Interleukin-12 (IL-12) is a cytokine important for cell mediated immunity and has potent anti-tumor activities. Systemic IL-12 therapy has generated substantial clinical interest as a treatment for several forms of refractory cancers. Unfortunately, the toxicities of IL-12 have severely limited its clinical use, and to date, no viable toxicity modifiers for IL-12 exist. The guanylhydrazone derivative CNI-1493 was recently shown to potently inhibit the toxicity of IL-2 in rats without reducing its anti- tumor effects. Our preliminary data indicate that CNI-1493 may similarly inhibit IL-12 toxicities in mice. Mice that received CNI-1493 treatment in addition to lethal doses of IL-12 survived longer and exhibited fewer severe side effects, which included reduced ascites, reduced lymphoid cell infiltration of normal tissues, and reduced lymphoid organ destruction. We will confirm these results in detailed histological analyses of the murine tissues normally susceptible to IL-12 toxicity. Using histological, immunochemical, and in situ hybridization methods, we will also determine whether CNI-1493 co-treatment affects IL-12-mediated anti-tumor responses, such as tumor lymphocyte infiltration, cytokine induction, expression of cytotoxic effector molecules, restoration of immunosuppression, and angiostasis. The results of these studies will be used in Phase II to support preclinical development of CNI-1493 as a toxicity modifier for IL- 12 anti-tumor therapy and for other clinical applications of IL-12. PROPOSED COMMERCIAL APPLICATION: Development of a drug that will extend the use of IL-12 to a variety of cancers, including melanoma, renal carcinoma, Kaposi sarcoma as well as others. It will also allow for development of a drug that will protect against systemic toxicities of IL-2. Commercialization could include many critical care applications as well.
