The Journal of Experimental Medicine
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Published 18 August 2003. doi:10.1084/jem.20030590
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© Rockefeller University Press, 0022-1007/2003/8/569 $5.00
The Journal of Experimental Medicine, Volume 198, Number 4, 569-580

Tumor Regression and Autoimmunity after Reversal of a Functionally Tolerant State of Self-reactive CD8+ T Cells

Willem W. Overwijk1,2, Marc R. Theoret3, Steven E. Finkelstein1, Deborah R. Surman1, Laurina A. de Jong2, Florry A. Vyth-Dreese2, Trees A. Dellemijn2, Paul A. Antony1, Paul J. Spiess1, Douglas C. Palmer1, David M. Heimann1, Christopher A. Klebanoff3, Zhiya Yu1, Leroy N. Hwang1, Lionel Feigenbaum4, Ada M. Kruisbeek2, Steven A. Rosenberg1 and Nicholas P. Restifo1

1 National Cancer Institute (NCI), National Institutes of Health, Bethesda, MD 20892
2 Division of Immunology, Netherlands Cancer Institute, 1066 CX, Amsterdam, Netherlands
3 Howard Hughes Medical Institute-National Institutes of Health, Research Scholars Program, Bethesda, MD 20815
4 Science Applications International Corporation, NCI, Frederick, MD 21702

Address correspondence to Nicholas P. Restifo, NCI, NIH, Building 10, Room 2B42, Bethesda, MD 20892-1502. Phone: (301) 496-4904; Fax: (301) 402-0922; email: restifo{at}nih.gov

Many tumor-associated antigens are derived from nonmutated "self" proteins. T cells infiltrating tumor deposits recognize self-antigens presented by tumor cells and can be expanded in vivo with vaccination. These T cells exist in a functionally tolerant state, as they rarely result in tumor eradication. We found that tumor growth and lethality were unchanged in mice even after adoptive transfer of large numbers of T cells specific for an MHC class I–restricted epitope of the self/tumor antigen gp100. We sought to develop new strategies that would reverse the functionally tolerant state of self/tumor antigen-reactive T cells and enable the destruction of large (with products of perpendicular diameters of >50 mm2), subcutaneous, unmanipulated, poorly immunogenic B16 tumors that were established for up to 14 d before the start of treatment. We have defined three elements that are all strictly necessary to induce tumor regression in this model: (a) adoptive transfer of tumor-specific T cells; (b) T cell stimulation through antigen-specific vaccination with an altered peptide ligand, rather than the native self-peptide; and (c) coadministration of a T cell growth and activation factor. Cells, vaccination, or cyto-kine given alone or any two in combination were insufficient to induce tumor destruction. Autoimmune vitiligo was observed in mice cured of their disease. These findings illustrate that adoptive transfer of T cells and IL-2 can augment the function of a cancer vaccine. Furthermore, these data represent the first demonstration of complete cures of large, established, poorly immunogenic, unmanipulated solid tumors using T cells specific for a true self/tumor antigen and form the basis for a new approach to the treatment of patients with cancer.

Key Words: adoptive cell transfer • immunotherapy • IL-2 • recombinant poxvirus • T cell epitope


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