title: TGF-β blockade depletes T regulatory cells from metastatic pancreatic tumors in a vaccine dependent manner.
abstract: Our neoadjuvant clinical trial of a GM-CSF secreting allogeneic pancreas tumor vaccine (GVAX) revealed the development of tertiary lymphoid aggregates (TLAs) within the pancreatic ductal adenocarcinoma (PDA) tumor microenvironment 2 weeks after GVAX treatment. Microarray studies revealed that multiple components of the TGF-β pathway were suppressed in TLAs from patients who survived greater than 3 years and who demonstrated vaccine-enhanced mesothelin-specific T cell responses. We tested the hypothesis that combining GVAX with TGF-β inhibitors will improve the anti-tumor immune response of vaccine therapy. In a metastatic murine model of pancreatic cancer, combination therapy with GVAX vaccine and a TGF-β blocking antibody improved the cure rate of PDA-bearing mice. TGF-β blockade in combination with GVAX significantly increased the infiltration of effector CD8+ T lymphocytes, specifically anti-tumor-specific IFN-g producing CD8+ T cells, when compared to monotherapy controls (all p < 0.05). TGF-β blockade alone did not deplete T regulatory cells (Tregs), but when give in combination with GVAX, GVAX induced intratumoral Tregs were depleted. Therefore, our PDA preclinical model demonstrates a survival advantage in mice treated with an anti-TGF-β antibody combined with GVAX therapy and provides strong rational for testing this combinational therapy in clinical trials.
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|The Sol Goldman Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Soares
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|The Sol Goldman Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Agnieszka A
authors.initials: AA
authors.lastname: Rucki
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|The Sol Goldman Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Victoria
authors.initials: V
authors.lastname: Kim
authors.affiliation: The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|The Sol Goldman Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Foley
authors.affiliation: The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|The Sol Goldman Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Solt
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|The Sol Goldman Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Wolfgang
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|The Sol Goldman Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Jaffee
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|The Sol Goldman Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Zheng
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D057134:Antibodies, Neutralizing / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D019496:Cancer Vaccines / Q000008:administration & dosage*; D021441:Carcinoma, Pancreatic Ductal / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects; D000090204:Mesothelin; D051379:Mice; D010190:Pancreatic Neoplasms / Q000276:immunology* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D019496:Cancer Vaccines; C000593794:GVAX vaccine; C000715528:Msln protein, mouse; D016212:Transforming Growth Factor beta; D000090204:Mesothelin
keywords: TGF-beta; immunotherapy; pancreatic cancer; regulatory T cells; vaccine