A phase I trial of hyperthermia-induced interleukin-12 gene therapy in spontaneously arising feline soft tissue sarcomas.
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.
Siddiqui
Farzan
F
Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, 4700 Hillsborough Street, Raleigh, NC 27606, USA.
Li
Chuan-Yuan
CY
Larue
Susan M
SM
Poulson
Jean M
JM
Avery
Paul R
PR
Pruitt
Amy F
AF
Zhang
Xiuwu
X
Ullrich
Robert L
RL
Thrall
Donald E
DE
Dewhirst
Mark W
MW
Hauck
Marlene L
ML
D000256:Adenoviridae; D000818:Animals; D002415:Cats; D003587:Cytomegalovirus / Q000235:genetics; D005240:Feasibility Studies; D015316:Genetic Therapy / Q000009:adverse effects; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006979:Hyperthermia, Induced; D018664:Interleukin-12 / Q000097:blood / Q000235:genetics* / Q000627:therapeutic use*; D008099:Liver / Q000473:pathology; D051379:Mice; D011401:Promoter Regions, Genetic / Q000235:genetics; D011994:Recombinant Proteins / Q000009:adverse effects / Q000096:biosynthesis / Q000235:genetics / Q000627:therapeutic use; D012509:Sarcoma / Q000188:drug therapy / Q000235:genetics / Q000532:radiotherapy / Q000662:veterinary*
D011994:Recombinant Proteins; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D018664:Interleukin-12