title: Potent antitumor effects of combination therapy with IFNs and monocytes in mouse models of established human ovarian and melanoma tumors.
abstract: Interferon-activated monocytes are known to exert cytocidal activity against tumor cells in vitro. Here, we have examined whether a combination of IFN-α2a and IFN-γ and human monocytes mediate significant antitumor effects against human ovarian and melanoma tumor xenografts in mouse models. OVCAR-3 tumors were treated i.t. with monocytes alone, IFN-α2a and IFN-γ alone or combination of all three on day 0, 15 or 30 post-tumor implantation. Mice receiving combination therapy beginning day 15 showed significantly reduced tumor growth and prolonged survival including complete regression in 40% mice. Tumor volumes measured on day 80 in mice receiving combination therapy (206 mm(3)) were significantly smaller than those of mice receiving the IFNs alone (1,041 mm(3)), monocytes alone (1,111 mm(3)) or untreated controls (1,728 mm(3)). Similarly, combination therapy with monocytes and IFNs of much larger tumor also inhibited OVCAR-3 tumor growth. Immunohistochemistry studies showed a large number of activated macrophages (CD31(+)/CD68(+)) infiltrating into OVCAR-3 tumors and higher densities of IL-12, IP10 and NOS2, markers of M1 (classical) macrophages in tumors treated with combination therapy compared to the controls. Interestingly, IFNs-activated macrophages induced apoptosis of OVCAR-3 tumor cells as monocytes alone or IFNs alone did not mediate significant apoptosis. Similar antitumor activity was observed in the LOX melanoma mouse model, but not as profound as seen with the OVCAR-3 tumors. Administration of either mixture of monocytes and IFN-α2a or monocytes and IFN-γ did not inhibit Lox melanoma growth; however, a significant inhibition was observed when tumors were treated with a mixture of monocytes, IFN-α2a and IFN-γ. These results indicate that monocytes and both IFN-α2a and IFN-γ may be required to mediate profound antitumor effect against human ovarian and melanoma tumors in mouse models.
authors.affiliation: Tumor Vaccines and Biotechnology Branch, Division of Cellular and Gene Therapies, Food and Drug Administration, Center for Biologics Evaluation and Research, NIH, Bethesda, MD 20892, USA.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Nakashima
authors.forename: Kotaro
authors.initials: K
authors.lastname: Miyake
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Clark
authors.forename: Joseph
authors.initials: J
authors.lastname: Bekisz
authors.forename: Joel
authors.initials: J
authors.lastname: Finbloom
authors.forename: Syed R
authors.initials: SR
authors.lastname: Husain
authors.forename: Samuel
authors.initials: S
authors.lastname: Baron
authors.forename: Raj K
authors.initials: RK
authors.lastname: Puri
authors.forename: Kathryn C
authors.initials: KC
authors.lastname: Zoon
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D016219:Immunotherapy, Adoptive / Q000379:methods*; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000276:immunology / Q000494:pharmacology*; D007371:Interferon-gamma / Q000276:immunology / Q000494:pharmacology*; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000276:immunology*; D010051:Ovarian Neoplasms / Q000276:immunology / Q000628:therapy*; D011897:Random Allocation; D011994:Recombinant Proteins / Q000276:immunology / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D007371:Interferon-gamma