Effective tumor vaccines generated by in vitro modification of tumor cells with cytokines and bispecific monoclonal antibodies

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Abstract
Antitumor immune responses are mediated primarily by T cells1. Downregulation of the major histocompatiblity complex (MHC) and the molecules that costimulate the immune response is associated with defective signaling by tumor cells for T-cell activation2–14. In vitro treatment with a combination of cytokines significantly increased the expression of MHC class I and adhesion molecules on tumor cell surfaces. When tumor cells were first incubated with a bispecific monoclonal antibody that binds antigen on tumor cells to CD28 on T cells, the modified tumor cells become immunogenic and are able to stimulate naive T cells, generating tumor-specific cytotoxic T cells in vitro. Immunization with the modified tumor cells elicits an immune response mediated by CD8+ T cells. This response protected against a challenge with parental tumor cells and cured established tumors. The approach was effective in both low immunogenic and nonimmunogenic tumor model systems. Modification of tumor cells with this two-step procedure may provide a strategy for development of tumor vaccines that is effective for cancer immunotherapy.