title: Donor CD19 CAR T cells exert potent graft-versus-lymphoma activity with diminished graft-versus-host activity.
abstract: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for hematological malignancies. However, graft-versus-host disease (GVHD) and relapse after allo-HSCT remain major impediments to the success of allo-HSCT. Chimeric antigen receptors (CARs) direct tumor cell recognition of adoptively transferred T cells. CD19 is an attractive CAR target, which is expressed in most B cell malignancies, as well as in healthy B cells. Clinical trials using autologous CD19-targeted T cells have shown remarkable promise in various B cell malignancies. However, the use of allogeneic CAR T cells poses a concern in that it may increase risk of the occurrence of GVHD, although this has not been reported in selected patients infused with donor-derived CD19 CAR T cells after allo-HSCT. To understand the mechanism whereby allogeneic CD19 CAR T cells may mediate anti-lymphoma activity without causing a significant increase in the incidence of GVHD, we studied donor-derived CD19 CAR T cells in allo-HSCT and lymphoma models in mice. We demonstrate that alloreactive T cells expressing CD28-costimulated CD19 CARs experience enhanced stimulation, resulting in the progressive loss of both their effector function and proliferative potential, clonal deletion, and significantly decreased occurrence of GVHD. Concurrently, the other CAR T cells that were present in bulk donor T cell populations retained their anti-lymphoma activity in accordance with the requirement that both the T cell receptor (TCR) and CAR be engaged to accelerate T cell exhaustion. In contrast, first-generation and 4-1BB-costimulated CAR T cells increased the occurrence of GVHD. These findings could explain the reduced risk of GVHD occurring with cumulative TCR and CAR signaling.
authors.affiliation: Department of Medicine and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Arnab
authors.initials: A
authors.lastname: Ghosh
authors.affiliation: Department of Medicine and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Melody
authors.initials: M
authors.lastname: Smith
authors.affiliation: Department of Medicine and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Center of Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Scott E
authors.initials: SE
authors.lastname: James
authors.affiliation: Center of Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Marco L
authors.initials: ML
authors.lastname: Davila
authors.affiliation: Department of Medicine and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Enrico
authors.initials: E
authors.lastname: Velardi
authors.affiliation: Department of Medicine and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Kimon V
authors.initials: KV
authors.lastname: Argyropoulos
authors.affiliation: Center of Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Gertrude
authors.initials: G
authors.lastname: Gunset
authors.affiliation: Center of Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Perna
authors.affiliation: Department of Medicine and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Fabiana M
authors.initials: FM
authors.lastname: Kreines
authors.affiliation: Department of Medicine and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Emily R
authors.initials: ER
authors.lastname: Levy
authors.affiliation: Department of Medicine and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Sophie
authors.initials: S
authors.lastname: Lieberman
authors.affiliation: Department of Medicine and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Hillary V
authors.initials: HV
authors.lastname: Jay
authors.affiliation: Department of Medicine and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Andrea Z
authors.initials: AZ
authors.lastname: Tuckett
authors.affiliation: Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Johannes L
authors.initials: JL
authors.lastname: Zakrzewski
authors.affiliation: Department of Medicine and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Tan
authors.affiliation: Department of Medicine and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Lauren F
authors.initials: LF
authors.lastname: Young
authors.affiliation: Department of Medicine and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Kate
authors.initials: K
authors.lastname: Takvorian
authors.affiliation: Department of Medicine and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Jarrod A
authors.identifier: http://orcid.org/0000-0001-6220-5632
authors.initials: JA
authors.lastname: Dudakov
authors.affiliation: Department of Medicine and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Robert R
authors.initials: RR
authors.lastname: Jenq
authors.affiliation: Department of Medicine and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Alan M
authors.initials: AM
authors.lastname: Hanash
authors.affiliation: Program in Dermatopathology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Ana Carolina F
authors.identifier: http://orcid.org/0000-0002-3887-9239
authors.initials: AC
authors.lastname: Motta
authors.affiliation: Program in Dermatopathology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: George F
authors.initials: GF
authors.lastname: Murphy
authors.affiliation: Department of Pathology and Laboratory Medicine, Rutgers-Robert Wood Johnson Medical School, New Jersey, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Medicine and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Schietinger
authors.affiliation: Department of Medicine and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Center of Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Michel
authors.initials: M
authors.lastname: Sadelain
authors.affiliation: Department of Medicine and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Center of Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Marcel R M
authors.initials: MR
authors.lastname: van den Brink
mesh_terms: D053330:4-1BB Ligand / Q000276:immunology; D019264:Adoptive Transfer; D000818:Animals; D018941:Antigens, CD19 / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology; D018106:CD28 Antigens; D002678:Chimera; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000276:immunology; D006087:Graft vs Host Reaction / Q000276:immunology*; D020350:Graft vs Tumor Effect / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation; D008223:Lymphoma / Q000276:immunology*; D051379:Mice; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014184:Transplantation, Homologous
chemical_list: D053330:4-1BB Ligand; D018941:Antigens, CD19; D018106:CD28 Antigens; D016207:Cytokines; D011948:Receptors, Antigen, T-Cell