Promising results for treating patients with aggressive lymphoblastic leukemia using genome-edited allogeneic CAR T-cells

Autologous CD19-targeted chimeric antigen receptor (CAR) T-cell products are established for the treatment of children and young adult patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukaemia (ALL). However, the manufacturing process of this therapy is time consuming, logistically challenging, and expensive.

Genome-edited allogeneic anti-CD19 CAR T-cells may offer a new approach for treating patients with an aggressive form of leukemia, available for immediate clinical use. However, there are concerns about whether allogeneic CAR T-cells can expand safely and become active in non-HLA-matched settings. UCART19 is an allogeneic CD19-directed CAR T-cell product, in which the genes encoding the T-cell receptor α constant chain and CD52 have been removed using transcription activator-like effector nucleases (TALENs), thus, minimising CAR T-cells’ rejection.

In December 2020, Reuben Benjamin and colleagues published in The Lancet,¹ promising results from two multicenter phase I clinical studies investigating the feasibility, safety, and antileukemic activity of UCART19 in children and adults with R/R ALL. The findings from these studies are summarized below.

Study design

There are two ongoing, open-label phase I trials, PALL and CALM, assessing UCART19, which are being conducted across three centers in France, two centers in the UK, and two centres in the US.

Patients had to show evidence of CD19-positive B-cell ALL with more than 5% leukemic blasts in bone marrow, or a minimal residual disease of 1 × 10⁻³ cells assessed by either flow cytometry or quantitative PCR.

All patients underwent lymphodepletion with fludarabine and cyclophosphamide with or without alemtuzumab. Children in the PALL trial received UCART19 at 1.1–2.3 × 10⁶ cells/kg, and adults in the CALM trial received UCART19 at escalating doses of 6 × 10⁶ cells, 6–8 × 10⁷ cells, or 1.8–2.4 × 10⁸ cells.

Primary endpoint was adverse events (AEs), and secondary endpoints were objective response rate, duration of response, progression-free survival, and overall survival.

Patient characteristics

A total of 21 patients were enrolled; patient characteristics are depicted in Table 1. The PALL trial enrolled seven patients aged between 6 months and 18 years, and the CALM trial enrolled 14 patients aged from 16–70 years.

Table 1. Patient characteristics in the CALM and PALL trials and pooled population¹

Allo-HSCT, allogeneic hematopoietic stem cell transplantation; BM, bone marrow.
Characteristic	CALM (n = 14)	PALL (n = 7)	Pooled (n = 21)
Median age, years (range)	29.5 (22.0–45.0)	2.7 (2.2–14.0)	22.0 (14.0–39.0)
Median number of previous therapies, n (range)	4 (3–4)	4 (3–6)	4 (3–5)
High cytogenetic risk, %	43	43	43
Previous treatment, %
Inotuzumab ozogamicin	43	29	38
Blinatumomab	29	14	24
Allo-HSCT	71	43	62
Cytoreduction before lymphodepletion, %	50	71	57
BM tumor burden (% blast cells)	27.5	6.0	8.0

Safety

Cytokine release syndrome (CRS) was the most common AE, observed in 19 patients (91%); three patients (14%) had Grade 3–4 CRS. Other CAR T-cell-specific AEs were:

• Grade 1 or 2 neurotoxicity in eight patients (38%)
• Grade 1 acute cutaneous GvHD in two patients (10%)
• Grade 4 prolonged cytopenia in six patients (32%)
• Infections in 13 patients (62%); four (20%) cases were Grade 4–5
• Grade 3 tumour lysis syndrome in two patients (10%)

Ten patients died due to progressive disease, and five patients died due to infections. Two treatment-related deaths occurred; one caused by neutropenic sepsis in a patient with concurrent CRS and one from pulmonary hemorrhage in a patient with persistent cytopenia.

Efficacy

An overall response rate was observed in 67% (n = 14) of 21 patients, with 71% of patients being MRD-negative at 10⁻⁴ sensitivity. The median duration of follow-up was 24.3 months, and 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%, with a 6-month overall survival rate of 55%. Five (24%) of the 21 patients were still alive after the data cutoff.

Conclusion

There is an unmet therapeutic need for patients with R/R ALL who are not candidates for autologous CAR T-cell therapy. Recent results from these two phase I trials in pediatric and adult patients demonstrate the feasibility, safety, and activity of UCART19. This off-the-shelf CAR T-cell product can treat patients more rapidly than is possible with patient-derived CAR T-cells.

These data represent a substantial step forward in the development of CAR T-cells and could herald a new, effective, and easily accessible cell therapy for patients with B-cell ALL.