Re-designing Interleukin-12 to enhance its safety and potential as an anti-tumor immunotherapeutic agent.
1395 - ?
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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.
AuthorsWang, P; Li, X; Wang, J; Gao, D; Li, Y; Li, H; Chu, Y; Zhang, Z; Liu, H; Jiang, G; Cheng, Z; Wang, S; Dong, J; Feng, B; Chard, LS; Lemoine, NR; Wang, Y
- College Publications