title: Impact of a New Fusion Receptor on PD-1-Mediated Immunosuppression in Adoptive T Cell Therapy.
abstract: BACKGROUND
  Adoptive T cell transfer (ACT) is currently under investigation for the treatment of metastatic cancer. Recent evidence suggests that the coinhibitory PD-1-PD-L1 axis plays a major role in ACT failure. We hypothesized that a new fusion receptor reverting PD-1-mediated inhibition into CD28 costimulation may break peripheral tolerance.
  
  
  METHODS
  Different PD-1-CD28 fusion receptor constructs were created and retrovirally transduced into primary T cell receptor transgenic murine CD8(+) T cells specific for ovalbumin (OT-1). Cytokine release, proliferation, cytotoxicity, and tumor recognition were analyzed in vitro. Antitumor efficacy and mode of action were investigated in mice bearing subcutaneous tumors induced with the pancreatic carcinoma cell line Panc02 expressing the model antigen ovalbumin (Panc-OVA). For antitumoral efficacy, six to eight mice per group were used. All statistical tests are two-sided.
  
  
  RESULTS
  Transduction of the PD-1-CD28 receptor constructs mediated enhanced cytokine release, T cell proliferation, and T cell-induced lysis of target tumor cells. The PD-1-CD28 receptor function was dependent on two of the CD28-signaling motifs and IFN-γ release. Treatment of mice with established Panc-OVA tumors with fusion receptor-transduced OT-1 T cells mediated complete tumor regression. Mice rejecting the tumor were protected upon subsequent rechallenge with either ovalbumin-positive or -negative tumors, indicative of a memory response and epitope spreading in nine of 11 mice vs none of the six naïve mice (P < .001). Treatment efficacy was associated with accumulation of IFN-γ-producing T cells and an increased ratio of CD8(+) T cells to immunosuppressive myeloid-derived suppressor cells in the tumors.
  
  
  CONCLUSIONS
  Transduction of T cells with this new PD-1-CD28 receptor has the potential of breaking the PD-1-PD-L1-immunosuppressive axis in ACT.
authors.affiliation: Center of Integrated Protein Science Munich and Division of Clinical Pharmacology, Department of Internal Medicine IV, Ludwig-Maximilians-Universität München, Munich, Germany, Member of the German Center for Lung Research (SK, SG, MC, CL, SW, FK, MR, PD, YZ, JCS, MS, SE SR).
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kobold
authors.affiliation: Center of Integrated Protein Science Munich and Division of Clinical Pharmacology, Department of Internal Medicine IV, Ludwig-Maximilians-Universität München, Munich, Germany, Member of the German Center for Lung Research (SK, SG, MC, CL, SW, FK, MR, PD, YZ, JCS, MS, SE SR).
authors.forename: Simon
authors.initials: S
authors.lastname: Grassmann
authors.affiliation: Center of Integrated Protein Science Munich and Division of Clinical Pharmacology, Department of Internal Medicine IV, Ludwig-Maximilians-Universität München, Munich, Germany, Member of the German Center for Lung Research (SK, SG, MC, CL, SW, FK, MR, PD, YZ, JCS, MS, SE SR).
authors.forename: Michael
authors.initials: M
authors.lastname: Chaloupka
authors.affiliation: Center of Integrated Protein Science Munich and Division of Clinical Pharmacology, Department of Internal Medicine IV, Ludwig-Maximilians-Universität München, Munich, Germany, Member of the German Center for Lung Research (SK, SG, MC, CL, SW, FK, MR, PD, YZ, JCS, MS, SE SR).
authors.forename: Christopher
authors.initials: C
authors.lastname: Lampert
authors.affiliation: Center of Integrated Protein Science Munich and Division of Clinical Pharmacology, Department of Internal Medicine IV, Ludwig-Maximilians-Universität München, Munich, Germany, Member of the German Center for Lung Research (SK, SG, MC, CL, SW, FK, MR, PD, YZ, JCS, MS, SE SR).
authors.forename: Susanne
authors.initials: S
authors.lastname: Wenk
authors.affiliation: Center of Integrated Protein Science Munich and Division of Clinical Pharmacology, Department of Internal Medicine IV, Ludwig-Maximilians-Universität München, Munich, Germany, Member of the German Center for Lung Research (SK, SG, MC, CL, SW, FK, MR, PD, YZ, JCS, MS, SE SR).
authors.forename: Fabian
authors.initials: F
authors.lastname: Kraus
authors.affiliation: Center of Integrated Protein Science Munich and Division of Clinical Pharmacology, Department of Internal Medicine IV, Ludwig-Maximilians-Universität München, Munich, Germany, Member of the German Center for Lung Research (SK, SG, MC, CL, SW, FK, MR, PD, YZ, JCS, MS, SE SR).
authors.forename: Moritz
authors.initials: M
authors.lastname: Rapp
authors.affiliation: Center of Integrated Protein Science Munich and Division of Clinical Pharmacology, Department of Internal Medicine IV, Ludwig-Maximilians-Universität München, Munich, Germany, Member of the German Center for Lung Research (SK, SG, MC, CL, SW, FK, MR, PD, YZ, JCS, MS, SE SR).
authors.forename: Peter
authors.initials: P
authors.lastname: Düwell
authors.affiliation: Center of Integrated Protein Science Munich and Division of Clinical Pharmacology, Department of Internal Medicine IV, Ludwig-Maximilians-Universität München, Munich, Germany, Member of the German Center for Lung Research (SK, SG, MC, CL, SW, FK, MR, PD, YZ, JCS, MS, SE SR).
authors.forename: Yi
authors.initials: Y
authors.lastname: Zeng
authors.affiliation: Center of Integrated Protein Science Munich and Division of Clinical Pharmacology, Department of Internal Medicine IV, Ludwig-Maximilians-Universität München, Munich, Germany, Member of the German Center for Lung Research (SK, SG, MC, CL, SW, FK, MR, PD, YZ, JCS, MS, SE SR).
authors.forename: Jan C
authors.initials: JC
authors.lastname: Schmollinger
authors.affiliation: Center of Integrated Protein Science Munich and Division of Clinical Pharmacology, Department of Internal Medicine IV, Ludwig-Maximilians-Universität München, Munich, Germany, Member of the German Center for Lung Research (SK, SG, MC, CL, SW, FK, MR, PD, YZ, JCS, MS, SE SR).
authors.forename: Max
authors.initials: M
authors.lastname: Schnurr
authors.affiliation: Center of Integrated Protein Science Munich and Division of Clinical Pharmacology, Department of Internal Medicine IV, Ludwig-Maximilians-Universität München, Munich, Germany, Member of the German Center for Lung Research (SK, SG, MC, CL, SW, FK, MR, PD, YZ, JCS, MS, SE SR).
authors.forename: Stefan
authors.initials: S
authors.lastname: Endres
authors.affiliation: Center of Integrated Protein Science Munich and Division of Clinical Pharmacology, Department of Internal Medicine IV, Ludwig-Maximilians-Universität München, Munich, Germany, Member of the German Center for Lung Research (SK, SG, MC, CL, SW, FK, MR, PD, YZ, JCS, MS, SE SR).
authors.forename: Simon
authors.initials: S
authors.lastname: Rothenfußer
mesh_terms: D019264:Adoptive Transfer / Q000379:methods*; D000818:Animals; D060890:B7-H1 Antigen / Q000276:immunology*; D018106:CD28 Antigens / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D000939:Epitopes; D007165:Immunosuppression Therapy; D007371:Interferon-gamma / Q000378:metabolism*; D018655:Lymphocyte Count; D051379:Mice; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology*; D010190:Pancreatic Neoplasms / Q000276:immunology* / Q000628:therapy*; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D014161:Transduction, Genetic; D016896:Treatment Outcome
chemical_list: D060890:B7-H1 Antigen; D018106:CD28 Antigens; C498919:Cd274 protein, mouse; D000939:Epitopes; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D007371:Interferon-gamma; D010047:Ovalbumin