We propose to further develop and test novel reagents that can be used for immunotherapy of humanadenocarcinomas, particularly those of the pancreas. The reagents under development in this project includehighly specific murine monoclonal antibodies to circulating tumor-associated antigens (TAA), which formimmune complexes that are taken up by dendritic cells (DCs) and other antigen-presenting cells (APCs) andare efficiently presented to the immune system. As a result, humoral and cellular immune responses againstTAA are activated. The fundamental hypothesis under investigation is that murine antibodies againstcirculating human tumor antigens will bind to those antigens when administered to patients, form immunecomplexes that will be bound to APCs either directly or subsequent to the development of human anti-mouseantibody (HAMA) responses that capture these complexes, and that antigen processing by the APCs willproduce immune responses against the targeted antigen. We specifically hypothesize that the anti-MUC1antibody BrevaRex MAb-AR20.5, when combined with soluble and/or cell-bound MUC1 in patients, willinduce humoral and cellular immune responses to MUC1 that will be protective against pancreatic cancer inpatients with MUC1 -expressing pancreatic and other tumors. The strategy has the unique capacity to providea method of vaccinating each patient with their own tumor antigens through in vivo capture and presentationof circulating and cell associated tumor antigens. We will target the cell surface associated mucin MUC1with BrevaRex MAb-AR20.5, a murine IgGlK specific for the tandem repeat region of MUC1, which shouldprovide effective targets for cell mediated responses against the tumor cells that produced the circulatingantigen. One important challenge of producing effective tumor vaccines is developing reagents that breakimmunological tolerance to tumor-associated antigens. For preclinical studies, will utilize an inbred mousestrain on the C57BL/6 background that expresses human MUC1 in the correct temporal and spatial pattern(MUC1 Tg), develops tolerance and is refractory to immunization with MUC1. This experimental model hasenabled us to study the effect of endogenous expression of the MUC1 gene on the ability of mice to produceprotective immune responses to tumors, and represents an improved model system for evaluating theefficacy of anti-MUC1 formulations in vivo within the context of existing tolerance. We have developed andinvestigated a model in which a murine pancreatic tumor (Panc02) syngeneic to C57BL/6 transfected withhuman MUC1 (Panc02.MUC1), can be transplanted subcutaneously and orthotopically. In the studiesproposed here, we will evaluate the mechanism of action of BrevaRex MAb-AR20.5 in the murine model,conduct preclinical studies to determine its mechanism of action, and investigate the utility of combining thistherapy with other interventions in a clinical trial in humans with pancreatic cancer.
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