title: Local immunotherapy with interleukin-2 delivered from biodegradable polymer microspheres combined with interstitial chemotherapy: a novel treatment for experimental malignant glioma.
abstract: OBJECTIVE
  Local delivery of carmustine (BCNU) from biodegradable polymers prolongs survival against experimental brain tumors. Moreover, paracrine administration of interleukin-2 (IL-2) has been shown to elicit a potent antitumor immune response and to improve survival in animal brain tumor models. We report the use of a novel polymeric microsphere delivery vehicle to release IL-2. We demonstrate both in vitro release of cytokine from the microspheres and histological evidence of the inflammatory response elicited by IL-2 released from the microspheres in the rat brain. These microspheres are 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 synergistic effect.
  
  
  METHODS
  Fischer 344 rats challenged intracranially with 9L gliosarcoma received an intracranial implant of either empty microspheres or microspheres containing IL-2 (IL-2 MS). Five days later, animals in each group were randomized to receive polymer implants loaded with 0, 3.8, or 10% BCNU at the tumor site.
  
  
  RESULTS
  Animals that received the combination of IL-2 MS and 3.8% BCNU polymer (median survival, 28.5 d) or IL-2 MS and 10% BCNU polymer (median survival, 45.5 d) showed significantly improved survival compared with animals that received monotherapy with IL-2 microspheres (median survival, 24 d), 3.8% BCNU polymer (median survival, 24 d), or 10% BCNU polymer (median survival, 32.5 d). Control animals had a median survival of 18 days. The combination of either 3.8 or 10% BCNU polymer with IL-2 MS resulted in 7 and 25% long-term survivors, respectively.
  
  
  CONCLUSIONS
  By showing synergy of IL-2 and BCNU in an animal glioma model and using a reproducible synthetic delivery system for each agent (i.e., one that did not rely on genetically engineered cells or viruses), we hope that the combination of local immunotherapy and chemotherapy can take an important step closer to clinical application in patients with malignant brain tumors.
authors.affiliation: Department of Neurosurgery, University of Texas M.D. Anderson Cancer Center, Houston, USA.
authors.forename: Laurence D
authors.initials: LD
authors.lastname: Rhines
authors.forename: Prakash
authors.initials: P
authors.lastname: Sampath
authors.forename: Francesco
authors.initials: F
authors.lastname: DiMeco
authors.forename: H Christopher
authors.initials: HC
authors.lastname: Lawson
authors.forename: Betty M
authors.initials: BM
authors.lastname: Tyler
authors.forename: Justin
authors.initials: J
authors.lastname: Hanes
authors.forename: Alessandro
authors.initials: A
authors.lastname: Olivi
authors.forename: Henry
authors.initials: H
authors.lastname: Brem
mesh_terms: D000818:Animals; D001673:Biodegradation, Environmental; D001682:Biological Availability; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002330:Carmustine / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002809:Chondroitin Sulfates; D005260:Female; D005780:Gelatin; D018316:Gliosarcoma / Q000188:drug therapy* / Q000473:pathology; D015552:Injections, Intralesional; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008863:Microspheres; D009368:Neoplasm Transplantation; D010296:Parietal Lobe / Q000187:drug effects / Q000473:pathology; D011108:Polymers; D051381:Rats; D011916:Rats, Inbred F344; D013238:Stereotaxic Techniques; D014407:Tumor Cells, Cultured
chemical_list: D007376:Interleukin-2; D011108:Polymers; D005780:Gelatin; D002809:Chondroitin Sulfates; D002330:Carmustine