Sung Max W, Chen Shu-Hsia, Thung Swan N, Zhang David Y, Huang Tian-Gui, Mandeli John P, Woo Savio L C
Carl C. Icahn Institute for Gene Therapy and Molecular Medicine, Mount Sinai School of Medicine, 1425 Madison Avenue, Room 13-20, New York, NY 10029, USA.
Hum Gene Ther. 2002 Apr 10;13(6):731-43. doi: 10.1089/104303402317322294.
Clinical trials of recombinant human interleukin-12 (rhIL-12) delivered by intravenous administration have shown dose-limiting toxicities with limited tumor responses at the doses tested. We have previously reported that intratumoral injection of an adenovirus vector expressing murine interleukin-12 (Adv.RSV-mIL-12) was effective in inducing antitumor immune responses, tumor regression, and long-term survival in mice with established metastatic cancer in the liver. We now report additional studies in the same murine tumor model to assess the safety of intratumoral Adv.RSV-mIL-12 injection. At vector doses that were previously shown to be therapeutically effective, no inflammation in the liver or lungs, and no significant elevations in serum creatinine and aminotransferases were seen after vector injection. Serum elevations of IL-12 and interferon-gamma (IFN-gamma) were 17- and 19-fold lower than peak levels after intravenous recombinant IL-12 at the maximal tolerated dose in clinical trials. No elevations in serum proinflammatory cytokines (interleukin-6, tumor necrosis factor-alpha) were noted up to 2 weeks after vector injection. No systemic dissemination of the vector was detected on polymerase chain reaction (PCR) assays at therapeutically effective vector doses. At higher supratherapeutic vector doses of Adv.RSV-mIL-12, however, inflammation in the liver and lungs with elevation in serum aminotransferases were seen, but not in controls injected with the equivalent particle number of an empty adenoviral vector. These results support the cautious testing in patients with hepatic metastases of adenovirus mediated IL-12 gene delivery by intratumoral injection.
静脉注射重组人白细胞介素-12（rhIL-12）的临床试验表明，在所测试的剂量下存在剂量限制性毒性，且肿瘤反应有限。我们之前报道过，瘤内注射表达鼠白细胞介素-12的腺病毒载体（Adv.RSV-mIL-12）可有效诱导抗肿瘤免疫反应、肿瘤消退，并使已发生肝转移癌的小鼠长期存活。我们现在报告在同一小鼠肿瘤模型中的进一步研究，以评估瘤内注射Adv.RSV-mIL-12的安全性。在先前显示具有治疗效果的载体剂量下，注射载体后未观察到肝脏或肺部炎症，血清肌酐和转氨酶也未显著升高。血清白细胞介素-12和干扰素-γ（IFN-γ）的升高幅度比临床试验中最大耐受剂量静脉注射重组白细胞介素-12后的峰值水平低17倍和19倍。在注射载体后长达2周的时间内，未观察到血清促炎细胞因子（白细胞介素-6、肿瘤坏死因子-α）升高。在治疗有效的载体剂量下，通过聚合酶链反应（PCR）检测未发现载体的全身扩散。然而，在更高的超治疗性载体剂量的Adv.RSV-mIL-12下，观察到肝脏和肺部炎症以及血清转氨酶升高，但在注射等量空腺病毒载体颗粒的对照组中未观察到。这些结果支持在肝转移患者中谨慎测试通过瘤内注射进行腺病毒介导的白细胞介素-12基因递送。
