An oncolytic adenovirus with improved tumor selectivity was used by Wang et al. to express the potent anti-tumor cytokine IL-12 intracellularly or as a secreted protein in a hamster pancreatic tumor model. Vectors expressing intracellular IL-12 led to cytokine release following infected cell lysis, were potent and safe in all disease models (subcutaneous, peritoneal, orthotopic), and induced significant, durable, and CD8+ T cell-dependent tumor control. In contrast, severe toxicity was observed with secreted IL-12 due to increased induction of inflammatory cytokines.
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.