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Durable responses and low toxicity after fast off-rate cd19 chimeric antigen receptor-t therapy in adults with relapsed or refractory b-cell acute lymphoblastic leukemia

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Claire Roddie, Juliana Dias, Maeve A. O'Reilly, Mahnaz Abbasian, Amaia Cadinanos-Garai, Ketki Vispute, Leticia Bosshard-Carter, Marina Mitsikakou, Vedika Mehra, Harriet Roddy, John A. Hartley, Victoria Spanswick, Helen Lowe, Bilyana Popova, Laura Clifton-Hadley, Graham Wheeler, Joanna Olejnik, Adrian Bloor, David Irvine, Leigh Wood & 7 more Maria A.V. Marzolini, Sabine Domning, Farzin Farzaneh, Mark W. Lowdell, David C. Linch, Martin A. Pule, Karl S. Peggs

Original languageEnglish
Pages (from-to)3352-3363
Number of pages12
JournalJournal of Clinical Oncology
Volume39
Issue number30
DOIs
Published20 Oct 2021

Bibliographical note

Funding Information: Supported by the UK National Institute for Health Research i4i grant II-C3-0714-20005. M.A.P., C.R., K.S.P., and D.C.L. were supported by the University College London NIHR Biomedical Research Center (BRC), by the UCL NIHR Blood and Transplant Research Unit (BTRU) in Stem Cells and Immunotherapy at UCL in partnership with the NHS Blood and Transplant Research Unit, and by core funding through the CRUK London Center. The Cancer Trials Center was supported by a CRUK core grant. Publisher Copyright: © 2021 American Society of Clinical Oncology. All rights reserved.

King's Authors

Abstract

PURPOSE Prognosis for adult B-cell acute lymphoblastic leukemia (B-ALL) is poor, and there are currently no licensed CD19 chimeric antigen receptor (CAR) therapeutics. We developed a novel second-generation CD19-CAR (CAT19-41BB-Z) with a fast off rate, designed for more physiologic T-cell activation to reduce toxicity and improve engraftment. We describe the multicenter phase I ALLCAR19 ( NCT02935257 ) study of autologous CAT19-41BB-Z CAR T cells (AUTO1) in relapsed or refractory (r/r) adult B-ALL. METHODS Patients age ≥ 16 years with r/r B-ALL were eligible. Primary outcomes were toxicity and manufacturing feasibility. Secondary outcomes were depth of response at 1 and 3 months, persistence of CAR-T, incidence and duration of hypogammaglobulinemia and B-cell aplasia, and event-free survival and overall survival at 1 and 2 years. RESULTS Twenty-five patients were leukapheresed, 24 products were manufactured, and 20 patients were infused with AUTO1. The median age was 41.5 years; 25% had prior blinatumomab, 50% prior inotuzumab ozogamicin, and 65% prior allogeneic stem-cell transplantation. At the time of preconditioning, 45% had ≥ 50% bone marrow blasts. No patients experienced ≥ grade 3 cytokine release syndrome; 3 of 20 (15%) experienced grade 3 neurotoxicity that resolved to ≤ grade 1 within 72 hours with steroids. Seventeen of 20 (85%) achieved minimal residual disease–negative complete response at month 1, and 3 of 17 underwent allogeneic stem-cell transplantation while in remission. The event-free survival at 6 and 12 months was 68.3% (42.4%-84.4%) and 48.3% (23.1%-69.7%), respectively. High-level expansion (Cmax 127,152 copies/µg genomic DNA) and durable CAR-T persistence were observed with B-cell aplasia ongoing in 15 of 20 patients at last follow-up. CONCLUSION AUTO1 demonstrates a tolerable safety profile, high remission rates, and excellent persistence in r/r adult B-ALL. Preliminary data support further development of AUTO1 as a stand-alone treatment for r/r adult B-ALL.

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