AGR2-superantigen vaccine conjugate for the treatment of pancreaticductal adenocarcinoma

Project Summary/Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer. Poor survival rates are largely due to the late stage at which PDAC is diagnosed and a lack of effective targeted therapies. While the field of immunotherapy has significantly increased overall survival in some malignancies, they have not translated to PDAC. The long-term goal of this research program is to develop a novel cancer vaccine for the treatment of PDAC. Preliminary studies by our group and others have shown that the Anterior Gradient-2 (AGR2) protein, a member of the protein disulfide isomerase (PDI) family, is induced during PDAC oncogenesis and highly expressed in >90% of PDAC patients. AGR2 has intracellular oxidative folding function and is also released from the cell where it localizes to the surface of PDAC cells and is shed into the tumor microenvironment. We hypothesize that AGR2 is an actionable target for the development of a PDAC targeted vaccine and will test that theory using a new immunotherapy drug candidate. Streptococcal Mitogenic Exotoxin Z-2 (SMEZ-2) from Streptococcus pyogenes is a bacterial superantigen (SAg) that binds to MHC II molecules on antigen presenting cells (APCs) with high affinity. In preliminary studies we generated a detoxified AGR2-SMEZ-2 conjugate that we hypothesize will stimulate a robust anti-PDAC immune response. We found in preliminary studies that AGR2- SMEZ-2 generates a robust anti-AGR2 response in mice and displays no overt toxicity. The objectives of Phase 1 of this study are: (1) to demonstrate anti-PDAC efficacy of AGR2-SMEZ-2 in vivo, and (2) to measure B and T cell biomarkers of an anti-AGR2 response in vaccinated mice. Upon success in Phase 1, the objectives of Phase 2 of this study are: (1) to show synergy between AGR2-SMEZ-2 vaccination and checkpoint inhibition in vivo, (2) to compare the superior immunogenicity of SMEZ-2 mediated through MHC II-specific binding over existing vaccine carrier proteins, and (3) to determine the optimal dose, schedule, and toxicology profile of AGR2-SMEZ-2 in vivo. This work is innovative because we will investigate the anti-PDAC mechanism of our proprietary AGR2- SMEZ-2 vaccine and characterize the induced immune response in different mouse models. This work will support the development of a first-in-class vaccine for the treatment of PDAC, a cancer with few existing therapies. In addition, we expect that this study will allow for other immunotherapies (namely checkpoint inhibition) to become effective in providing a PDAC response in patients.