This proposal investigates the CD40 pathway as a key regulator of immune surveillance in a genetically engineered mouse (GEM) model of pancreatic ductal adenocarcinoma (PDA). The candidate is a physician-scientist with training in immunology, hematology, and oncology who is proposing a 5 year mentored research plan with Drs. Carl June and Robert Vonderheide. Formal course work in biostatistics and clinical trial design and interpretation will advance the candidate's skills in interpreting the translational potential of findings obtained in preclinical models. The goal of this career plan is to establish an independent laboratory in an academic department of a university medical center. Research will focus on investigating mechanisms that regulate the capacity of CD40 activation to coordinate productive innate and adaptive anti-tumor immunity. This proposal will use a GEM model of PDA that recapitulates the salient features of human disease. Preliminary data demonstrate that systemic activation of the CD40 pathway can induce tumor regression in pancreatic cancer in mice and humans through a mechanism that is dependent on macrophages but not T cells or chemotherapy. CD40 activated macrophages actively infiltrate the tumor microenvironment, become tumoricidal, and deplete tumor stroma. The recruitment of T cells to the tumor microenvironment is shown to be restrained by IL-10 and the B7-CTLA-4 inhibitory signaling pathway. It is the central hypothesis of this proposal that CD40 plays a critical role in regulating immune surveillance in pancreatic ductal adenocarcinoma through activation of innate immunity but its ability to coordinate productive adaptive anti-tumor immunity is restrained by immunoregulatory pathways controlled by cancer inflammation. To test this hypothesis, three specific aims are proposed.
AIM ONE will evaluate the role of leukocytes within the tumor microenvironment in regulating the capacity of CD40- activated macrophages to modulate the tumor microenvironment and induce tumor regression.
AIM TWO will examine the role of cytokines in regulating CD40-induced anti-tumor activity.
AIM THREE will investigate how cross-talk between antigen presenting cells and T cells regulates the ability of CD40 activation to recruit T cell specific immunity.

Public Health Relevance

Pancreatic cancer is a devastating disease with few therapeutic options. This proposal will use a mouse model that is indistinguishable from human PDA. Studies in this model will improve the understanding of pathways regulating immune activation within the tumor microenvironment of PDA and may identify novel therapeutic strategies for the treatment of PDA.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA138907-04
Application #
8699019
Study Section
Subcommittee G - Education (NCI)
Program Officer
Perkins, Susan N
Project Start
2011-08-01
Project End
2016-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
4
Fiscal Year
2014
Total Cost
$162,462
Indirect Cost
$12,034
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Beatty, Gregory L; Haas, Andrew R; Maus, Marcela V et al. (2014) Mesothelin-specific chimeric antigen receptor mRNA-engineered T cells induce anti-tumor activity in solid malignancies. Cancer Immunol Res 2:112-20
Beatty, Gregory L; Torigian, Drew A; Chiorean, E Gabriela et al. (2013) A phase I study of an agonist CD40 monoclonal antibody (CP-870,893) in combination with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma. Clin Cancer Res 19:6286-95
Vonderheide, Robert H; Bajor, David L; Winograd, Rafael et al. (2013) CD40 immunotherapy for pancreatic cancer. Cancer Immunol Immunother 62:949-54
Rhim, Andrew D; Mirek, Emily T; Aiello, Nicole M et al. (2012) EMT and dissemination precede pancreatic tumor formation. Cell 148:349-61