title: Immune response against large tumors eradicated by treatment with cyclophosphamide and IL-12.
abstract: Previous studies have demonstrated eradication of small (4-8 mm) established murine MCA207 sarcomas by treatment with systemic IL-12. Analysis of the mechanism has revealed a cellular and molecular immune response at the tumor typical of a Th1 cell-mediated, macrophage-effected, delayed-type hypersensitivity (DTH) response. In the current study we investigate the immune response against long term established, large MCA207 tumors induced by combined treatment with IL-12 and cyclophosphamide (Cy), an agent known to potentiate the DTH response. Our results demonstrate that s.c. large MCA207 tumors (15-20 mm) that are refractory to treatment by either IL-12 or Cy alone can be completely eradicated by the combination of Cy and IL-12. IL-12 is apparently the only cytokine capable of mediating tumor eradication, and the effect is dependent on IFN-gamma. The contribution of Cy is probably due to immunopotentiation of DTH rather than to direct cytotoxicity to the tumor. The regression of these large tumors takes >4 wk and, in many cases, is self-sustained, in that little or no additional IL-12 is needed beyond the initial week of administration. Analysis of the cellular and molecular events at the tumor site suggests that the mechanism is a Th1-mediated antitumor immune response.
authors.affiliation: Department of Surgery, University of California, San Francisco, VA Medical Center 94121, USA.
authors.forename: K
authors.initials: K
authors.lastname: Tsung
authors.forename: J B
authors.initials: JB
authors.lastname: Meko
authors.forename: Y L
authors.initials: YL
authors.lastname: Tsung
authors.forename: G R
authors.initials: GR
authors.lastname: Peplinski
authors.forename: J A
authors.initials: JA
authors.lastname: Norton
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D003520:Cyclophosphamide / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D007371:Interferon-gamma / Q000502:physiology; D018664:Interleukin-12 / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012513:Sarcoma, Experimental / Q000188:drug therapy* / Q000276:immunology* / Q000628:therapy; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D018906:Antineoplastic Agents, Alkylating; D016207:Cytokines; D018664:Interleukin-12; D007371:Interferon-gamma; D003520:Cyclophosphamide