A safety and efficacy study of local delivery of interleukin-12 transgene by PPC polymer in a model of experimental glioma.
Interleukin-12 (IL-12) triggers an antitumoral immune response and an antiangiogenic effect against cancer. In this study, we tested a novel polymeric vehicle for IL-12 gene therapy along with adjuvant local biodegradable carmustine (BCNU) chemotherapy for the treatment of malignant glioma. Highly concentrated DNA/PPC (polyethylenimine covalently modified with methoxypolyethyleneglycol and cholesterol) complexes were used to deliver a murine plasmid encoding IL-12 (pmIL-12). For toxicity assessment, mice received intracranial injections with different volumes of pmIL-12/PPC. For efficacy, mice with intracranial GL261 glioma were treated with local delivery of pmIL-12/PPC and/or BCNU-containing polymers. Intracranial injections of 5-10 microl of pmIL-12/PPC were well tolerated and led to IL-12 expression in the brains of treated animals. Treatment with pmIL-12/PPC led to a significant increase in survival compared with untreated mice (median survival 57 days; 25% long-term survival >95 vs. 45 days for control; P<0.05). Treatment with BCNU led to a significant increase in survival compared with untreated mice, with 75% of treated mice having a long-term survival >95 days, (P<0.05). Most importantly, the combination of BCNU and pmIL-12/PPC led to a survival of 100% of the mice for 95 days after treatment (P<0.0001). This novel strategy is safe and effective for the treatment of malignant glioma. The synergy resultant from the combination of locally administered pmIL-12/PPC and BCNU suggests a role for this approach in the treatment of malignant brain tumors.
Sonabend
Adam M
AM
The Brain Tumor Center, The University of Chicago, Chicago, Illinois 60637, USA.
Velicu
Simona
S
Ulasov
Ilya V
IV
Han
Yu
Y
Tyler
Betty
B
Brem
Henry
H
Matar
Majed M
MM
Fewell
Jason G
JG
Anwer
Khursheed
K
Lesniak
Maciej S
MS
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology; D019556:COS Cells; D002522:Chlorocebus aethiops; D002784:Cholesterol / Q000737:chemistry; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods; D015316:Genetic Therapy / Q000379:methods* / Q000639:trends; D005910:Glioma / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D007267:Injections; D018664:Interleukin-12 / Q000235:genetics* / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010957:Plasmids / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D014162:Transfection; D019076:Transgenes / Q000235:genetics
D011108:Polymers; D018664:Interleukin-12; D011092:Polyethylene Glycols; C028210:monomethoxypolyethylene glycol; D002784:Cholesterol