title: Engineered CAR T Cells Targeting the Cancer-Associated Tn-Glycoform of the Membrane Mucin MUC1 Control Adenocarcinoma.
abstract: Genetically modified T cells expressing chimeric antigen receptors (CARs) demonstrate robust responses against lineage restricted, non-essential targets in hematologic cancers. However, in solid tumors, the full potential of CAR T cell therapy is limited by the availability of cell surface antigens with sufficient cancer-specific expression. The majority of CAR targets have been normal self-antigens on dispensable hematopoietic tissues or overexpressed shared antigens. Here, we established that abnormal self-antigens can serve as targets for tumor rejection. We developed a CAR that recognized cancer-associated Tn glycoform of MUC1, a neoantigen expressed in a variety of cancers. Anti-Tn-MUC1 CAR T cells demonstrated target-specific cytotoxicity and successfully controlled tumor growth in xenograft models of T cell leukemia and pancreatic cancer. These findings demonstrate the therapeutic efficacy of CAR T cells directed against Tn-MUC1 and present aberrantly glycosylated antigens as a novel class of targets for tumor therapy with engineered T cells.
authors.affiliation: Center for Cellular Immunotherapies, Abramson Cancer Center and the Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: aposey@mail.med.upenn.edu.
authors.forename: Avery D
authors.initials: AD
authors.lastname: Posey
authors.affiliation: Center for Cellular Immunotherapies, Abramson Cancer Center and the Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Schwab
authors.affiliation: Center for Cellular Immunotherapies, Abramson Cancer Center and the Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Alina C
authors.initials: AC
authors.lastname: Boesteanu
authors.affiliation: Copenhagen Center for Glycomics, Departments of Cellular and Molecular Medicine and Odontology, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen N, Denmark.
authors.forename: Catharina
authors.initials: C
authors.lastname: Steentoft
authors.affiliation: Copenhagen Center for Glycomics, Departments of Cellular and Molecular Medicine and Odontology, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen N, Denmark.
authors.forename: Ulla
authors.initials: U
authors.lastname: Mandel
authors.affiliation: Department of Pathology, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Boris
authors.initials: B
authors.lastname: Engels
authors.affiliation: Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
authors.forename: Jennifer D
authors.initials: JD
authors.lastname: Stone
authors.affiliation: Copenhagen Center for Glycomics, Departments of Cellular and Molecular Medicine and Odontology, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen N, Denmark.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Madsen
authors.affiliation: Department of Pathology, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Karin
authors.initials: K
authors.lastname: Schreiber
authors.affiliation: Center for Cellular Immunotherapies, Abramson Cancer Center and the Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Haines
authors.affiliation: Center for Cellular Immunotherapies, Abramson Cancer Center and the Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Alexandria P
authors.initials: AP
authors.lastname: Cogdill
authors.affiliation: Center for Cellular Immunotherapies, Abramson Cancer Center and the Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Taylor J
authors.initials: TJ
authors.lastname: Chen
authors.affiliation: Center for Cellular Immunotherapies, Abramson Cancer Center and the Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Decheng
authors.initials: D
authors.lastname: Song
authors.affiliation: Center for Cellular Immunotherapies, Abramson Cancer Center and the Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: John
authors.initials: J
authors.lastname: Scholler
authors.affiliation: Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Kranz
authors.affiliation: Department of Pathology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Feldman
authors.affiliation: Center for Cellular Immunotherapies, Abramson Cancer Center and the Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Regina
authors.initials: R
authors.lastname: Young
authors.affiliation: Center for Cellular Immunotherapies, Abramson Cancer Center and the Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Keith
authors.affiliation: Department of Pathology, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Hans
authors.initials: H
authors.lastname: Schreiber
authors.affiliation: Copenhagen Center for Glycomics, Departments of Cellular and Molecular Medicine and Odontology, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen N, Denmark.
authors.forename: Henrik
authors.initials: H
authors.lastname: Clausen
authors.affiliation: Center for Cellular Immunotherapies, Abramson Cancer Center and the Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Pathology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Johnson
authors.affiliation: Center for Cellular Immunotherapies, Abramson Cancer Center and the Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Pathology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. Electronic address: cjune@exchange.upenn.edu.
authors.forename: Carl H
authors.initials: CH
authors.lastname: June
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology / Q000628:therapy*; D000818:Animals; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005818:Genetic Engineering; D006031:Glycosylation; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D019169:Jurkat Cells; D051379:Mice; D008815:Mice, Inbred Strains; D018396:Mucin-1 / Q000737:chemistry / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D018984:Epitopes, T-Lymphocyte; D018396:Mucin-1; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins