Gene-Modified Dendritic Cells as Vaccines for the Induction of Anti-Tumor Immunity

In the last few years several laboratories have provided evidence that tumor-specific antigens can be defined by T lymphocytes in humans (Boon et al. 1994). These antigens have been identified mainly by cloning T lymphocytes that were isolated from peripheral blood or from tumor tissues (tumor-infiltrating lymphocytes). The restricted reactivity of the T-cell clones for specific alleles of the major histocompatibility complex (MHC) was a remarkably constant finding that was clarified and understood by the demonstration that small peptides can bind to the antigen-binding groove of molecules of the MHC. Intracellular proteins are degraded in the proteasomes into small peptides 8–14 amino acids in length, which are transported to the endoplasmic reticulum and loaded into the peptide-binding groove of newly synthesized MHC class I molecules. The MHC-peptide complexes are then exported on the cell membrane and presented to CD8 + T cells. It is now clear that tumor cells can also present autologous tissue-specific antigens. A number of molecules that are preferentially expressed in tumor cells have been identified in melanoma, renal cell carcinoma, breast cancer, ovarian and gastrointestinal cancer. The amino acid sequence of several peptides that interact with different MHC molecules has been defined in melanoma (Cox et al. 1994; Boon et al. 1994). However, most of these peptides are not strictly tumor-specific, being expressed either in normal melanocytes or in other tissues, such as testes or lung.