title: Anti-PD-1 antibody therapy potently enhances the eradication of established tumors by gene-modified T cells.
abstract: OBJECTIVE
  To determine the antitumor efficacy and toxicity of a novel combination approach involving adoptive T-cell immunotherapy using chimeric antigen receptor (CAR) T cells with an immunomodulatory reagent for blocking immunosuppression.
  
  
  METHODS
  We examined whether administration of a PD-1 blocking antibody could increase the therapeutic activity of CAR T cells against two different Her-2(+) tumors. The use of a self-antigen mouse model enabled investigation into the efficacy, mechanism, and toxicity of this combination approach.
  
  
  RESULTS
  In this study, we first showed a significant increase in the level of PD-1 expressed on transduced anti-Her-2 CD8(+) T cells following antigen-specific stimulation with PD-L1(+) tumor cells and that markers of activation and proliferation were increased in anti-Her-2 T cells in the presence of anti-PD-1 antibody. In adoptive transfer studies in Her-2 transgenic recipient mice, we showed a significant improvement in growth inhibition of two different Her-2(+) tumors treated with anti-Her-2 T cells in combination with anti-PD-1 antibody. The therapeutic effects observed correlated with increased function of anti-Her-2 T cells following PD-1 blockade. Strikingly, a significant decrease in the percentage of Gr1(+) CD11b(+) myeloid-derived suppressor cells (MDSC) was observed in the tumor microenvironment of mice treated with the combination therapy. Importantly, increased antitumor effects were not associated with any autoimmune pathology in normal tissue expressing Her-2 antigen.
  
  
  CONCLUSIONS
  This study shows that specifically blocking PD-1 immunosuppression can potently enhance CAR T-cell therapy that has significant implications for potentially improving therapeutic outcomes of this approach in patients with cancer.
authors.affiliation: Authors' Affiliations: Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria; Department of Pathology, University of Melbourne; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville; Department of Immunology, Monash University, Clayton; Immunology in Cancer and Infection Laboratory, Queensland Institute of Medical Research; and School of Medicine, University of Queensland, Herston, Queensland, Australia.
authors.forename: Liza B
authors.initials: LB
authors.lastname: John
authors.forename: Christel
authors.initials: C
authors.lastname: Devaud
authors.forename: Connie P M
authors.initials: CP
authors.lastname: Duong
authors.forename: Carmen S
authors.initials: CS
authors.lastname: Yong
authors.forename: Paul A
authors.initials: PA
authors.lastname: Beavis
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Haynes
authors.forename: Melvyn T
authors.initials: MT
authors.lastname: Chow
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.forename: Michael H
authors.initials: MH
authors.lastname: Kershaw
authors.forename: Phillip K
authors.initials: PK
authors.lastname: Darcy
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D000941:Antigens / Q000276:immunology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D015551:Autoimmunity; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000276:immunology; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*; D047368:Tumor Burden / Q000187:drug effects / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D000941:Antigens; D000970:Antineoplastic Agents; D061026:Programmed Cell Death 1 Receptor; D018719:Erb-b2 Receptor Tyrosine Kinases