Dendritic Cell-based Immunization for Cancer Therapy
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DENDRITIC CELL-BASED IMMUNIZATION FOR CANCER THERAPY Michael A. Morse1 and H. Kim Lyerly2 1
Department of Medicine and Department of Surgery Duke University Medical Center Box 2606, Durham, North Carolina, 27710
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1. INTRODUCTION Immunotherapy is showing renewed promise as a modality for treating malignancies. Although the past clinical and experimental experiences of immunotherapy with non-specific immunogens (such as BCG or KLH) and systemic or local administration of various cytokines (such as IL-2 and interferon) have had mixed results (Rosenberg, 1987; Rosenberg, 1989; Robinson, 1977; Bulbul, 1989), an emerging understanding of the biologic basis of antigen-specific cellular recognition and the demonstration in experimental animal studies of an anti-tumor effect mediated through the cellular immune system provide compelling evidence to explore the role of specific cellular immunotherapy in human malignancies. Among the most potent agents for actively stimulating specific cellular immune responses are dendritic cells (DC) loaded with tumor antigen. This chapter will discuss the preclinical support for DC-based immunotherapy, methods for obtaining DC for clinical studies, strategies for delivering antigens to DC, and results of early human studies of DC vaccines.
2. BASIS FOR DENDRITIC CELL-BASED IMMUNOTHERAPY Most tumors are thought to express rejection antigens (van Pel, 1982) that are recognizable by CD8+ cytotoxic T cells (CTL) as peptide fragments bound in the groove of the tumor cell MHC class I molecule (Darrow, 1989). Such antigens found on human tumors include carcinoembryonic antigen (CEA) (gastrointestinal, breast, lung) (Thompson, 1991), MAGE-1 and -3 (melanoma, breast, ovarian) (Van der Bruggen, 1991), HER2/neu (breast, ovarian) (Disis, 1997), MART-1 (melanoma) (Kawakami, 1994), MUC1 (breast, gastrointestinal) (Barnd, 1989), mutated Ki-ras (pancreatic) (Bos, 1989), and E6 and E7 (cervical) (Halbert, 1991). Unfortunately, tumors may fail to stimulate primary immune responses because they lack the required costimulatory molecules Cancer Gene Therapy: Past Achievements and Future Challenges, edited by Habib Kluwer Academic/Plenum Publishers, New York, 2000.
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(such as CD80 and CD86) and thus, tumor antigen-specific T cells are usually absent, or present at low frequencies, in patients with malignancies (Van den Eynde, 1989; Fisk, 1995; Disis, 1994; Tsang, 1995, Coulie, 1992; Mazzocchi, 1994). Based on the hypothesis that once stimulated, naive T cells gain the capacity to recognize and destroy tumors for which they are specific, numerous approaches to inducing primary immune responses have been developed including gene-modified tumor vaccines, tumor lysates, naked DNA, peptide fragments of tumor proteins, and viral vectors carrying the genes for antigens of interest. Recent observations suggest that these modalities may indirectly stimulate immune responses by a process called cross-priming (Matzinger, 1994) in which the delivered antigen is released by infl
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