title: Coexpressed Catalase Protects Chimeric Antigen Receptor-Redirected T Cells as well as Bystander Cells from Oxidative Stress-Induced Loss of Antitumor Activity.
abstract: Treatment of cancer patients by adoptive T cell therapy has yielded promising results. In solid tumors, however, T cells encounter a hostile environment, in particular with increased inflammatory activity as a hallmark of the tumor milieu that goes along with abundant reactive oxygen species (ROS) that substantially impair antitumor activity. We present a strategy to render antitumor T cells more resilient toward ROS by coexpressing catalase along with a tumor specific chimeric Ag receptor (CAR) to increase their antioxidative capacity by metabolizing H2O2. In fact, T cells engineered with a bicistronic vector that concurrently expresses catalase, along with the CAR coexpressing catalase (CAR-CAT), performed superior over CAR T cells as they showed increased levels of intracellular catalase and had a reduced oxidative state with less ROS accumulation in both the basal state and upon activation while maintaining their antitumor activity despite high H2O2 levels. Moreover, CAR-CAT T cells exerted a substantial bystander protection of nontransfected immune effector cells as measured by CD3ζ chain expression in bystander T cells even in the presence of high H2O2 concentrations. Bystander NK cells, otherwise ROS sensitive, efficiently eliminate their K562 target cells under H2O2-induced oxidative stress when admixed with CAR-CAT T cells. This approach represents a novel means for protecting tumor-infiltrating cells from tumor-associated oxidative stress-mediated repression.
authors.affiliation: Immune and Gene Therapy Laboratory, Cancer Center Karolinska, Department of Oncology and Pathology, Karolinska Institutet, 17176 Stockholm, Sweden;
authors.forename: Maarten A
authors.initials: MA
authors.lastname: Ligtenberg
authors.affiliation: Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, 91054 Erlangen Germany;
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Mougiakakos
authors.affiliation: Immune and Gene Therapy Laboratory, Cancer Center Karolinska, Department of Oncology and Pathology, Karolinska Institutet, 17176 Stockholm, Sweden;
authors.forename: Madhura
authors.initials: M
authors.lastname: Mukhopadhyay
authors.affiliation: Immune and Gene Therapy Laboratory, Cancer Center Karolinska, Department of Oncology and Pathology, Karolinska Institutet, 17176 Stockholm, Sweden;
authors.forename: Kristina
authors.initials: K
authors.lastname: Witt
authors.affiliation: Laboratorio de Inmunoterapia Génica, Fundación Ciencia y Vida, 7780272 Santiago, Chile;
authors.forename: Alvaro
authors.initials: A
authors.lastname: Lladser
authors.affiliation: Labor Tumorgenetik, Klinik I für Innere Medizin, Universität zu Köln, 50931 Cologne, Germany; and Zentrum für Molekulare Medizin Köln, Universität zu Köln, 50931 Cologne, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Chmielewski
authors.affiliation: Labor Tumorgenetik, Klinik I für Innere Medizin, Universität zu Köln, 50931 Cologne, Germany; and Zentrum für Molekulare Medizin Köln, Universität zu Köln, 50931 Cologne, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Riet
authors.affiliation: Labor Tumorgenetik, Klinik I für Innere Medizin, Universität zu Köln, 50931 Cologne, Germany; and Zentrum für Molekulare Medizin Köln, Universität zu Köln, 50931 Cologne, Germany.
authors.forename: Hinrich
authors.initials: H
authors.lastname: Abken
authors.affiliation: Immune and Gene Therapy Laboratory, Cancer Center Karolinska, Department of Oncology and Pathology, Karolinska Institutet, 17176 Stockholm, Sweden; rolf.kiessling@ki.se.
authors.forename: Rolf
authors.initials: R
authors.lastname: Kiessling
mesh_terms: D015153:Blotting, Western; D024201:Bystander Effect / Q000276:immunology; D002374:Catalase / Q000276:immunology*; D002460:Cell Line; D002469:Cell Separation; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007694:Killer Cells, Natural / Q000276:immunology*; D018384:Oxidative Stress / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014162:Transfection
chemical_list: D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; C577219:CAT protein, human; D002374:Catalase