Cancer vaccine development: protein transfer of membrane-anchored cytokines and immunostimulatory molecules.

Many tumor cells escape host-immune recognition by the downregulation or lack of immunostimulatory molecules. Expression of immunostimulatory molecules on tumor cells by gene transfer can be used to induce an antitumor immune response. However, we have previously shown that protein transfer of glycosyl-phosphatidylinositol (GPI)-linked costimulatory molecules is a successful alternative to traditional gene transfer in preparing such a tumor vaccine. Vaccination with membranes modified by protein transfer to express GPI-linked B7.1 (CD80), a costimulatory adhesion molecule, induces protective immunity in mice and allogeneic antitumor T-cell proliferation in humans in vitro. Our goal is to develop an optimal tumor vaccine using tumor membranes modified by protein transfer to target and stimulate antigen-presenting cells (APCs) and T cells. We have investigated the efficacy of expressing GPI-anchored cytokine molecules on the surface of tumor cells. Expression of interleukin-12 (IL-12) on tumor-cell membranes in a GPI-anchored form induces a strong antitumor immune response that is comparable to the effects of secretory IL-12. Because many cytokines act synergistically, we are testing the membrane expression and immunostimulatory effects of cytokines individually as well as in combination to determine potential complementary effects of coexpression on the antitumor immune response. Ultimately, the protein-transfer vaccination may be used in humans alone or in multimodal combination therapies to induce tumor regression and to serve as a protective measure to prevent postsurgical secondary metastases.