This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Siddiqui, F. Articles by Hauck, M. L. Search for Related Content PubMed PubMed Citation Articles by Siddiqui, F. Articles by Hauck, M. L.

Research Articles: Therapeutics, Targets, and Development

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

Departments of ¹ Environmental and Radiological Health Sciences and ² Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado; ³ Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina; and Departments of ⁴ Molecular and Biomedical Sciences and ⁵ Clinical Sciences, North Carolina State University College of Veterinary Medicine, Raleigh, North Carolina

Requests for reprints: Marlene L. Hauck, Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, 4700 Hillsborough Street, Raleigh, NC 27606. Phone: 919-513-8274; Fax: 919-513-6336. E-mail: marlene_hauck{at}ncsu.edu

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- 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- mRNA following gene therapy. Hematologic and hepatic toxicities were noted at the highest viral doses and were associated with detection of IFN- 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. [Mol Cancer Ther 2007;6(1):380–9]

Grant support: Department of Health and Human Services, NIH grant P01CA42745.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 6/12/06; revised 9/15/06; accepted 11/15/06.