title: Vaccination to improve the persistence of CD19CAR gene-modified T cells in relapsed pediatric acute lymphoblastic leukemia.
abstract: Trials with second generation CD19 chimeric antigen receptors (CAR) T-cells report unprecedented responses but are associated with risk of cytokine release syndrome (CRS). Instead, we studied the use of donor Epstein-Barr virus-specific T-cells (EBV CTL) transduced with a first generation CD19CAR, relying on the endogenous T-cell receptor for proliferation. We conducted a multi-center phase I/II study of donor CD19CAR transduced EBV CTL in pediatric acute lymphoblastic leukaemia (ALL). Patients were eligible pre-emptively if they developed molecular relapse (>5 × 10-4) post first stem cell transplant (SCT), or prophylactically post second SCT. An initial cohort showed poor expansion/persistence. We therefore investigated EBV-directed vaccination to enhance expansion/persistence. Eleven patients were treated. No CRS, neurotoxicity or graft versus host disease (GVHD) was observed. At 1 month, 5 patients were in CR (4 continuing, 1 de novo), 1 PR, 3 had stable disease and 3 no response. At a median follow-up of 12 months, 10 of 11 have relapsed, 2 are alive with disease and 1 alive in CR 3 years. Although CD19CAR CTL expansion was poor, persistence was enhanced by vaccination. Median persistence was 0 (range: 0-28) days without vaccination compared to 56 (range: 0-221) days with vaccination (P=0.06). This study demonstrates the feasibility of multi-center studies of CAR T cell therapy and the potential for enhancing persistence with vaccination.
authors.affiliation: Department of Pediatric Hematology and Oncology, University Children's Hospital, Münster, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Rossig
authors.affiliation: Department of Haematology, Cancer Institute, University College London, London, UK.
authors.forename: M
authors.identifier: 0000-0002-8347-9867
authors.initials: M
authors.lastname: Pule
authors.affiliation: Department of Pediatric Hematology and Oncology, University Children's Hospital, Münster, Germany.
authors.forename: B
authors.identifier: 0000-0003-4936-4879
authors.initials: B
authors.lastname: Altvater
authors.affiliation: Unite de Therapie Cellulaire et Genetique, CHU Nantes, Nantes, France.
authors.forename: S
authors.initials: S
authors.lastname: Saiagh
authors.affiliation: Department of Paediatric Haematology and Bone Marrow Transplant, Molecular and Cellular Immunology, UCL Great Ormond Street Institute of Child Health, London, UK.
authors.forename: G
authors.initials: G
authors.lastname: Wright
authors.affiliation: Molecular and Cellular Immunology Section, Institute of Child Health, University College London, London, UK.
authors.forename: S
authors.initials: S
authors.lastname: Ghorashian
authors.affiliation: Cancer Research UK and UCL Cancer Trials Centre, London, UK.
authors.forename: L
authors.initials: L
authors.lastname: Clifton-Hadley
authors.affiliation: Cancer Research UK and UCL Cancer Trials Centre, London, UK.
authors.forename: K
authors.initials: K
authors.lastname: Champion
authors.affiliation: Cancer Research UK and UCL Cancer Trials Centre, London, UK.
authors.forename: Z
authors.initials: Z
authors.lastname: Sattar
authors.affiliation: Cancer Research UK and UCL Cancer Trials Centre, London, UK.
authors.forename: B
authors.initials: B
authors.lastname: Popova
authors.affiliation: Cancer Research UK and UCL Cancer Trials Centre, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Hackshaw
authors.affiliation: Cancer Research UK and UCL Cancer Trials Centre, London, UK.
authors.forename: P
authors.initials: P
authors.lastname: Smith
authors.affiliation: Cancer Research UK and UCL Cancer Trials Centre, London, UK.
authors.forename: T
authors.initials: T
authors.lastname: Roberts
authors.affiliation: Clinica Pediatrica, Università Milano Bicocca, Osp. San Gerardo/Fondazione MBBM, Monza, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Biagi
authors.affiliation: Unite de Therapie Cellulaire et Genetique, CHU Nantes, Nantes, France.
authors.forename: B
authors.initials: B
authors.lastname: Dreno
authors.affiliation: Department of Pediatric Haemato-Oncology, Centre Leon Berard, Lyon, France.
authors.forename: R
authors.initials: R
authors.lastname: Rousseau
authors.affiliation: Department of Pediatric Hematology and Oncology, University Children's Hospital, Münster, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Kailayangiri
authors.affiliation: Department of Pediatric Hematology and Oncology, University Children's Hospital, Münster, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Ahlmann
authors.affiliation: Department of Haematology, Cancer Institute, University College London, London, UK.
authors.forename: R
authors.initials: R
authors.lastname: Hough
authors.affiliation: Department of Pediatric Hematology and Oncology, University Children's Hospital Essen, Essen, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Kremens
authors.affiliation: Department of Pediatric Hematology/Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: M G
authors.initials: MG
authors.lastname: Sauer
authors.affiliation: Department of Paediatric Haematology and Bone Marrow Transplant, Molecular and Cellular Immunology, UCL Great Ormond Street Institute of Child Health, London, UK.
authors.forename: P
authors.initials: P
authors.lastname: Veys
authors.affiliation: Department of Paediatric Haematology and Bone Marrow Transplant, Molecular and Cellular Immunology, UCL Great Ormond Street Institute of Child Health, London, UK.
authors.forename: N
authors.initials: N
authors.lastname: Goulden
authors.affiliation: Department of Bone Marrow Transplant, Bristol Royal Hospital for Children, Bristol, UK.
authors.forename: M
authors.initials: M
authors.lastname: Cummins
authors.affiliation: Department of Paediatric Haematology and Bone Marrow Transplant, Molecular and Cellular Immunology, UCL Great Ormond Street Institute of Child Health, London, UK.|Molecular and Cellular Immunology Section, Institute of Child Health, University College London, London, UK.
authors.forename: P J
authors.initials: PJ
authors.lastname: Amrolia
mesh_terms: D018941:Antigens, CD19; D002648:Child; D002675:Child, Preschool; D002678:Chimera; D005260:Female; D004854:Herpesvirus 4, Human; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D016219:Immunotherapy, Adoptive; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000276:immunology; D012008:Recurrence; D013602:T-Lymphocytes, Cytotoxic / Q000637:transplantation* / Q000821:virology; D014611:Vaccination
chemical_list: D018941:Antigens, CD19; C000598123:CTL019 chimeric antigen receptor; D011948:Receptors, Antigen, T-Cell