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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA169123-02
Application #
8522173
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Timmer, William C
Project Start
2012-08-03
Project End
2017-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
2
Fiscal Year
2013
Total Cost
$585,722
Indirect Cost
$214,372
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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Vonderheide, Robert H (2014) Tumor-promoting inflammatory networks in pancreatic neoplasia: another reason to loathe Kras. Cancer Cell 25:553-4
Rhim, Andrew D; Oberstein, Paul E; Thomas, Dafydd H et al. (2014) Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell 25:735-47
Zhang, Yaqing; Yan, Wei; Mathew, Esha et al. (2014) CD4+ T lymphocyte ablation prevents pancreatic carcinogenesis in mice. Cancer Immunol Res 2:423-35
Vonderheide, Robert H; Bajor, David L; Winograd, Rafael et al. (2013) CD40 immunotherapy for pancreatic cancer. Cancer Immunol Immunother 62:949-54
Bajor, David L; Vonderheide, Robert H (2013) Cracking the stone: combination vaccination and CTLA-4 blockade in pancreatic cancer. J Immunother 36:362-4
Byrne, Katelyn T; Vonderheide, Robert H (2013) CD40 therapy and surgery: a potential immunologic partnership. J Immunother 36:359-61
Vonderheide, Robert H; Bayne, Lauren J (2013) Inflammatory networks and immune surveillance of pancreatic carcinoma. Curr Opin Immunol 25:200-5