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Clinical Trial
. 2020 Dec 12;396(10266):1885-1894.
doi: 10.1016/S0140-6736(20)32334-5.

Genome-edited, donor-derived allogeneic anti-CD19 chimeric antigen receptor T cells in paediatric and adult B-cell acute lymphoblastic leukaemia: results of two phase 1 studies

Reuben Benjamin  1 , Charlotte Graham  2 , Deborah Yallop  3 , Agnieszka Jozwik  2 , Oana C Mirci-Danicar  4 , Giovanna Lucchini  4 , Danielle Pinner  4 , Nitin Jain  5 , Hagop Kantarjian  5 , Nicolas Boissel  6 , Marcela V Maus  7 , Matthew J Frigault  7 , André Baruchel  8 , Mohamad Mohty  9 , Athos Gianella-Borradori  10 , Florence Binlich  10 , Svetlana Balandraud  10 , Fabien Vitry  11 , Elisabeth Thomas  10 , Anne Philippe  12 , Sylvain Fouliard  10 , Sandra Dupouy  10 , Ibtissam Marchiq  13 , Maria Almena-Carrasco  10 , Nicolas Ferry  10 , Sylvain Arnould  14 , Cyril Konto  15 , Paul Veys  4 , Waseem Qasim  4 ; UCART19 Group
Collaborators, Affiliations
Clinical Trial

Genome-edited, donor-derived allogeneic anti-CD19 chimeric antigen receptor T cells in paediatric and adult B-cell acute lymphoblastic leukaemia: results of two phase 1 studies

Reuben Benjamin et al. Lancet. .

Abstract

Background: Genome-edited donor-derived allogeneic anti-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 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.

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Conflict of interest statement

AB reports personal fees from Servier, during the conduct of the study; personal fees from Novartis, personal fees from Celgene, personal fees from jazz, personal fees from Janssen, personal fees from Amgen, outside the submitted work; AJ reports honorarium and research activities sponsored by Servier; CG reports grants from Servier, during the conduct of the study; non-financial support from Gilead, non-financial support from Sanofi, non-financial support from Pfizer, outside the submitted work; CK reports personal fees from Allogene Therapeutics, during the conduct of the study and personal fees from Allogene Therapeutics, other from Pfizer, other from Forty-Seven, other from Bristol-Myers Squibb, outside the submitted work; a patent “methods and compositions for dosing of allogeneic chimeric antigen receptor t cells” licensed to Allogene Therapeutics, and a patent “chimeric antigen receptors targeting b-cell maturation antigen and methods of use” issued to Allogene Therapeutics; DY reports grants and non-financial support from Servier, during the conduct of the study; non-financial support from Amgen, personal fees from Pfizer, outside the submitted work; HK reports grants and other from AbbVie, grants and other from Agios, grants and other from Amgen, grants from Ariad, grants from Astex, grants from BMS, from Cyclacel, grants from Daiichi-Sankyo, grants and other from Immunogen, grants from Jazz Pharma, grants from Novartis, grants and other from Pfizer, other from Actinium, other from Takeda, outside the submitted work; MJF reports personal fees from Novartis, personal fees from Kite/Gilead, personal fees from Juno/Celgene, outside the submitted work; MM reports personal fees from Janssen, grants and personal fees from Sanofi, grants and personal fees from jazz Pharmaceuticals, personal fees from Celgene, personal fees from Bristol-Myers Squibb, personal fees from Takeda, personal fees from Amgen, grants from Roche, outside the submitted work; MVM reports a patent “method to generate allogeneic cells” pending and financial relationship with Adaptimmune Therapeutics, Agentus, Agenus inc., Arcellx, Bluebird Bio, Century, CRISPR Therapeutics, Kite Pharma, TCR2, WindMIL Therapeutics, Novartis, GSK, Incysus, Allogene Therapeutics, MicroMedicine outside the submitted work; NB reports personal fees from Servier, outside the submitted work; NJ reports grants and personal fees from Servier, during the conduct of the study; grants, personal fees and non-financial support from Pharmacyclics, personal fees and non-financial support from Janssen, grants, personal fees and non-financial support from AstraZeneca, grants, personal fees and non-financial support from Genentech, grants and non-financial support from BMS, grants, personal fees and non-financial support from Verastem, grants, personal fees and non-financial support from Pfizer, grants and non-financial support from Celgene, grants and non-financial support from Seattle Genetics, grants and non-financial support from Incyte, grants, personal fees and non-financial support from AbbVie, grants and non-financial support from Cellectis, grants, personal fees and non-financial support from ADC Therapeutics, grants, personal fees and non-financial support from Precision Biosciences, grants, personal fees and non-financial support from Adaptive Biotechnologies, outside the submitted work; OMD reports personal fees from Servier, during the conduct of the study; PV reports grants from Servier, during the conduct of the study; personal fees from Novartis, from Jazz, outside the submitted work; RB reports grants from Servier, during the conduct of the study; grants from Allogene, grants and personal fees from Pfizer, personal fees from Celgene, personal fees from Novartis, personal fees from Gilead, personal fees from EUSA Pharm, grants from Amgen, personal fees from Janssen, outside the submitted work; WQ reports grants and other from Servier, grants from Cellectis, grants from NIHR, during the conduct of the study; grants from Bellicum, personal fees and other from Orchard, personal fees and other from Autolus, personal fees from Novartis, grants from Miltenyi, outside the submitted work; a patent EP17822762 pending, and a patent EP3559215A1 pending; AGB, ET, FB, IM, MAC, NF, SB, SD, SF, SA are full time employee from Servier; AP, DP, FV, GL declare no competing interest.

Figures

Figure 1:
Figure 1:. Screening, enrolment and study completion.
CRS=cytokine release syndrome. FC=fludarabine and cyclophosphamide. FCA=fludarabine, cyclophosphamide and alemtuzumab. SCT=stem cell transplant. Among the 31 patients who were screened, ten patients did not meet eligibility criteria. In 5 patients who died from infection 3 viral and 3 bacterial infections were recorded, 1 patient experienced both viral and bacterial infections.
Figure 2:
Figure 2:. Clinical course of individual patients after UCART19 infusion at month 0.
# Denotes patients re-dosed with UCART19 in compassionate use after withdrawal from the parent trial, who were then included in the long-term follow-up trial. Allo-SCT=allogeneic stem cell transplant. C=CALM trial. FC=fludarabine and cyclophosphamide. FCA=fludarabine, cyclophosphamide and alemtuzumab. P=PALL trial. *Patient received a single dose (0·3 mg/m2) of inotuzumab ozogamicin 5 months post UCART19 infusion for maintenance of response, prior to Allo-SCT (data reported post cut-off date) **Patients received new anti-leukaemic treatment due to disease relapse. Grey colour is not visible on the figure because the occurrence of relapses and new treatment initiation were concomitant
Figure 3:
Figure 3:. UCART19 cell kinetics.
Kinetics measured by (A) quantitative PCR (log scale) in six patients in the PALL trial, and (B) flow cytometry (log scale) in 14 patients in the CALM trial and two in the PALL trial; (C) comparison of area under the curve for UCART19 cell count to day 28 (AUCD28) in patients with complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) and patients with residual disease (RD). VCN=vector copy number.
Figure 3:
Figure 3:. UCART19 cell kinetics.
Kinetics measured by (A) quantitative PCR (log scale) in six patients in the PALL trial, and (B) flow cytometry (log scale) in 14 patients in the CALM trial and two in the PALL trial; (C) comparison of area under the curve for UCART19 cell count to day 28 (AUCD28) in patients with complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) and patients with residual disease (RD). VCN=vector copy number.
Figure 4:
Figure 4:. Kaplan-Meier curve of relapse-free survival in patients who achieved complete remission or complete remission with incomplete hematologic recovery at day 28 after the first UCART19 infusion
See this image and copyright information in PMC

Comment in

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