Research involves the development of novel immunotherapeutic approaches to cancer, including the design and analyses of recombinant vaccines directed against gene products of oncogenes and antigens overexpressed in tumors. Vaccine targets include human carcinoembryonic antigen (CEA), point mutated ras oncogenes, prostate specific antigen (PSA), and the muc-1 breast, lung, and pancreatic associated mucin. Vehicles for vaccine delivery for induction of host cellular immune responses include recombinant vaccinia (rV), replication defective avian pox viruses (avipox), immunodominant peptides, and recombinant proteins. Phase I clinical trials have now demonstrated that when advanced carcinoma patients are vaccinated with recombinant vaccinia virus or recombinant avipox containing the CEA gene, cytotoxic T-cell (CTL) responses are induced to the self antigen CEA. The actual epitopes recognized by these T-cells have now been defined and used to establish CEA-specific CTL lines and clones. The utility of these and other CTL lines in the adoptive transfer of epitope specific T-cells is currently under investigation.Vaccine trials employing CEA CTL peptides, either in adjuvant or pulsed on dendritic cells, are in progress.Studies are ongoing in the elucidation and analyses of agonist peptides of the identified CEA CTL immunodominant epitopes. Initial studies have indicated that peptides can be designed that are more efficient than the natural peptide in the generation of cytotoxic T-cell lines. Clinical trials are also ongoing in prostate cancer patients with a recombinant vaccinia PSA vaccine. PSA CTL immunodominant epitope peptides have also recently been identified in in vitro studies. A Phase I clinical trial is now in progress in which peptides reflecting ras oncogene point mutations at codon 12 are administered to patients whose tumors have been shown to contain the individual mutation. These studies have shown the induction of both CD4+ helper T-cells and CD8+ CTL specific for the mutated ras peptide and not proto-ras. Ongoing preclinical studies include the use of multidimensional fusion proteins as immunogens and the exploitation of T-cell co-stimulatory molecules in pox virus vectors in both gene therapy and vaccine strategies.
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