Induction of anti-self-immunity to cure cancer

A quiet but profound revolution in theoretical framework, a paradigm shift, now has infused the consideration of therapies in autoimmune diseases and cancers, as exem-It is becoming accepted that a large set of antigenic determinants of the self have not induced self-tolerance (reviewed by Sercarz et al., 1993) and that these peptide determinants furnish target structures for autoimmune attack (reviewed by Lanzavecchia, 1995) and could provide potential targets for immune responses directed against tumors. It is not necessary to seek mysterious nonself-or neoself-antigens expressed by the tumor. The bulk of the lively and open discussion, characteristic of these free format workshops with no fixed presentations, was modulated very capably by A. and focused on how to initiate, maintain, and regulate antitumor autoimmunity, which could translate into effective treatment in cancer clinics. Are there in fact certain tumor-related determinants that can be rendered into crucial targets of attack by the immune system? The pertinent focus is on suitable antigen processing and subsequent presentation by major histo-compatibility complex (MHC) class I and class II molecules expressed by tumor cells. Any of the peptides that is bound in the groove of an MHC molecule on tumor cells provides a potential target determinant for attack by the immune system. The peptides bound by the MHC molecules of all ceils, including tumor cells, are derived from endogenous cellular (or viral) proteins, and the antigen-processing machinery of the cells manages to display certain antigen determinants to ambient T cells. Tumor cells are distinct in that they possess additional oncoproteins that either are overexpressed owing to dysregulation or are mutated and have thereby conferred the tumor phenotype to these cells, to developmental antigens reexpressed during the process of tumorigenesis, or to passenger mutations in nononcogenic proteins that result from the loss of mechanisms that maintain genomic stability. Using T cell clones that are specifically able to kill the tumor as detectors for immunogenic tumor-derived determinants bound to MHC molecules of the tumor, several investigators have shown that T cells indeed recognize peptides from endogenous normal (and occasionally mutant) self-proteins. T. Boon and colleagues (van der Bruggen et al., 1991), in their pioneering studies, drew a page from bacterial genetics and cloned genes encoding tumor antigens recognized by CD8 T cells specific for human melanomas. Melanoma antigen 1 (MAGE-1) to MAGE-3 were the original family of human melanoma-specific antigens that were molecularly defined in this way and were …