title: Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells.
abstract: Autologous T cells engineered to express chimeric antigen receptor against the B cell antigen CD19 (CAR19) are achieving marked leukemic remissions in early-phase trials but can be difficult to manufacture, especially in infants or heavily treated patients. We generated universal CAR19 (UCART19) T cells by lentiviral transduction of non-human leukocyte antigen-matched donor cells and simultaneous transcription activator-like effector nuclease (TALEN)-mediated gene editing of T cell receptor α chain and CD52 gene loci. Two infants with relapsed refractory CD19+B cell acute lymphoblastic leukemia received lymphodepleting chemotherapy and anti-CD52 serotherapy, followed by a single-dose infusion of UCART19 cells. Molecular remissions were achieved within 28 days in both infants, and UCART19 cells persisted until conditioning ahead of successful allogeneic stem cell transplantation. This bridge-to-transplantation strategy demonstrates the therapeutic potential of gene-editing technology.
authors.affiliation: Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK. w.qasim@ucl.ac.uk.|Great Ormond Street Hospital National Health Service Trust, London WC1N 1LE, UK.
authors.forename: Waseem
authors.initials: W
authors.lastname: Qasim
authors.affiliation: Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhan
authors.affiliation: Great Ormond Street Hospital National Health Service Trust, London WC1N 1LE, UK.
authors.forename: Sujith
authors.initials: S
authors.lastname: Samarasinghe
authors.affiliation: Great Ormond Street Hospital National Health Service Trust, London WC1N 1LE, UK.
authors.forename: Stuart
authors.initials: S
authors.lastname: Adams
authors.affiliation: Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.|Great Ormond Street Hospital National Health Service Trust, London WC1N 1LE, UK.
authors.forename: Persis
authors.initials: P
authors.lastname: Amrolia
authors.affiliation: Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.
authors.forename: Sian
authors.initials: S
authors.lastname: Stafford
authors.affiliation: Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.
authors.forename: Katie
authors.initials: K
authors.lastname: Butler
authors.affiliation: Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.
authors.forename: Christine
authors.initials: C
authors.lastname: Rivat
authors.affiliation: Great Ormond Street Hospital National Health Service Trust, London WC1N 1LE, UK.
authors.forename: Gary
authors.initials: G
authors.lastname: Wright
authors.affiliation: Great Ormond Street Hospital National Health Service Trust, London WC1N 1LE, UK.
authors.forename: Kathy
authors.initials: K
authors.lastname: Somana
authors.affiliation: Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.
authors.forename: Sara
authors.initials: S
authors.lastname: Ghorashian
authors.affiliation: Great Ormond Street Hospital National Health Service Trust, London WC1N 1LE, UK.
authors.forename: Danielle
authors.initials: D
authors.lastname: Pinner
authors.affiliation: Great Ormond Street Hospital National Health Service Trust, London WC1N 1LE, UK.
authors.forename: Gul
authors.initials: G
authors.lastname: Ahsan
authors.affiliation: Great Ormond Street Hospital National Health Service Trust, London WC1N 1LE, UK.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Gilmour
authors.affiliation: Great Ormond Street Hospital National Health Service Trust, London WC1N 1LE, UK.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Lucchini
authors.affiliation: Great Ormond Street Hospital National Health Service Trust, London WC1N 1LE, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Inglott
authors.affiliation: Great Ormond Street Hospital National Health Service Trust, London WC1N 1LE, UK.
authors.forename: William
authors.initials: W
authors.lastname: Mifsud
authors.affiliation: Great Ormond Street Hospital National Health Service Trust, London WC1N 1LE, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Chiesa
authors.affiliation: Cancer Institute, University College London, London WC1E 6DD, UK.
authors.forename: Karl S
authors.initials: KS
authors.lastname: Peggs
authors.affiliation: Division of Cancer Studies, Department of Haematological Medicine, King's College London, London SE5 9NU, UK.
authors.forename: Lucas
authors.initials: L
authors.lastname: Chan
authors.affiliation: Division of Cancer Studies, Department of Haematological Medicine, King's College London, London SE5 9NU, UK.
authors.forename: Farzin
authors.initials: F
authors.lastname: Farzeneh
authors.affiliation: Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Thrasher
authors.affiliation: Sheffield Children's Hospital, Sheffield S10 2TH, UK.
authors.forename: Ajay
authors.initials: A
authors.lastname: Vora
authors.affiliation: Cancer Institute, University College London, London WC1E 6DD, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Pule
authors.affiliation: Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Veys
mesh_terms: D000074323:Alemtuzumab / Q000627:therapeutic use; D018941:Antigens, CD19 / Q000378:metabolism; D000074301:CD52 Antigen / Q000378:metabolism; D057176:Compassionate Use Trials; D005260:Female; D000072669:Gene Editing; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D016086:Lentivirus / Q000235:genetics; D009364:Neoplasm Recurrence, Local; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D012074:Remission Induction; D033581:Stem Cell Transplantation; D013601:T-Lymphocytes / Q000166:cytology*; D000069896:Transcription Activator-Like Effector Nucleases / Q000235:genetics*; D000071336:Transcription Activator-Like Effectors; D014184:Transplantation, Homologous
chemical_list: D018941:Antigens, CD19; D000074301:CD52 Antigen; C000613862:CD52 protein, human; D011948:Receptors, Antigen, T-Cell; D000071336:Transcription Activator-Like Effectors; D000074323:Alemtuzumab; D000069896:Transcription Activator-Like Effector Nucleases