Gene gun-mediated skin transfection with interleukin 12 gene results in regression of established primary and metastatic murine tumors.
Particle-mediated (gene gun) in vivo delivery of the murine interleukin 12 (IL-12) gene in an expression plasmid was evaluated for antitumor activity. Transfer of IL-12 cDNA into epidermal cells overlying an implanted intradermal tumor resulted in detectable levels (266.0 +/- 27.8 pg) of the transgenic protein at the skin tissue treatment site. Despite these low levels of transgenic IL-12, complete regression of established tumors (0.4-0.8 cm in diameter) was achieved in mice bearing Renca, MethA, SA-1, or L5178Y syngeneic tumors. Only one to four treatments with IL-12 cDNA-coated particles, starting on day 7 after tumor cell implantation, were required to achieve complete tumor regression. This antitumor effect was CD8+ T cell-dependent and led to the generation of tumor-specific immunological memory. By using a metastatic P815 tumor model, we further showed that a delivery of IL-12 cDNA into the skin overlying an advanced intradermal tumor, followed by tumor excision and three additional IL-12 gene transfections, could significantly inhibit systemic metastases, resulting in extended survival of test mice. These results suggest that gene gun-mediated in vivo delivery of IL-12 cDNA should be further developed for potential clinical testing as an approach for human cancer gene therapy.
Rakhmilevich
A L
AL
Cancer Gene Therapy, Auragen, Inc., Middletown, WI 53562, USA.
Turner
J
J
Ford
M J
MJ
McCabe
D
D
Sun
W H
WH
Sondel
P M
PM
Grota
K
K
Yang
N S
NS
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D018076:DNA, Complementary; D005260:Female; D015316:Genetic Therapy; D007156:Immunologic Memory; D018664:Interleukin-12 / Q000008:administration & dosage / Q000235:genetics*; D051379:Mice; D008815:Mice, Inbred Strains; D009362:Neoplasm Metastasis; D009374:Neoplasms, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D012867:Skin; D014162:Transfection / Q000379:methods*
D018076:DNA, Complementary; D018664:Interleukin-12