We propose to further develop and test novel reagents that can be used for immunotherapy of human adenocarcinomas, particularly those of the pancreas. The reagents under development in this project include highly specific murine monoclonal antibodies to circulating tumor-associated antigens (TAA), which form immune complexes that are taken up by dendritic cells (DCs) and other antigen-presenting cells (APCs) and are efficiently presented to the immune system. As a result, humoral and cellular immune responses against TAA are activated. The fundamental hypothesis under investigation is that murine antibodies against circulating human tumor antigens will bind to those antigens when administered to patients, form immune complexes that will be bound to APCs either directly or subsequent to the development of human anti-mouse antibody (HAMA) responses that capture these complexes, and that antigen processing by the APCs will produce immune responses against the targeted antigen. We specifically hypothesize that the anti-MUC1 antibody BrevaRex? MAb-AR20.5, when combined with soluble and/or cell-bound MUC1 in patients, will induce humoral and cellular immune responses to MUC1 that will be protective against pancreatic cancer in patients with MUC1 -expressing pancreatic and other tumors. The strategy has the unique capacity to provide a method of vaccinating each patient with their own tumor antigens through in vivo capture and presentation of circulating and cell associated tumor antigens. We will target the cell surface associated mucin MUC1 with BrevaRex? MAb-AR20.5, a murine IgGlK specific for the tandem repeat region of MUC1, which should provide effective targets for cell mediated responses against the tumor cells that produced the circulating antigen. One important challenge of producing effective tumor vaccines is developing reagents that break immunological tolerance to tumor-associated antigens. For preclinical studies, will utilize an inbred mouse strain 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 has enabled us to study the effect of endogenous expression of the MUC1 gene on the ability of mice to produce protective immune responses to tumors, and represents an improved model system for evaluating the efficacy of anti-MUC1 formulations in vivo within the context of existing tolerance. We have developed and investigated a model in which a murine pancreatic tumor (Panc02) syngeneic to C57BL/6 transfected with human MUC1 (Panc02.MUC1), can be transplanted subcutaneously and orthotopically. In the studies proposed 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 this therapy with other interventions in a clinical trial in humans with pancreatic cancer.
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| Wiest, Edwin J; Smith, Heather Jensen; Hollingsworth, Michael A (2018) Met receptor inhibitor SU11274 localizes in the endoplasmic reticulum. Biochem Biophys Res Commun 501:858-862 |
| Chugh, Seema; Barkeer, Srikanth; Rachagani, Satyanarayana et al. (2018) Disruption of C1galt1 Gene Promotes Development and Metastasis of Pancreatic Adenocarcinomas in Mice. Gastroenterology 155:1608-1624 |
| Jahan, Rahat; Macha, Muzafar A; Rachagani, Satyanarayana et al. (2018) Axed MUC4 (MUC4/X) aggravates pancreatic malignant phenotype by activating integrin-?1/FAK/ERK pathway. Biochim Biophys Acta Mol Basis Dis 1864:2538-2549 |
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