Local immunotherapy with interleuk in-2 delivered from biodegradable p olymer microspheres combined with interstitial chemotherapy:a novel treatme nt for experimental malignant glioma

摘要

OBJECTIVE:Local delivery of carmustine(BCNU)from biodegradable polymers prolon gs survival against experimental brain tumors.Moreover,paracrine administration of inte rleukin-2(IL-2)has been shown to elicit a potent antitumor immune response and to improve survival in animal brain tumor models.We r eport the use of a novel polymeric mic rosphere delivery vehicle to release IL-2.We demonstr ate both in vitro release of cytokine from the microspheres and histological evidence of the inflammatory response elicited by I L-2released from the microspheres i n the rat brain.These microspheres a re used to deliver IL-2,and biodegradable polymer wafers are used to deliver BCNU,directly at the site of an intracranially implanted glioma in the rat.The two agents administered locally show a s ynergistic effect.METHODS:Fischer 344rats challenged intracranially with 9L gliosarcoma received an intracranial implant of either empty microspheres or microspheres containing IL-2(IL-2MS ).Five days later,animals in each group were randomized to receiv e polymer implants loaded with 0,3.8,or 10%BCNU at the tumor site.RESULTS:Animals that received the combination of IL-2MS a nd 3.8%BCNU polymer(median survival,28.5d )or IL-2MS and 10%BCNU polymer(median survival,45.5d )showed significantly improved surv ival compared with animals that rece ived monotherapy with IL-2microsph eres(median survival,24d ),3.8%BCNU polymer(median survival,24d ),or 10%BCNU polymer(median survival,32.5d ).Control animals had a median survival of 18days.The combination of either 3.8or 10%BCNU polymer with IL-2MS resulted in 7and 25%long-term survivors,respectively.CONCLUSION:By showing synergy of IL-2and BCNU in an animal glioma model and using a reproducible synthetic delivery sy stem for each agent (i.e.,one that did not rely on genetic ally engineered cells or viruses),we hope that the combination of local immunotherapy and chemotherapy can take an important step closer to clinical applic ation in patients with malignant brain