DESCRIPTION (Applicant's Description) Nearly 500,000 patients are diagnosed annually with solid tumors that express carcinoembryonic antigen (CEA). Recent studies suggest that CEA may be a useful target for vaccine development and could, thus, benefit a large number of cancer patients. However, CEA is a self-antigen and avoiding or breaking tolerance may be required for effective anti-tumor immunity. Activation of T-cells requires both the interaction of a peptide-MHC complex with the corresponding T-cell receptor and the interaction of co-stimulatory molecules on antigen-presenting cells (APCs) with the appropriate T-cell ligand. The goal of this project is to evaluate the clinical and immunological effects of a recombinant canarypox virus (ALVAC) expressing human carcinoembryonic antigen (CEA) and the co-stimulatory molecule B7-1 in patients with advanced CEA-expressing tumors. The addition of B7-1 to the vaccine is predicted to enhance the generation of CEA-specific T-cell responses and thus break tolerance to the weakly immunogenic CEA. The optimum tolerated dose, clinical toxicity, and anti-tumor activity of the vaccine will be determined in a dose escalation phase I clinical trial. Since patients in this trial will have advanced disease and the effectiveness of a vaccine may be limited, the patients will be evaluated for evidence of humoral and cellular immune responses as proof of vaccination. Evaluation of anti-CEA immunity will include serum CEA and cytokine levels, anti-CEA and anti-viral antibody titers by standard ELISA assays. Cellular immunity will be determined by using an intracellular interferon-gamma assay or, alternatively, by ELISPOT or in vitro stimulation assays to determine the change in CEA-reactive precursor frequency T-cells through the course of multiple vaccinations in individual patients. The phenotype of reactive T-cells will be determined and long-term cultures established. The results of this project should provide insights into the immunologic and clinical effects of this new vaccine and guide future strategies for the application of tumor vaccines.
NIH ExPorter
NIH ExPorter