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

Publication ,  Journal Article
Siddiqui, F; Li, C-Y; Larue, SM; Poulson, JM; Avery, PR; Pruitt, AF; Zhang, X; Ullrich, RL; Thrall, DE; Dewhirst, MW; Hauck, ML
Published in: Mol Cancer Ther
January 2007

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 degrees C, 60 min). Tumor expression of feline IL-12 and IFN-gamma 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 10(11) 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-gamma mRNA following gene therapy. Hematologic and hepatic toxicities were noted at the highest viral doses and were associated with detection of IFN-gamma 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 10(10) pfu/tumor as dose-limiting toxicities were noted at the 4 x 10(10) pfu dose.

Duke Scholars

Published In

Mol Cancer Ther

DOI

ISSN

1535-7163

Publication Date

January 2007

Volume

6

Issue

1

Start / End Page

380 / 389

Location

United States

Related Subject Headings

  • Sarcoma
  • Recombinant Proteins
  • Promoter Regions, Genetic
  • Oncology & Carcinogenesis
  • Mice
  • Liver
  • Interleukin-12
  • Hyperthermia, Induced
  • Green Fluorescent Proteins
  • Genetic Therapy
 

Citation

APA
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ICMJE
MLA
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Siddiqui, F., Li, C.-Y., Larue, S. M., Poulson, J. M., Avery, P. R., Pruitt, A. F., … Hauck, M. L. (2007). A phase I trial of hyperthermia-induced interleukin-12 gene therapy in spontaneously arising feline soft tissue sarcomas. Mol Cancer Ther, 6(1), 380–389. https://doi.org/10.1158/1535-7163.MCT-06-0342
Siddiqui, Farzan, Chuan-Yuan Li, Susan M. Larue, Jean M. Poulson, Paul R. Avery, Amy F. Pruitt, Xiuwu Zhang, et al. “A phase I trial of hyperthermia-induced interleukin-12 gene therapy in spontaneously arising feline soft tissue sarcomas.Mol Cancer Ther 6, no. 1 (January 2007): 380–89. https://doi.org/10.1158/1535-7163.MCT-06-0342.
Siddiqui F, Li C-Y, Larue SM, Poulson JM, Avery PR, Pruitt AF, et al. A phase I trial of hyperthermia-induced interleukin-12 gene therapy in spontaneously arising feline soft tissue sarcomas. Mol Cancer Ther. 2007 Jan;6(1):380–9.
Siddiqui, Farzan, et al. “A phase I trial of hyperthermia-induced interleukin-12 gene therapy in spontaneously arising feline soft tissue sarcomas.Mol Cancer Ther, vol. 6, no. 1, Jan. 2007, pp. 380–89. Pubmed, doi:10.1158/1535-7163.MCT-06-0342.
Siddiqui F, Li C-Y, Larue SM, Poulson JM, Avery PR, Pruitt AF, Zhang X, Ullrich RL, Thrall DE, Dewhirst MW, Hauck ML. A phase I trial of hyperthermia-induced interleukin-12 gene therapy in spontaneously arising feline soft tissue sarcomas. Mol Cancer Ther. 2007 Jan;6(1):380–389.

Published In

Mol Cancer Ther

DOI

ISSN

1535-7163

Publication Date

January 2007

Volume

6

Issue

1

Start / End Page

380 / 389

Location

United States

Related Subject Headings

  • Sarcoma
  • Recombinant Proteins
  • Promoter Regions, Genetic
  • Oncology & Carcinogenesis
  • Mice
  • Liver
  • Interleukin-12
  • Hyperthermia, Induced
  • Green Fluorescent Proteins
  • Genetic Therapy