TY - JOUR
T1 - Local immunotherapy with interleukin-2 delivered from biodegradable polymer microspheres combined with interstitial chemotherapy
T2 - A novel treatment for experimental malignant glioma
AU - Rhines, Laurence D.
AU - Sampath, Prakash
AU - DiMeco, Francesco
AU - Christopher Lawson, H.
AU - Tyler, Betty M.
AU - Hanes, Justin
AU - Olivi, Alessandro
AU - Brem, Henry
AU - Raffel, Corey
AU - Westphal, Manfred
AU - Dietrich, Pierre Yves
AU - De Tribolet, Nicolas
AU - Kaye, Andrew H.
AU - Berger, Mitchel S.
PY - 2003/4/1
Y1 - 2003/4/1
N2 - 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. CONCLUSION: 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.
AB - 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. CONCLUSION: 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.
KW - Biodegradable polymer
KW - Brain tumors
KW - Cytokine
KW - Interleukin-2
KW - Interstitial chemotherapy
KW - Microspheres
UR - http://www.scopus.com/inward/record.url?scp=0037386047&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0037386047&partnerID=8YFLogxK
U2 - 10.1227/01.NEU.0000053211.39087.D1
DO - 10.1227/01.NEU.0000053211.39087.D1
M3 - Article
C2 - 12657184
AN - SCOPUS:0037386047
SN - 0148-396X
VL - 52
SP - 872
EP - 880
JO - Neurosurgery
JF - Neurosurgery
IS - 4
ER -