://doi.org/10.1158/1535-7163.MCT-06-0342
Siddiqui, Farzan ; Li, Chuan Yuan ; LaRue, Susan M. ; Poulson, Jean M. ; Avery, Paul R. ; Pruitt, Amy F. ; Zhang, Xiuwu ; Ullrich, Robert L. ; Thrall, Donald E. ; Dewhirst, Mark W. ; Hauck, Marlene L. / A phase I trial of hyperthermia-induced interleukin-12 gene therapy in spontaneously arising feline soft tissue sarcomas. In: Molecular Cancer Therapeutics. 2007 ; Vol. 6, No. 1. pp. 380-391.
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