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.
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.
|Beatty, Gregory L; O'Hara, Mark H; Lacey, Simon F et al. (2018) Activity of Mesothelin-Specific Chimeric Antigen Receptor T Cells Against Pancreatic Carcinoma Metastases in a Phase 1 Trial. Gastroenterology 155:29-32
|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
|Long, Kristen B; Tooker, Graham; Tooker, Evan et al. (2017) IL6 Receptor Blockade Enhances Chemotherapy Efficacy in Pancreatic Ductal Adenocarcinoma. Mol Cancer Ther 16:1898-1908
|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
|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
|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
Showing the most recent 10 out of 22 publications