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Experimental Therapeutics, Molecular Targets, and Chemical Biology |
1 Department of Immunology, The Scripps Research Institute, La Jolla, California and 2 Universitaets Hautklinik, Wuerzburg, Germany
Requests for reprints: Ralph A. Reisfeld, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037. Phone: 858-784-8105; Fax: 858-784-2708; Email: reisfeld{at}scripps.edu.
A novel strategy achieved the eradication of lung tumor metastases by joint suppression of angiogenesis in the tumor neovasculature and induction of tumor cell apoptosis. This was accomplished by CTLs induced by a DNA vaccine encoding secretory chemokine CCL21 and the inhibitor of apoptosis protein survivin, overexpressed by both proliferating endothelial cells in the tumor vasculature and tumor cells. Oral delivery of this DNA vaccine by doubly attenuated Salmonella typhimurium (dam– and AroA–) to such secondary lymphoid organs as Peyer's patches in the small intestine, elicited marked activation of antigen-presenting dendritic cells, and an effective CD8+T cell immune response against the survivin self-antigen. This resulted in eradication or suppression of pulmonary metastases of non–small cell lung carcinoma in both prophylactic and therapeutic settings in C57BL/6J mice. Moreover, the suppression of angiogenesis induced by the vaccine did not impair wound healing or fertility of treated mice. It is anticipated that such novel DNA vaccines will aid in the rational design of future strategies for the prevention and treatment of cancer.
Key Words: DNA vaccine • survivin • lung cancer • metastases • T cells
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