Transforming Human Pancreatic Cancer Into An Immunologic Disease

Pancreatic ductal adenocarcinoma (PDA) is rising in incidence but remains deadly for most patients. Some progress has occurred in activating immune responses against PDA, however there are unanswered questions that need to be addressed for immunotherapy to have a significant impact on the lives of PDA patients. Our Team will address two critical problems: 1) inefficient generation of high quality T cells targeted against PDA antigens capable of tumor trafficking and killing; and 2) multiple cellular barriers that comprise stromal and myeloid cells that inhibit effector T cell trafficking and function in the PDA tumor microenvironment (TME). Both clinical studies (“science in patients”) and pre-clinical studies (mouse models) will be conducted to address these issues, and to evaluate novel combinatorial therapies that successfully modulate PDA stroma and chronic inflammation to facilitate improved tumor infiltration of high quality and durable cancer targeted T cells. This program is composed of 4 Projects and 4 Cores. The four projects will address the common overarching theme that PDA is composed of multiple cell types and signals that inhibit T cell induction, trafficking into, and function in tumors. Each project will address either the induction of quality T cells or the modulation of suppressive cell populations as major barriers to T cell infiltration and activation, and all will integrate agents that bypass these suppressive mechanisms with optimal T cell therapies. Projects 1, 2, and 4 will combine ongoing preclinical studies aimed at uncovering mechanisms of suppression of different barriers with translational clinical trials that study combination therapy to bypass these suppressive mechanisms. Project 3 will conduct a biomarker heavy clinical trial using a multi-arm Platform design that will add and delete immune modulatory arms based on data from biomarker analysis in this Project and from data that feeds into this Project from the other 3 Projects. Standard procedures will be used across Projects to collect and bank serial biospecimens obtained from patients treated on the clinical trials. The Cores will be critical for conducting the proposed assays and for analysis and integration of the data. A Program database will be developed to allow for integration of data generated from these assays across the entire Program. This will be a unique database that will also bring in data from other sources such as the TCGA database, and will provide the Program Team with the ability to compare results based on the genetics and inflammatory composition of each patient’s tumor and their response to the therapy they received. The final outcomes will include results from a number of therapeutic interventions, approaches to optimize each therapeutic, the potential to further integrate therapies that were tested in one or more projects in future trials, and the ability to develop TME signatures that may further stratify patients for therapeutic interventions. This program will substantially accelerate progress in PDA therapy, and allow otherwise nearly impossible achievements in defining predictors of successful immunological therapeutic intervention for PDAs.