Preliminary data suggest UCART19 is safe, effective
SAN DIEGO—Preliminary data on UCART19—the first off-the-shelf, anti-CD19, allogeneic chimeric antigen receptor (CAR) T-cell therapy—suggest it can produce complete responses (CRs) and minimal residual disease (MRD) negativity, and side effects are manageable.
Investigators pooled data from the phase 1 pediatric (PALL) and adult (CALM) trials of UCART19 in patients with relapsed or refractory acute lymphoblastic leukemia (ALL) and observed a 67% CR rate in the overall population and an 82% CR rate in patients who received a three-drug lymphodepleting regimen.
Additionally, investigators reported no instance of moderate or severe acute graft-versus-host disease (GVHD) with UCART19.
“We’ve been blessed with the new treatments that have emerged in recent years,” said Reuben Benjamin, MD, PhD, “that include BiTEs, antibody-drug conjugates, and most excitingly, the autologous CAR T-cell therapies.”
Nevertheless, some logistical issues with the autologous CAR T cells leave an unmet need in this group of patients, he noted.
“So an off-the-shelf approach using a product like UCART19 may potentially overcome some of these hurdles that we see in the autologous CAR T-cell therapy field,” he said.
Dr. Benjamin, of King’s College Hospital in London, U.K., presented the analysis of PALL and CALM data at the 2018 ASH Annual Meeting as abstract 896.*
UCART19 product
UCART19 is an allogeneic, genetically modified, CAR T-cell product (anti-CD19 scFv- 41BB-CD3ζ) manufactured from healthy donor T cells.
It has a safety switch—RQR8, which is a CD20 mimotope—that allows the CAR T cells to be targeted by rituximab.
“And importantly,” Dr. Benjamin explained, “the T-cell alpha gene has been knocked out using TALEN® gene-editing technology to prevent T-cell receptor-mediated graft-versus-host disease.”
The CD52 gene is also knocked out, which permits an anti-CD52 monoclonal antibody, such as alemtuzumab, to be used in lymphodepletion.
Study design
The primary objective of both the adult (NCT02746952) and pediatric (NCT02808442) studies was to determine the safety and tolerability of UCART19. Also, the adult study was to determine the maximum tolerated dose of UCART19 and the optimal lymphodepleting regimen.
A secondary objective of both studies was to determine the remission rate at day 28.
Eligible patients received a lymphodepleting regimen for 7 days, followed by a single infusion of UCART19.
Lymphodepletion in the pediatric trial consisted of fludarabine (F) at 150 mg/m2 and cyclophosphamide (C) at 120 mg/kg, with or without alemtuzumab (A) at 1 mg/kg capped at 40 mg.
Adults received lower doses of each agent—90 mg/m2, 1,500 mg/m2, and (optionally) 1 mg/kg or 40 mg, respectively.
Investigators included alemtuzumab in the regimen to minimize viral infections.
The UCART19 dose was weight-banded in the pediatric trial and ranged from 1.1 to 2.3 x 106 cells/kg.
The adult trial included three UCART19 dose levels:
- 6 x 106 cells (≈1 x 105 cells/kg)
- 6 or 8 x 107 cells (≈1 x 106 cells/kg)
- 8 or 2.4 x 108 cells (≈3 x 106 cells/kg).
Patients were assessed for safety and response at day 28 and regularly thereafter for up to 12 months. Patients had the option during the follow-up period to receive a second dose if they did not respond or lost their response.
Patient characteristics/status
Twenty-one patients were enrolled in the trials—seven children and 14 adults. Median ages were 2.7 years (PALL; range, 0.8–16.4) and 29.5 years (CALM; range, 18–62).
Both studies included high-risk, heavily pretreated populations, Dr. Benjamin noted.
The pooled population had a median of 4 prior lines of therapy (range, 1–6), and nine patients had a high-risk cytogenetics, including complex karyotypes, MLL rearrangements, and Ph+ disease.
