Combined CXC chemokine and interleukin-12 gene transfer enhances antitumor immunity.
It has been shown that intratumor administration of an adenovirus vector expressing IL-12 produces a potent T cell-mediated response that leads to significant tumor regression in a murine breast cancer model. IP-10 and MIG are CXC chemokines that recruit mononuclear cells in vivo. In addition to their chemotactic roles, IP-10 and MIG inhibit angiogenesis. We tested whether the addition of IP-10 or MIG may both enhance the antitumor immune response of IL-12 through T cell recruitment and inhibit tumor growth through angiostasis. Adenovirus vectors expressing IP-10 or MIG and/or IL-12 were administered intratumorally in a murine model of mammary adenocarcinoma and fibrosarcoma. Administration of IP-10 or MIG in combination with IL-12 resulted in considerable tumor regression and increased survival time of tumor-bearing animals as compared with IP-10, MIG, IL-12 alone or control-treated animals, with the IP-10 IL-12 combination being most effective. These results suggest augmenting the antitumor immune response and inhibiting tumor angiogenesis with adenoviral vectors expressing IP-10 in combination with IL-12 is a novel way to enhance tumor regression.
Palmer
K
K
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada.
Hitt
M
M
Emtage
P C
PC
Gyorffy
S
S
Gauldie
J
J
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D015152:Blotting, Northern; D017252:CD3 Complex / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019743:Chemokines, CXC / Q000235:genetics*; D003094:Collagen; D003601:Cytotoxicity Tests, Immunologic; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000473:pathology; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D015552:Injections, Intralesional; D007371:Interferon-gamma / Q000032:analysis; D018664:Interleukin-12 / Q000235:genetics*; D015847:Interleukin-4 / Q000032:analysis; D007797:Laminin; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D009389:Neovascularization, Pathologic; D011509:Proteoglycans; D013601:T-Lymphocytes / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
D017252:CD3 Complex; D019743:Chemokines, CXC; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D016222:Fibroblast Growth Factor 2; C059485:matrigel; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma; D003094:Collagen