title: Interleukin-12 and B7.1 co-stimulation cooperate in the induction of effective antitumor immunity and therapy of established tumors.
abstract: Interleukin-12 (IL-12) promotes specific and long-lasting anti-tumor immunity mediated by T cells in a variety of murine tumor models. IL-12 also synergizes with B7.1 (CD80) co-stimulation to induce proliferation and cytokine production by both human and murine T cells in vitro. We evaluated the combined anti-tumor efficacy of IL-12 and B7.1 gene delivery in two apparently poorly immunogenic tumor models (TS/A and MCA207). In both of these models, expression of B7.1 and production of IL-12 in the inoculum led to improved anti-tumor immunity, with up to 80% long-term tumor-free animals (vs 0-20% of mice remaining tumor free when inoculated with either B7.1- or IL-12-transfected tumors alone). Tumor-free mice were capable of rejecting a subsequent rechallenge with the wild-type tumor in 66% of the cases. Cooperativity was dependent upon the level of IL-12 secreted by engineered cells. IL-12 delivery required B7 expression of therapeutic effects to be observed in these models. Vaccines provided at a site distal to a control, non-transfected tumor slowed (TS/A) or abrogated (MCA207) the progression of wild-type tumors. The synergistic anti-tumor effects associated with combined application of B7.1- and IL-12-transfected tumors were partially negated by systemic administration of the CD28-B7.1/B7.2 antagonist CTLA4-Ig or by inoculation with neutralizing antibodies directed against murine interferon-gamma or tumor necrosis factor-alpha, two cytokines elicited in response to IL-12 stimulation. These data support the potential clinical utility of combined gene therapy using IL-12- and B7.1-engineered autologous cells (tumor or fibroblasts) as a vaccine to elicit specific anti-tumor immunity.
authors.affiliation: Department of Surgery, University of Pittsburgh Medical Center, USA.
authors.forename: L
authors.initials: L
authors.lastname: Zitvogel
authors.forename: P D
authors.initials: PD
authors.lastname: Robbins
authors.forename: W J
authors.initials: WJ
authors.lastname: Storkus
authors.forename: M R
authors.initials: MR
authors.lastname: Clarke
authors.forename: M J
authors.initials: MJ
authors.lastname: Maeurer
authors.forename: R L
authors.initials: RL
authors.lastname: Campbell
authors.forename: C G
authors.initials: CG
authors.lastname: Davis
authors.forename: H
authors.initials: H
authors.lastname: Tahara
authors.forename: R D
authors.initials: RD
authors.lastname: Schreiber
authors.forename: M T
authors.initials: MT
authors.lastname: Lotze
mesh_terms: D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000502:physiology; D018122:B7-1 Antigen / Q000502:physiology*; D018106:CD28 Antigens / Q000502:physiology; D060908:CTLA-4 Antigen; D005260:Female; D018796:Immunoconjugates; D007167:Immunotherapy; D007371:Interferon-gamma / Q000502:physiology; D018664:Interleukin-12 / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000276:immunology / Q000628:therapy*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D014612:Vaccines
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D014409:Tumor Necrosis Factor-alpha; D014612:Vaccines; D018664:Interleukin-12; D000069594:Abatacept; D007371:Interferon-gamma