title: PD-1/PD-L1 blockade together with vaccine therapy facilitates effector T-cell infiltration into pancreatic tumors.
abstract: Pancreatic ductal adenocarcinoma (PDA) has a poor prognosis due to late detection and resistance to conventional therapies. Published studies show that the PDA tumor microenvironment is predominantly infiltrated with immune suppressive cells and signals that if altered, would allow effective immunotherapy. However, single-agent checkpoint inhibitors including agents that alter immune suppressive signals in other human cancers such as cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed death 1 (PD-1), and its ligand PD-L1, have failed to demonstrate objective responses when given as single agents to PDA patients. We recently reported that inhibition of the CTLA-4 pathway when given together with a T cell inducing vaccine gives objective responses in metastatic PDA patients. In this study, we evaluated blockade of the PD-1/PD-L1 pathway. We found that PD-L1 is weakly expressed at a low frequency in untreated human and murine PDAs but treatment with a granulocyte macrophage colony-stimulating factor secreting PDA vaccine (GVAX) significantly upregulates PD-L1 membranous expression after treatment of tumor-bearing mice. In addition, combination therapy with vaccine and PD-1 antibody blockade improved murine survival compared with PD-1 antibody monotherapy or GVAX therapy alone. Furthermore, PD-1 blockade increased effector CD8 T lymphocytes and tumor-specific interferon-γ production of CD8 T cells in the tumor microenvironment. Immunosuppressive pathways, including regulatory T cells and CTLA-4 expression on T cells were overcome by the addition of vaccine and low-dose cyclophosphamide to PD-1 blockade. Collectively, our study supports combining PD-1 or PD-L1 antibody therapy with a T cell inducing agent for PDA treatment.
authors.affiliation: Departments of *Oncology #Pathology †Surgery ‡The Sidney Kimmel Cancer Center §The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care ∥The Sol Goldman Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD ¶Amplimmune Inc., Gaithersburg, MD **Department of Surgery, University of Colorado School of Medicine, Aurora, CO.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Soares
authors.forename: Agnieszka A
authors.initials: AA
authors.lastname: Rucki
authors.forename: Annie A
authors.initials: AA
authors.lastname: Wu
authors.forename: Kelly
authors.initials: K
authors.lastname: Olino
authors.forename: Qian
authors.initials: Q
authors.lastname: Xiao
authors.forename: Yi
authors.initials: Y
authors.lastname: Chai
authors.forename: Anthony
authors.initials: A
authors.lastname: Wamwea
authors.forename: Elaine
authors.initials: E
authors.lastname: Bigelow
authors.forename: Eric
authors.initials: E
authors.lastname: Lutz
authors.forename: Linda
authors.initials: L
authors.lastname: Liu
authors.forename: Sheng
authors.initials: S
authors.lastname: Yao
authors.forename: Robert A
authors.initials: RA
authors.lastname: Anders
authors.forename: Daniel
authors.initials: D
authors.lastname: Laheru
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Wolfgang
authors.forename: Barish H
authors.initials: BH
authors.lastname: Edil
authors.forename: Richard D
authors.initials: RD
authors.lastname: Schulick
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Jaffee
authors.forename: Lei
authors.initials: L
authors.lastname: Zheng
mesh_terms: D000818:Animals; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors*; D019496:Cancer Vaccines / Q000276:immunology*; D021441:Carcinoma, Pancreatic Ductal / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D010190:Pancreatic Neoplasms / Q000276:immunology*; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors*
chemical_list: D060890:B7-H1 Antigen; D019496:Cancer Vaccines; C000593794:GVAX vaccine; D061026:Programmed Cell Death 1 Receptor