Interleukin‐12 and B7.1 co‐stimulation cooperate in the induction of effective antitumor immunity and therapy of established tumors

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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 antitumor 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‐γ or tumor necrosis factor‐α, 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.