Immunotherapy of established tumors in mice by intratumoral injection of interleukin-2 plasmid DNA: induction of CD8+ T-cell immunity.
Intratumoral (i.t.) injection of a plasmid DNA vector encoding the murine interleukin-2 (IL-2) gene was used to treat established renal cell carcinoma (Renca) tumors in BALB/c mice. Tumor regression was observed in 60-90% of mice that were injected i.t. for 4 days with IL-2 plasmid DNA complexed with the cationic lipid DMRIE/DOPE ((+/-)-N-(2-hydroxyethyl)-N,N-dimethyl-2,3-bis(tetradecyloxy)-1-propa naminium bromide/dioleoylphosphatidylethanolamine). The mice remained tumor-free until the conclusion of the study, which was 4 months after tumor challenge. In a rechallenge experiment, mice that were rendered tumor-free for 6 months by IL-2 plasmid DNA treatment rejected a subsequent challenge of Renca cells but could not reject a challenge with the unrelated, syngeneic CT-26 tumor. Spleen cells from cured mice contained Renca-specific cytotoxic T lymphocytes, and adoptive transfer of mixed lymphocyte cultures into naive mice at 2 days after challenge with Renca cells prevented tumor growth. In vivo depletion of T-cell subsets at the time of i.t. injection with IL-2 plasmid DNA demonstrated that CD8+ T cells, but not CD4+ T cells, were the primary effectors of the antitumor response.
Saffran
D C
DC
Vical Inc., San Diego, California 92121, USA.
Horton
H M
HM
Yankauckas
M A
MA
Anderson
D
D
Barnhart
K M
KM
Abai
A M
AM
Hobart
P
P
Manthorpe
M
M
Norman
J A
JA
Parker
S E
SE
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D015197:Carcinogenicity Tests; D002292:Carcinoma, Renal Cell / Q000276:immunology* / Q000628:therapy*; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000494:pharmacology; D007167:Immunotherapy / Q000379:methods*; D015552:Injections, Intralesional; D007376:Interleukin-2 / Q000235:genetics* / Q000494:pharmacology; D007680:Kidney Neoplasms / Q000276:immunology / Q000628:therapy; D008055:Lipids / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000276:immunology / Q000628:therapy; D010714:Phosphatidylethanolamines / Q000737:chemistry / Q000494:pharmacology; D010957:Plasmids / Q000235:genetics / Q000494:pharmacology*; D000644:Quaternary Ammonium Compounds / Q000737:chemistry / Q000494:pharmacology
D004337:Drug Carriers; D007376:Interleukin-2; D008055:Lipids; D010714:Phosphatidylethanolamines; D000644:Quaternary Ammonium Compounds; C087276:(3-dimyristyloxypropyl)(dimethyl)(hydroxyethyl)ammonium; C094877:dioleoyl phosphatidylethanolamine