Cytokine gene therapy of gliomas: effective induction of therapeutic immunity to intracranial tumors by peripheral immunization with interleukin-4 transduced glioma cells.
To provide a means for comparing strategies for cytokine gene therapy against intracranial (i.c.) tumors, we generated rat gliosarcoma 9L cells transfected with interleukin-4 (9L-IL4), interleukin-12 (9L-IL12), granulocyte-macrophage colony-stimulating factor (9L-GMCSF) or interferon-alpha (9L-IFNalpha). To simulate direct and highly efficient cytokine gene delivery, cytokine transfected 9L tumors were implanted i.c. into syngeneic rats. i.c. injection led to tumor-outgrowth in the brain and killed most animals, whereas these cell lines were rejected following intradermal (i.d.) injection. Cytokine-expressing i.c. 9L tumors, however, had a greater degree of infiltration by immune cells compared with control, mock-transfected 9L-neo, but to a lesser degree than i.d. cytokine-expressing tumors. Tumor angiogenesis was suppressed in cytokine-transfected tumors. In a prophylaxis model, i.d. vaccination with 9L-IL4 resulted in long-term survival of 90% of rats challenged i.c. with parental 9L; whereas 40% of 9L-GM-CSF, 40% of 9L-IFNalpha and 0% of 9L-IL12-immunized rats were protected. In a therapy model (day 3 i.c. 9L tumors), only i.d. immunization with 9L-IL4 had long-term therapeutic benefits as 43% of rats survived >100 days. These data indicate that peripheral immunization with 9L-IL4 had the most potent therapeutic benefit among various cytokines and approaches tested against established, i.c. 9L tumors.
Okada
H
H
Brain Tumor Center, University of Pittsburgh Cancer Institute and Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Villa
L
L
Attanucci
J
J
Erff
M
M
Fellows
W K
WK
Lotze
M T
MT
Pollack
I F
IF
Chambers
W H
WH
D000818:Animals; D001932:Brain Neoplasms / Q000276:immunology / Q000628:therapy*; D019496:Cancer Vaccines / Q000008:administration & dosage*; D016207:Cytokines / Q000235:genetics*; D015316:Genetic Therapy / Q000379:methods*; D005910:Glioma / Q000276:immunology / Q000628:therapy*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics; D007271:Injections, Intradermal; D016898:Interferon-alpha / Q000235:genetics; D018664:Interleukin-12 / Q000235:genetics; D015847:Interleukin-4 / Q000235:genetics; D008297:Male; D023421:Models, Animal; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000276:immunology / Q000628:therapy; D051381:Rats; D011916:Rats, Inbred F344; D014162:Transfection / Q000379:methods; D014407:Tumor Cells, Cultured
D019496:Cancer Vaccines; D016207:Cytokines; D016898:Interferon-alpha; D018664:Interleukin-12; D015847:Interleukin-4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor