Reuben Benjamin1, Charlotte Graham2, Deborah Yallop3, Agnieszka Jozwik2, Oana C Mirci-Danicar4, Giovanna Lucchini4, Danielle Pinner4, Nitin Jain5, Hagop Kantarjian5, Nicolas Boissel6, Marcela V Maus7, Matthew J Frigault7, André Baruchel8, Mohamad Mohty9, Athos Gianella-Borradori10, Florence Binlich10, Svetlana Balandraud10, Fabien Vitry11, Elisabeth Thomas10, Anne Philippe12, Sylvain Fouliard10, Sandra Dupouy10, Ibtissam Marchiq13, Maria Almena-Carrasco10, Nicolas Ferry10, Sylvain Arnould14, Cyril Konto15, Paul Veys4, Waseem Qasim4. 1. Department of Haematological Medicine, King's College Hospital NHS Foundation Trust, London, UK; School of Cancer and Pharmaceutical Sciences, Kings College London, London, UK. Electronic address: reuben.benjamin@kcl.ac.uk. 2. Department of Haematological Medicine, King's College Hospital NHS Foundation Trust, London, UK; School of Cancer and Pharmaceutical Sciences, Kings College London, London, UK. 3. Department of Haematological Medicine, King's College Hospital NHS Foundation Trust, London, UK. 4. Infection, Immunity & Inflammation Department, Great Ormond Street Hospital, London, UK. 5. The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 6. Department of Hematology, Hôpital Saint Louis, Paris, France. 7. Division of Hematology and Oncology, Massachusetts General Hospital, Boston, MA, USA. 8. Department of Pediatric Hematology, K Hôpital Universitaire Robert Debré, Paris, France. 9. INSERM UMRS 938, Sorbonne University, Saint-Antoine Hospital, Paris, France. 10. Institut de Recherches Internationales Servier, Suresnes, France. 11. Institut de Recherches Internationales Servier, Suresnes, France; Laboratoires Davolterra, Paris, France. 12. Institut de Recherches Internationales Servier, Suresnes, France; Pfizer, Paris, France. 13. Institut de Recherches Servier, Croissy sur seine, France. 14. Les Laboratoires Servier, Suresnes, France. 15. Allogene Therapeutics, South San Francisco, CA, USA.
Abstract
BACKGROUND:Genome-edited donor-derived allogeneicanti-CD19 chimeric antigen receptor (CAR) T cells offer a novel form of CAR-T-cell product that is available for immediate clinical use, thereby broadening access and applicability. UCART19 is one such product investigated in children and adults with relapsed or refractory B-cell acute lymphoblastic leukaemia. Two multicentre phase 1 studies aimed to investigate the feasibility, safety, and antileukaemic activity of UCART19 in children and adults with relapsed or refractory B-cell acute lymphoblastic leukaemia. METHODS: We enrolled paediatric or adult patients in two ongoing, multicentre, phase 1 clinical trials to evaluate the safety and antileukaemic activity of UCART19. All patients underwent lymphodepletion with fludarabine and cyclophosphamide with or without alemtuzumab, then children received UCART19 at 1·1-2·3 × 106 cells per kg and adults received UCART19 doses of 6 × 106 cells, 6-8 × 107 cells, or 1·8-2·4 × 108 cells in a dose-escalation study. The primary outcome measure was adverse events in the period between first infusion and data cutoff. These studies were registered at ClinicalTrials.gov, NCT02808442 and NCT02746952. FINDINGS:Between June 3, 2016, and Oct 23, 2018, seven children and 14 adults were enrolled in the two studies and receivedUCART19. Cytokine release syndrome was the most common adverse event and was observed in 19 patients (91%); three (14%) had grade 3-4 cytokine release syndrome. Other adverse events were grade 1 or 2 neurotoxicity in eight patients (38%), grade 1 acute skin graft-versus-host disease in two patients (10%), and grade 4 prolonged cytopenia in six patients (32%). Two treatment-related deaths occurred; one caused by neutropenic sepsis in a patient with concurrent cytokine release syndrome and one from pulmonary haemorrhage in a patient with persistent cytopenia. 14 (67%) of 21 patients had a complete response or complete response with incomplete haematological recovery 28 days after infusion. Patients not receiving alemtuzumab (n=4) showed no UCART19 expansion or antileukaemic activity. The median duration of response was 4·1 months with ten (71%) of 14 responders proceeding to a subsequent allogeneic stem-cell transplant. Progression-free survival at 6 months was 27%, and overall survival was 55%. INTERPRETATION: These two studies show, for the first time, the feasibility of using allogeneic, genome-edited CAR T cells to treat patients with aggressive leukaemia. UCART19 exhibited in-vivo expansion and antileukaemic activity with a manageable safety profile in heavily pretreated paediatric and adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia. The results this study are an encouraging step forward for the field of allogeneic CAR T cells, and UCART19 offers the opportunity to treat patients with rapidly progressive disease and where autologous CAR-T-cell therapy is unavailable. FUNDING: Servier.
RCT Entities:
BACKGROUND: Genome-edited donor-derived allogeneic anti-CD19chimeric antigen receptor (CAR) T cells offer a novel form of CAR-T-cell product that is available for immediate clinical use, thereby broadening access and applicability. UCART19 is one such product investigated in children and adults with relapsed or refractory B-cell acute lymphoblastic leukaemia. Two multicentre phase 1 studies aimed to investigate the feasibility, safety, and antileukaemic activity of UCART19 in children and adults with relapsed or refractory B-cell acute lymphoblastic leukaemia. METHODS: We enrolled paediatric or adult patients in two ongoing, multicentre, phase 1 clinical trials to evaluate the safety and antileukaemic activity of UCART19. All patients underwent lymphodepletion with fludarabine and cyclophosphamide with or without alemtuzumab, then children received UCART19 at 1·1-2·3 × 106 cells per kg and adults received UCART19 doses of 6 × 106 cells, 6-8 × 107 cells, or 1·8-2·4 × 108 cells in a dose-escalation study. The primary outcome measure was adverse events in the period between first infusion and data cutoff. These studies were registered at ClinicalTrials.gov, NCT02808442 and NCT02746952. FINDINGS: Between June 3, 2016, and Oct 23, 2018, seven children and 14 adults were enrolled in the two studies and received UCART19. Cytokine release syndrome was the most common adverse event and was observed in 19 patients (91%); three (14%) had grade 3-4 cytokine release syndrome. Other adverse events were grade 1 or 2 neurotoxicity in eight patients (38%), grade 1 acute skin graft-versus-host disease in two patients (10%), and grade 4 prolonged cytopenia in six patients (32%). Two treatment-related deaths occurred; one caused by neutropenic sepsis in a patient with concurrent cytokine release syndrome and one from pulmonary haemorrhage in a patient with persistent cytopenia. 14 (67%) of 21 patients had a complete response or complete response with incomplete haematological recovery 28 days after infusion. Patients not receiving alemtuzumab (n=4) showed no UCART19 expansion or antileukaemic activity. The median duration of response was 4·1 months with ten (71%) of 14 responders proceeding to a subsequent allogeneic stem-cell transplant. Progression-free survival at 6 months was 27%, and overall survival was 55%. INTERPRETATION: These two studies show, for the first time, the feasibility of using allogeneic, genome-edited CAR T cells to treat patients with aggressive leukaemia. UCART19 exhibited in-vivo expansion and antileukaemic activity with a manageable safety profile in heavily pretreated paediatric and adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia. The results this study are an encouraging step forward for the field of allogeneic CAR T cells, and UCART19 offers the opportunity to treat patients with rapidly progressive disease and where autologous CAR-T-cell therapy is unavailable. FUNDING: Servier.
Authors: Sjoukje J C van der Stegen; Pieter L Lindenbergh; Roseanna M Petrovic; Hongyao Xie; Mame P Diop; Vera Alexeeva; Yuzhe Shi; Jorge Mansilla-Soto; Mohamad Hamieh; Justin Eyquem; Annalisa Cabriolu; Xiuyan Wang; Ramzey Abujarour; Tom Lee; Raedun Clarke; Bahram Valamehr; Maria Themeli; Isabelle Riviere; Michel Sadelain Journal: Nat Biomed Eng Date: 2022-08-08 Impact factor: 29.234
Authors: Dimitrios L Wagner; Enrico Fritsche; Michael A Pulsipher; Nabil Ahmed; Mohamad Hamieh; Meenakshi Hegde; Marco Ruella; Barbara Savoldo; Nirali N Shah; Cameron J Turtle; Alan S Wayne; Mohamed Abou-El-Enein Journal: Nat Rev Clin Oncol Date: 2021-02-25 Impact factor: 66.675
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