It is widely accepted that the immune system can exert either positive or negative influences on tumor growth. In many instances, tumors create an immunosuppressive microenvironment which contributes to tumor escape from immune destruction, particularly in pancreatic ductal adenocarcinoma (PDA). We have previously demonstrated that CD40 agonists can alter the tumor microenvironment and trigger a macrophage-dependent destruction of PDA in both humans and genetically engineered mice. Moreover, using a novel genetic lineage-tracing methodology, we now have preliminary data that invasive behavior and other elements of the metastatic cascade occur at the earliest stages of disease and are critically regulated by inflammation. Thus, we hypothesize that targeting immunosuppressive mechanisms in PDA will provide novel approaches to therapy for this otherwise treatment-resistant disease. In particular, we hypothesize that CD40 activation can re-educate both macrophages and T cells to trigger regression of a primary PDA tumor and impede metastatic spread in concert with other elements of the immune system. Our ultimate goal is to devise new therapies for PDA based on an understanding of immune regulatory networks in the tumor microenvironment. This proposal uses the multi-PI mechanism and will incorporate both mouse models and human patients.
Specific Aims are to: (1) Understand the immunological mechanism(s) underlying the anti-tumor effect of agonist CD40 mAb, (2) Understand how inflammation and CD40 activation influence the metastatic cascade, 3) Determine the clinical and immunological impact of CD40 mAb in a clinical trial of patients with resectable pancreatic carcinoma.

Public Health Relevance

Pancreatic ductal adenocarcinoma (PDA) carries the poorest prognosis of any major cancer, and thus innovative new approaches to therapy are desperately needed. In this proposal, we seek to reprogram specific cells in the immune system, converting them from bystanders to tumor-cell killers (e.g. by CD40 activation). These studies will incorporate mouse models and human patients and thus set the stage for developing therapies for this treatment-refractory disease.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Immunopathology and Immunotherapy Study Section (CII)
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Timmer, William C
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University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
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Aiello, Nicole M; Bajor, David L; Norgard, Robert J et al. (2016) Metastatic progression is associated with dynamic changes in the local microenvironment. Nat Commun 7:12819
Merrell, Allyson J; Stanger, Ben Z (2016) Adult cell plasticity in vivo: de-differentiation and transdifferentiation are back in style. Nat Rev Mol Cell Biol 17:413-25
Lee, Kyoung Eun; Spata, Michelle; Bayne, Lauren J et al. (2016) Hif1a Deletion Reveals Pro-Neoplastic Function of B Cells in Pancreatic Neoplasia. Cancer Discov 6:256-69
Aiello, Nicole M; Stanger, Ben Z (2016) Echoes of the embryo: using the developmental biology toolkit to study cancer. Dis Model Mech 9:105-14
Chao, Timothy; Furth, Emma E; Vonderheide, Robert H (2016) CXCR2-Dependent Accumulation of Tumor-Associated Neutrophils Regulates T-cell Immunity in Pancreatic Ductal Adenocarcinoma. Cancer Immunol Res 4:968-982
Byrne, Katelyn T; Leisenring, Nathan H; Bajor, David L et al. (2016) CSF-1R-Dependent Lethal Hepatotoxicity When Agonistic CD40 Antibody Is Given before but Not after Chemotherapy. J Immunol 197:179-87
Byrne, Katelyn T; Vonderheide, Robert H (2016) CD40 Stimulation Obviates Innate Sensors and Drives T Cell Immunity in Cancer. Cell Rep 15:2719-32
Evans, Rebecca A; Diamond, Mark S; Rech, Andrew J et al. (2016) Lack of immunoediting in murine pancreatic cancer reversed with neoantigen. JCI Insight 1:
Byrne, Katelyn T; Vonderheide, Robert H; Jaffee, Elizabeth M et al. (2015) Special Conference on Tumor Immunology and Immunotherapy: A New Chapter. Cancer Immunol Res :
Vonderheide, Robert H (2015) CD47 blockade as another immune checkpoint therapy for cancer. Nat Med 21:1122-3

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