Re-designing Interleukin-12 to enhance its safety and potential as an anti-tumor immunotherapeutic agent. Issue 1 (December 2017)

• Record Type: Journal Article
• Authors: Wang, Pengju; Li, Xiaozhu; Wang, Jiwei; Gao, Dongling; Li, Yuenan; Li, Haoze; Chu, Yongchao; Zhang, Zhongxian; Liu, Hongtao; Jiang, Guozhong; Cheng, Zhenguo; Wang, Shengdian; Dong, Jianzeng; Feng, Baisui; Chard, Louisa; Lemoine, Nicholas; Wang, Yaohe
• Is Part Of: Nature communications. Volume 8:Issue 1(2017)
• Page Start: 1
• Page End: 15
• Publication Date: 2017-12
• Subjects: Biology -- Periodicals; Physical sciences -- Periodicals; 505
• DOI: 10.1038/s41467-017-01385-8
• Languages: English
• ISSNs: 2041-1723

Abstract

Abstract Interleukin-12 (IL-12) has emerged as one of the most potent agents for anti-tumor immunotherapy. However, potentially lethal toxicity associated with systemic administration of IL-12 precludes its clinical application. Here we redesign the molecule in such a way that its anti-tumor efficacy is not compromised, but toxic effects are eliminated. Deletion of the N-terminal signal peptide of IL-12 can effect such a change by preventing IL-12 secretion from cells. We use a newly designed tumor-targeted oncolytic adenovirus (Ad-TD) to deliver non-secreting (ns) IL-12 to tumor cells and examine the therapeutic and toxic effects in Syrian hamster models of pancreatic cancer (PaCa). Strikingly, intraperitoneal delivery of Ad-TD-nsIL-12 significantly enhanced survival of animals with orthotopic PaCa and cured peritoneally disseminated PaCa with no toxic side effects, in contrast to the treatment with Ad-TD expressing unmodified IL-12. These findings offer renewed hope for development of IL-12-based treatments for cancer. Interleukin-12 (IL-12) is a potent immunotherapeutic agent.