Administration of systemic or local interleukin-2 enhances the anti-tumor effects of interleukin-12 gene therapy.
Interleukin-12 (IL-12) is a cytokine with a wide variety of immunoregulatory activities. These include stimulation of interferon-gamma production, cytolytic activity of natural killer (NK) cells and T-cell subsets, the development of cellular immunity, and induction of maturation of Th1 cells. IL-12 also has potent anti-tumor activity in vivo. In the present study the possibility of enhanced anti-tumor activity was examined using a combination of local IL-12 by cytokine gene therapy at the tumor site, combined with systemic or local IL-2 delivery. NIH 3T3 fibroblasts transfected with the genes for both subunits of IL-12, p35 and p40, were used as the source of IL-12 therapy producing 240 HLRU/10(6) cells/48 hr. In the first part of the study the effect of different regimens of systemic IL-2 delivery with local IL-12 administration on the size and growth rate of subcutaneous MCA-105 murine sarcoma was examined. Local IL-12 alone reduced the sizes of tumors after 32 days from 163 to 26.8 mm2 (P < 0.002). Adding the longer-acting polyethylene-glycol-modified IL-2 (PEG IL-2; 30,000 IU) for 5 days prevented the development of tumors in all treated mice compared to 1/3 mice treated with PEG IL-2 alone and 3/6 mice with IL-12, but this was a highly toxic therapy and most of the animals died. Administration of 60,000 IU of IL-2 on Days 1-5 postinoculation of tumor, delivered with IL-12 gene therapy, reduced the tumor growth rate compared to animals treated with IL-2 alone (P < 0.02) or IL-12 (0.1).(ABSTRACT TRUNCATED AT 250 WORDS)
Pappo
I
I
Department of Surgery, University of Pittsburgh, Pennsylvania 15261.
Tahara
H
H
Robbins
P D
PD
Gately
M K
MK
Wolf
S F
SF
Barnea
A
A
Lotze
M T
MT
D016475:3T3 Cells; D000818:Animals; D005260:Female; D015316:Genetic Therapy; D007371:Interferon-gamma / Q000502:physiology; D018664:Interleukin-12 / Q000008:administration & dosage / Q000235:genetics*; D007376:Interleukin-2 / Q000008:administration & dosage*; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000628:therapy*; D014162:Transfection; D014407:Tumor Cells, Cultured
D007376:Interleukin-2; D018664:Interleukin-12; D007371:Interferon-gamma