A phase I trial of hyperthermia-induced interleukin-12 gene therapy in spontaneously arising feline soft tissue sarcomas
A phase I trial of hyperthermia-induced interleukin-12 gene therapy in spontaneously arising feline soft tissue sarcomas
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DOI：
10.1158/1535-7163.mct-06-0342
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发表时间：
2007-01-01
影响因子：
5.7
通讯作者：
Hauck, Marlene L.
中科院分区：
文献类型：
--
作者：
Siddiqui, Farzan;Li, Chuan-Yuan;Hauck, Marlene L.
白介素12(IL-12)是一种促炎细胞因子，具有抗癌作用。全身应用IL-12会引起剂量依赖的毒性。为了实现瘤内基因的定位表达，开发了一种由热诱导启动子(热休克启动子70B)控制的IL-12腺病毒基因治疗载体，并在猫自发性软组织肉瘤的I期临床试验中进行了测试。以巨细胞病毒或热休克启动子70为对照，用小鼠IL-12和/或增强型绿色荧光蛋白腺病毒载体对16只猫软组织肉瘤进行了可行性研究。随后，我们在13只患有软组织肉瘤的猫身上进行了使用腺病毒猫科IL-12构建的I期临床试验。软组织肉瘤放疗(48Gy16次)后腺病毒瘤内注射。注射后24小时，加热肿瘤(41℃，60分钟)。检测肿瘤组织中IL-12和干扰素-γ的表达。猫被监测全身毒性。对于小鼠IL-12结构，病毒剂量和肿瘤内小鼠IL-12水平之间存在关联，而血清水平很小。在10(11)个斑块形成单位(PFU)中观察到轻度毒性。通过构建猫科IL-12，在基因治疗后低水平或不含干扰素-γ的肿瘤活检组织中检测到高水平的猫科IL-12mRNA。血液学和肝脏毒性在病毒剂量最高时被观察到，并与肿瘤中干扰素-伽玛基因的检测有关。利用高温诱导的基因治疗方法，可以定位基因表达并限制IL-12的全身毒性。猫IL-12腺病毒载体的最大耐受量为10(10)pfu/肿瘤，因为在4×10(10)pfu剂量下观察到剂量限制性毒性。
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.