Genome-Edited Donor-Derived Anti-CD19 CAR T-Cell Therapy Is Active in B-Cell Acute Lymphoblastic Leukemia

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Pooled results of two phase I studies, reported in The Lancet by Reuben Benjamin, MBBS, of the Department of Haematological Medicine, King’s College Hospital, London, and colleagues, indicate that the genome-edited donor-derived allogeneic anti-CD19 chimeric antigen receptor (CAR) T-cell product UCART19 is active and has a manageable toxicity profile in pediatric and adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia.1

As explained by the investigators, UCART19 is an off-the-shelf, ready-to-use product including mRNA encoding transcription activator-like effector nucleases, which act to disrupt genes encoding T-cell receptor α and β chains and CD52. The result reduces the risk of graft-vs-host disease through reducing the number of T-cell receptor αβ–positive T cells and conferring resistance of the infused cells to the anti-CD52 monoclonal antibody alemtuzumab and other lymphodepleting drugs.

Study Details

The two ongoing phase I studies (CALM and PALL) included 21 patients enrolled at three centers in France, two in the United Kingdom, and two in the United States between June 2016 and October 2018. Median age of patients was 29.5 years (range = 18.0–62.0 years) among the 14 adult patients in CALM and 2.7 years (range = 0.8–16.4 years) among the 7 pediatric patients in PALL. Both adult and pediatric patients had received a median of four previous lines of therapy.

All patients underwent lymphodepletion with fludarabine and cyclophosphamide with (n = 17) or without (n = 4) alemtuzumab. Pediatric patients received UCART19 at 1.1 to 2.3 × 106 cells/kg and adults received UCART19 at 6 × 106 cells (n = 6), 6 to 8 × 107 cells (n = 6), or 1.8 to 2.4 × 108 cells (n = 2) in a dose-escalation scheme. Redosing with UCART19 could be considered if patients had suboptimal disease response or early CD19-positive relapse or had poor persistence of UCART19; overall, three adult patients received a second dose. The primary outcome measure was adverse events in the period between first infusion and data cutoff (August 2019).


The most common adverse events of any grade associated with UCART19 or lymphodepletion were cytokine-release syndrome (n = 19, 91%), infections (n = 13, 62%), neurotoxicity (n = 8, 38%), and cytopenias. Grade 3 or 4 cytokine-release syndrome occurred in three patients (14%). Neurotoxicity was grade 1 in seven patients and grade 2 in one. Grade 1 acute skin graft-vs-host disease occurred in one adult and one pediatric patient (10%), with no other manifestation of graft-vs-host disease and no detectable expansion of T-cell receptor αβ–positive cells in blood or bone marrow. Grade ≥ 3 cytopenia (neutropenia or thrombocytopenia) that had not resolved by day 28 was observed in 15 of 20 patients (75%) and in 10 of 19 patients (52%) on day 42; prolonged cytopenia (grade 4 cytopenia persisting beyond 42 days was observed in 6 patients (32%). Grade ≥ 3 infections occurred in eight patients (38%). Treatment-related death occurred in two patients, with causes consisting of neutropenic sepsis in a patient with concurrent cytokine-release syndrome and pulmonary hemorrhage in a patient with persistent cytopenia.


  • UCART19 produced a complete response or a complete response with incomplete hematologic recovery in 67% of patients.
  • UCART19 treatment was associated with a manageable toxicity profile.

Median time to onset of cytokine-release syndrome was 8 days following infusion, and the median duration was 6 days. Among the 19 patients with cytokine-release syndrome, 8 (42%) received tocilizumab, 3 (16%) required steroid treatment in addition to tocilizumab, 7 (37%) required intensive care unit admission, and 3 (16%) required inotropic support. Median duration of neurotoxicity was 3 days, with no specific treatment being required. Neurologic events included dyskinesia, hallucination, irritability, disorganized speech, confusion, dysarthria, chorea, myoclonus, and headache.


UCART19 cells showed rapid expansion in blood, with peak numbers observed at approximately 14 days, followed by a reduction in counts by day 28; persistence beyond day 42 was observed in three patients (up to 120 days in one). Expansion was observed in 15 of the 17 patients (88%) who received alemtuzumab, with no expansion occurring in the 4 who did not.

Overall, a complete response or a complete response with incomplete hematologic recovery at 28 days was observed in 14 patients (67%). A total of 15 patients (71%) were negative for minimal residual disease at 10-4 sensitivity. A response was observed in 14 patients (82%) who received alemtuzumab and in none who did not. The area under the curve for UCART19 cell count for the first 28 days after administration was larger in responders vs nonresponders.

Among the three adult patients who received a second dose of UCART19 after further lymphodepletion, two achieved a complete response or a complete response with incomplete hematologic recovery and received allogeneic stem cell transplantation. Remission lasted for 10 months and 2 months in these two patients; the remaining patient experienced disease progression with central nervous system involvement.

Median follow-up among responders was 24.3 months. Median duration of response was 4.1 months. A total of 10 responders proceeded to allogeneic stem cell transplantation. At 6 months, progression-free survival was 27% and overall survival was 55%. At data cutoff, five patients (24%) remained alive. Death due to progressive disease occurred in 10 patients, and 5 patients died of infection, including 3 after allogeneic stem cell transplantation.

The investigators concluded: “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 [of] 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.” 

DISCLOSURE: The study was funded by Servier. Dr. Benjamin has received research support from Servier, Allogene, Amgen, and Pfizer; and has received honoraria from Pfizer, Celgene, Novartis, Gilead, EUSA Pharm, and Janssen.


1. Benjamin R, Graham C, Yallop D, et al: 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. Lancet 396: 1885-1894, 2020.