We propose to design and test several MUC1 vaccines in preclinical studies in animals and in clinical trials in cancer patients. MUC1 is an epithelial tumor antigen. The vaccine design will be based on the new understanding of MUC1 immunogenicity derived through the aims of old Project 4 as well as the new knowledge about antigen uptake, presentation, and DC activation derived through the other projects in the PO1. We learned that the potential repertoire of MUC1 specific T cells could be much larger than had been observed in cancer patients. Difficulty we discovered in processing of the MUC1 glycoprotein by dendritic cells, severely limits the immune repertoire in vivo and, presumably the anti-tumor efficacy of anti-MUC1 immune responses. The hypothesis to be tested in pre-clinical studies in animals (Aim 1) and in clinical trials (Aim 2) is the following: if MUC1 glycoprotein is administered in forms that promote efficient processing and presentation by dendritic cells, resulting in a large number of peptide and glycopeptide epitopes, the anti-MUC1 T cell repertoire will broaden (including generation of helper T cells) and this will increase the tumor rejection potential of anti-MUC1 immune responses. The specific alms are:
SPECIFIC AIM 1. Sub-aim a) To test in MUC1 transgenic mice the tumor rejection potential of cancer vaccines composed of a MUC1 peptide and/or glycopeptide that can be processed and presented by DC; Sub-aim b) To better understand the mechanisms of immune surveillance (and failure thereof) of MUC 1 + tumors, by examining the effect of uptake and processing of various forms of MUC1 on the biology of various DC populations.
SPECIFIC AIM 2. To test in phase I/II clinical trials toxicity and immunogenicity of cancer vaccine, composed of a MUC1 peptide and/or glycopeptide processed and presented by DC and to evaluate immune effector mechanisms generated. The importance for tumor rejection and tumor specificity of soluble vs. particulate antigen and of peptide-specific versus glycopeptide-specific immune responses will be evaluated. The goal of both aims is to show that MUC1 is immunogenic in animals and patients and that the immune response it elicits could be a tumor rejection response.
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