Promoting Tumor Immunity by Cross-Linking B7-DC

Mayo Clinic Rochester, Rochester MN

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Abstract

A principal goal of active immunotherapy is to mobilize the immune response against cancer. The ability of host immunity to recognize and destroy tumor cells is well established. However, attempts to activate host anti-tumor immune responses have been only partially successful. Frequently CD8+ T cells are expanded and even infiltrate tumor beds, but tumor evasion mechanisms block their ability to destroy growing cancers. A new immune modulatory antibody, called B7-DC XAb, has been isolated from a patient with Waldenstrom[unreadable]s macroglobulinemia. This antibody activates both mouse and human dendritic cells in a manner distinct from other known immune activators, rapidly potentiating T cell cytotoxic responses that can recognize and kill tumor cells. Treatment of animals with the immune modulator prevented the outgrowth of melanoma, renal cell carcinoma, lymphoma, leukemia, and breast cancer, demonstrating the potential application of this reagent to the treatment of a wide variety of cancers. Remarkably, when B7-DC XAb was given to animals in conjunction with an otherwise ineffective vaccine, animals prone to the development of spontaneous and aggressive breast tumors remained cancer free. Experiments using mouse models are proposed (1) to define the essential components of this effective treatment against breast cancer, (2) to determine the mechanism of tumor destruction, (3) to characterize the targeted antigens and the origin of the T cells that recognize them, and (4) to elucidate the molecular mechanisms underlying dendritic cell activation, T cell activation, and modulation of the T regulatory cell network that are all associated with tumor immunity induced by the B7-DC XAb immune modulator. These studies are highly relevant to the development of an immunotherapy strategy for the treatment of human cancers because the immune potentiator being studied is a human antibody that binds to and stimulates human dendritic cells by activating similar signaling pathways to those originally defined in the mouse. Furthermore, human dendritic cells activated by B7-DC XAb-treatment display similar functional properties to those seen in the mouse, including enhanced antigen uptake, the patterns in cytokine release, and an enhanced ability to activate tumor specific cytotoxic T cells.