Controlled local delivery of interleukin-2 by biodegradable polymers protects animals from experimental brain tumors and liver tumors

Purpose. The purpose of our study was to develop an injectable polymeric sy stem for the long-term localized delivery of bioactive interleukin-2 for an titumor immunotherapy. Methods. IL-2 was encapsulated into gelatin and chondroitin-6-sulfate using an aqueous-based complex coacervation. CTLL-2 cells were used to measure t he bioactivity of released IL-2 and radiolabeled IL-2 was used for release studies in the rat brain and mouse liver. Antitumor efficacy studies were c arried out in primary (9L gliosarcoma) and metastatic (B16-F10 melanoma) br ain tumor models in rats and mice, respectively, as well as a murine liver tumor model (CT26 carcinoma). Survivors of the metastatic brain tumor chall enge were rechallenged with tumor in the opposite lobe of the brain to conf irm that antitumor immunologic memory had developed. Results. Bioactive IL-2 was released for over 2 weeks in vitro and in vivo IL-2 release showed significant IL-2 levels for up to 21 days. Polymeric IL -2 microspheres injected intratumorally were statistically more effective i n protecting animals challenged with fatal tumor doses in the brain and the liver than placebo or autologous tumor cells genetically engineered to sec rete IL-2. Immunologic memory was induced following IL-2 microsphere therap y in the B16-F10 brain tumor model that was capable of protecting 42% of an imals from a subsequent intracranial tumor challenge, suggesting that tumor destruction was mediated by the immune system. Conclusions. Local IL-2 therapy using novel polymeric carriers, aimed at st imulating long-lasting antitumor immunity, may provide an improved method o f treating a variety of cancers.