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

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 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-; 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 10

Cancer Electrogene Therapy with Interleukin-12

“…The delivery systems for IL-12 gene therapy are various and include transfer of naked plasmid DNA alone [27,28], adenoviral [29][30][31][32][33] or other viral vectors [34][35][36], as well as gene gun [37,38], electroporation [39][40][41][42] and other non-viral vectors [43,44]. Clinical studies in human and also in veterinary oncology were initiated and the first results showed that IL-12 gene therapy is a safe treatment with some beneficial clinical effect [28,[45][46][47][48][49][50][51][52][53][54][55].…”

Intramuscular IL-12 Electrogene Therapy for Treatment of Spontaneous Canine Tumors

“…With the advances in the field of gene therapy, this new therapeutic tool is steadily gaining its acceptance also in clinical veterinary medicine. In the last decade, a number of gene therapy clinical trials have been conducted on companion animals, employing both viral and nonviral vectors and evaluating its effects primarily in oncologic, haematologic, musculoskeletal and cardiovascular diseases (Bergmann et al, 2003;Bodles-Brakhop et al, 2008;Dow et al, 2005;Draghia-Akli et al 2002;Herzog et al, 2001;Huttinger et al, 2008;Jahnke et al, 2007;Kamstock et al, 2006;Kornegay et al, 2010;Ohshima et al, 2009;Pavlin et al, 2011;Siddiqui et al, 2007;Sleeper et al, 2010;Z. Wang et al, 2007).…”

Local and systemic antitumor effect of intratumoral and peritumoral IL-12 electrogene therapy on murine sarcoma

“…Viral delivery was instituted using adenoviral vectors, which were delivered primarily intratumorally, for example into different types of fibrosarcoma [4][5][6] and Ewing's sarcoma. 7 Adenoviral constructs expressing IL-12 were also delivered intranasally for treatment of osteosarcoma lung metastases.…”