Immunotherapy of Pancreatic Adenocarcinoma
Project Leaders: Michael A. Hollingsworth, Ph.D. and Jean Grem, M.D.
- Translational Goal: Development in a preclinical setting and use of specific immunotherapy strategies that are designed to provoke effective cell mediated immune responses to pancreatic tumors and conduct a clinical trial to test these reagents.
We are developing and testing novel reagents that can be used for immunotherapy of human adenocarcinomas, particularly those of the pancreas. These 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.
One important challenge of producing effective tumor vaccines is developing reagents that break immunological tolerance to tumor-associated antigens. For preclinical studies, we 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 are evaluating the mechanism of action of BrevaRex® MAb-AR20.5 in the murine model, conducting preclinical studies to determine its mechanism of action, and investigating the utility of combining this therapy with other interventions in a clinical trial in humans with pancreatic cancer.
Michael A. Hollingsworth, Ph.D.
Eppley Institute for Research and Allied Diseases
Jean L. Grem, M.D.
UNMC Internal Medicine