Recent clinical evidence supports the hypothesis that tumor specific cytotoxic T-lymphocyte (CTL) activity plays an important role in anti-tumor immunity. Generation of durable, tumor-specific CTL mediated anti-tumor immunity is a rationale goal for the immunotherapy of Cutaneous T-cell Lymphoma (CTCL), and is likely to require immunization strategies capable of inducing both tumor-specific CD8+ T-cell immunity and Th1 skewed CD4+ helper T-cell responses. Defining an appropriate source of tumor antigen and a strategy for engineering DCs in vaccines to induce efficacious T-cell immunity are two of the major challenges currently facing modern tumor vaccine design. The development of an effective tumor-specific immunotherapy for CTCL has been severely limited by the lack of identified tumor-specific antigens. Recent evidence suggests that the use of tumor cells as a source of antigen has several theoretical advantages over immunization schemes based on delivery of defined antigens. We propose that effective tumor specific immunotherapy may be achieved by utilizing autologous, in vitro matured and polarized, antigen-loaded DCs as an immunogen, and autologous tumor cells as a source of antigen. Our central hypothesis is that DCs loaded with antigens derived from tumor cells, and matured in vitro to express potent Th1 skewing T-cell stimulatory function, can induce effective anti-tumor immunity for the treatment of CTCL. Here we propose, through innovative clinical trials, to evaluate and develop therapeutic CTCL vaccines by exploiting these approaches. To accomplish this we will pursue a single focused Specific Aim. We will evaluate clinical responses and CTCL-specific tumor immunity resulting from DC-based immunization using tumor cells as a source of antigen in phase II clinical trials.
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