Targeted delivery of IFNgamma to tumor vessels uncouples antitumor from counterregulatory mechanisms.
Because of its immunomodulatory and anticancer activities, IFNgamma has been used as an anticancer drug in several clinical studies, unfortunately with modest results. Attempts to increase the response by increasing the dose or by repeated continuous injection often resulted in lower efficacy, likely due to counterregulatory effects. We show here that targeted delivery of low doses of IFNgamma to CD13, a marker of angiogenic vessels, can overcome major counterregulatory mechanisms and delay tumor growth in two murine models that respond poorly to IFNgamma. Tumor vascular targeting was achieved by coupling IFNgamma to GCNGRC, a CD13 ligand, by genetic engineering technology. The dose-response curve was bell-shaped. Maximal effects were induced with a dose of 0.005 microg/kg, about 500-fold lower than the dose used in patients. Nontargeted IFNgamma induced little or no effects over a range of 0.003 to 250 microg/kg. Studies on the mechanism of action showed that low doses of targeted IFNgamma could activate tumor necrosis factor (TNF)-dependent antitumor mechanisms, whereas high doses of either targeted or nontargeted IFNgamma induced soluble TNF-receptor shedding in circulation, a known counterregulatory mechanism of TNF activity. These findings suggest that antitumor activity and counterregulatory mechanisms could be uncoupled by tumor vascular targeting with extremely low doses of IFNgamma.
Curnis
Flavio
F
Department of Oncology, Cancer Immunotherapy and Gene Therapy Program, San Raffaele H Scientific Institute, Milan, Italy.
Gasparri
Anna
A
Sacchi
Angelina
A
Cattaneo
Angela
A
Magni
Fulvio
F
Corti
Angelo
A
D000818:Animals; D018826:CD13 Antigens / Q000378:metabolism; D045744:Cell Line, Tumor; D005354:Fibrosarcoma / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000008:administration & dosage* / Q000737:chemistry / Q000235:genetics; D008175:Lung Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism; D008546:Melanoma, Experimental / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000188:drug therapy* / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism; D009842:Oligopeptides / Q000008:administration & dosage* / Q000737:chemistry / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics
D009842:Oligopeptides; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; D007371:Interferon-gamma; D018826:CD13 Antigens