title: NY-ESO-1-specific TCR-engineered T cells mediate sustained antigen-specific antitumor effects in myeloma.
abstract: Despite recent therapeutic advances, multiple myeloma (MM) remains largely incurable. Here we report results of a phase I/II trial to evaluate the safety and activity of autologous T cells engineered to express an affinity-enhanced T cell receptor (TCR) recognizing a naturally processed peptide shared by the cancer-testis antigens NY-ESO-1 and LAGE-1. Twenty patients with antigen-positive MM received an average 2.4 × 10(9) engineered T cells 2 d after autologous stem cell transplant. Infusions were well tolerated without clinically apparent cytokine-release syndrome, despite high IL-6 levels. Engineered T cells expanded, persisted, trafficked to marrow and exhibited a cytotoxic phenotype. Persistence of engineered T cells in blood was inversely associated with NY-ESO-1 levels in the marrow. Disease progression was associated with loss of T cell persistence or antigen escape, in accordance with the expected mechanism of action of the transferred T cells. Encouraging clinical responses were observed in 16 of 20 patients (80%) with advanced disease, with a median progression-free survival of 19.1 months. NY-ESO-1-LAGE-1 TCR-engineered T cells were safe, trafficked to marrow and showed extended persistence that correlated with clinical activity against antigen-positive myeloma.
authors.affiliation: The Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Aaron P
authors.initials: AP
authors.lastname: Rapoport
authors.affiliation: Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Stadtmauer
authors.affiliation: Adaptimmune Ltd, Oxford, UK.
authors.forename: Gwendolyn K
authors.initials: GK
authors.lastname: Binder-Scholl
authors.affiliation: The Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.|Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Goloubeva
authors.affiliation: Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Dan T
authors.initials: DT
authors.lastname: Vogl
authors.affiliation: Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Department of Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Simon F
authors.initials: SF
authors.lastname: Lacey
authors.affiliation: The Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Ashraf Z
authors.initials: AZ
authors.lastname: Badros
authors.affiliation: Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Alfred
authors.initials: A
authors.lastname: Garfall
authors.affiliation: Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Brendan
authors.initials: B
authors.lastname: Weiss
authors.affiliation: Department of Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Finklestein
authors.affiliation: Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Department of Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Kulikovskaya
authors.affiliation: School of Mathematics and Statistics, Carleton University, Ottawa, Canada.
authors.forename: Sanjoy K
authors.initials: SK
authors.lastname: Sinha
authors.affiliation: The Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.|Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD USA.
authors.forename: Shari
authors.initials: S
authors.lastname: Kronsberg
authors.affiliation: Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Department of Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Minnal
authors.initials: M
authors.lastname: Gupta
authors.affiliation: Cambridge Biomedical, Cambridge, Massachusetts, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Bond
authors.affiliation: Adaptimmune Ltd, Oxford, UK.
authors.forename: Luca
authors.initials: L
authors.lastname: Melchiori
authors.affiliation: Adaptimmune Ltd, Oxford, UK.
authors.forename: Joanna E
authors.initials: JE
authors.lastname: Brewer
authors.affiliation: Adaptimmune Ltd, Oxford, UK.
authors.forename: Alan D
authors.initials: AD
authors.lastname: Bennett
authors.affiliation: Adaptimmune Ltd, Oxford, UK.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Gerry
authors.affiliation: Adaptimmune Ltd, Oxford, UK.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Pumphrey
authors.affiliation: Adaptimmune Ltd, Oxford, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Williams
authors.affiliation: Adaptimmune Ltd, Oxford, UK.
authors.forename: Helen K
authors.initials: HK
authors.lastname: Tayton-Martin
authors.affiliation: Adaptimmune Ltd, Oxford, UK.
authors.forename: Lilliam
authors.initials: L
authors.lastname: Ribeiro
authors.affiliation: Adaptimmune Ltd, Oxford, UK.
authors.forename: Tom
authors.initials: T
authors.lastname: Holdich
authors.affiliation: The Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Saul
authors.initials: S
authors.lastname: Yanovich
authors.affiliation: The Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Hardy
authors.affiliation: The Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Jean
authors.initials: J
authors.lastname: Yared
authors.affiliation: Department of Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Naseem
authors.initials: N
authors.lastname: Kerr
authors.affiliation: The Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Sunita
authors.initials: S
authors.lastname: Philip
authors.affiliation: The Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Westphal
authors.affiliation: Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Department of Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Don L
authors.initials: DL
authors.lastname: Siegel
authors.affiliation: Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Department of Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Levine
authors.affiliation: Adaptimmune Ltd, Oxford, UK.
authors.forename: Bent K
authors.initials: BK
authors.lastname: Jakobsen
authors.affiliation: Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Department of Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Kalos
authors.affiliation: Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Department of Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Carl H
authors.initials: CH
authors.lastname: June
mesh_terms: D000368:Aged; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D000954:Antigens, Surface / Q000235:genetics / Q000276:immunology; D005260:Female; D005818:Genetic Engineering; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D008875:Middle Aged; D009101:Multiple Myeloma / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D053668:Syndecan-1 / Q000032:analysis; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; D000954:Antigens, Surface; C104948:CTAG1B protein, human; C510162:CTAG2 protein, human; D008565:Membrane Proteins; D011948:Receptors, Antigen, T-Cell; C508241:SDC1 protein, human; D053668:Syndecan-1