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.

Public Health Relevance

Pancreatic adenocarcinoma is an almost uniformly lethal disease that is profoundly resistant to current therapies. The candidate's research uses a genetically defined mouse model of pancreatic cancer to study mechanisms that regulate the capacity of the CD40 pathway to induce productive anti-tumor immunity. Findings will have direct implication for novel immunotherapies targeting CD40 in pancreas cancer. The written critiques and criteria scores of individual reviewers are provided in essentially unedited form in the """"""""Critique"""""""" section below. Please note that these critiques and criteria scores were prepared prior to the meeting and may not have been revised subsequent to any discussions at the review meeting. The """"""""Resume and Summary of Discussion"""""""" section above summarizes the final opinions of the committee.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08CA138907-01A2
Application #
8190222
Study Section
Subcommittee G - Education (NCI)
Program Officer
Myrick, Dorkina C
Project Start
2011-08-01
Project End
2016-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
1
Fiscal Year
2011
Total Cost
$162,462
Indirect Cost
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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Zhang, Yaqing; Velez-Delgado, Ashley; Mathew, Esha et al. (2017) Myeloid cells are required for PD-1/PD-L1 checkpoint activation and the establishment of an immunosuppressive environment in pancreatic cancer. Gut 66:124-136
Kalbasi, Anusha; Komar, Chad; Tooker, Graham M et al. (2017) Tumor-Derived CCL2 Mediates Resistance to Radiotherapy in Pancreatic Ductal Adenocarcinoma. Clin Cancer Res 23:137-148
Bengsch, Fee; Knoblock, Dawson M; Liu, Anni et al. (2017) CTLA-4/CD80 pathway regulates T cell infiltration into pancreatic cancer. Cancer Immunol Immunother 66:1609-1617
Beatty, Gregory L; Li, Yan; Long, Kristen B (2017) Cancer immunotherapy: activating innate and adaptive immunity through CD40 agonists. Expert Rev Anticancer Ther 17:175-186
Beatty, Gregory L; O'Dwyer, Peter J; Clark, Jason et al. (2017) First-in-Human Phase I Study of the Oral Inhibitor of Indoleamine 2,3-Dioxygenase-1 Epacadostat (INCB024360) in Patients with Advanced Solid Malignancies. Clin Cancer Res 23:3269-3276
Beatty, Gregory L; O'Hara, Mark (2016) Chimeric antigen receptor-modified T cells for the treatment of solid tumors: Defining the challenges and next steps. Pharmacol Ther 166:30-9
Long, Kristen B; Gladney, Whitney L; Tooker, Graham M et al. (2016) IFN? and CCL2 Cooperate to Redirect Tumor-Infiltrating Monocytes to Degrade Fibrosis and Enhance Chemotherapy Efficacy in Pancreatic Carcinoma. Cancer Discov 6:400-413
Lee, Jae W; Komar, Chad A; Bengsch, Fee et al. (2016) Genetically Engineered Mouse Models of Pancreatic Cancer: The KPC Model (LSL-Kras(G12D/+) ;LSL-Trp53(R172H/+) ;Pdx-1-Cre), Its Variants, and Their Application in Immuno-oncology Drug Discovery. Curr Protoc Pharmacol 73:14.39.1-14.39.20
Beatty, Gregory L; Gladney, Whitney L (2015) Immune escape mechanisms as a guide for cancer immunotherapy. Clin Cancer Res 21:687-92

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