- Infusion of base-edited CAR7 T cells for T-cell acute lymphoblastic leukemia enabled 82% of patients in a phase I study to achieve a deep remission after receiving the therapy, allowing them to continue to stem cell transplant.
- Of the 11 patients treated, 64% were in ongoing remission 3 to 36 months following transplant.
- Three patients had clinically significant virus-related complications after transplant.
The use of base editing to generate universal off-the-shelf CAR T cells induced durable remissions -- up to 36 months in one case -- in patients with relapsed or refractory T-cell acute lymphoblastic leukemia (ALL), according to results from a phase I study.
An infusion of a single dose of base-edited CAR7 T cells resulted in a morphologic remission with incomplete count recovery by day 28 among all 11 patients in the study, most of whom were under the age of 16 and considered to be otherwise incurable, reported Waseem Qasim, MBBS, PhD, of the Great Ormond Street Hospital for Children in London, and colleagues in the New England Journal of Medicine.
Among those patients, 82% achieved a deep remission after receiving the therapy that allowed them to continue to allogeneic stem cell transplant, while 64% were alive and in ongoing remission 3 to 36 months post-transplant.
Qasim and his team had previously reported on the safety and efficacy of these edited cells in three patients, two of whom had relapsed after previous allogeneic stem-cell transplantation but are now in ongoing, long-term remission.
"We previously showed promising results using precision genome editing for children with aggressive blood cancer and this larger number of patients confirms the impact of this type of treatment," said Qasim in a release. "We've shown that universal or 'off the shelf' base-edited CAR T cells can seek and destroy very resistant cases of CD7+ leukemia."
As explained by Qasim and his team, applying CAR T-cell therapy to T-cell leukemia is challenging because targeting T-cell antigens can trigger CAR T-cell fratricide.
To address this, they applied a universal cell-based intervention in which healthy volunteer donor T cells were transduced with the use of a lentivirus to express a CAR with specificity for CD7, which is expressed in T-cell ALL.
They used base editing to inactivate three genes expressed on the surfaces of T cells -- CD7, CD52, and TCRαβ -- with the aim of avoiding CAR T-cell fratricide, lymphodepleting serotherapy, and graft-versus-host disease (GVHD). They then inserted a CAR gene into these edited cells to recognize CD7 in the diseased T cells of patients.
The phase I study, which began at Great Ormond Street Hospital in April 2022, eventually enrolled 11 children between the ages of 5 and 15 years -- nine of whom received a single-dose infusion of the base-edited CAR7 T cells -- as well as two adults enrolled on a compassionate basis.
Eligible patients had to have relapsed or refractory CD7-positive T-cell ALL ahead of a planned stem cell transplant, with CD7 expression over 99% on blasts. Key exclusion criteria were progressive disease, uncontrolled infection, preexisting GVHD, or the presence of anti-HLA antibodies against base-edited CAR7 batches.
All the patients had previously received multiple lines of standard therapies, and three patients had undergone at least one previous transplantation from a matched, unrelated donor.
Patients in the study received lymphodepletion with fludarabine, cyclophosphamide, and alemtuzumab (Lemtrada) followed by an infusion of 0.2-2.0 × 106 base-edited CAR7 T cells/kg, with a maximum of 5 × 104/kg of T-cell receptor αβ+ T cells, to limit the risk of GVHD.
Between 1 and 5 days after the base-edited CAR7 T-cell infusion, grade 1/2 cytokine release syndrome (CRS) developed in nine patients who were managed under standard institutional procedures. Two patients had grade 3/4 CRS. Three patients had grade 1 immune effector cell-associated neurotoxicity syndrome.
Ten patients experienced erythematous maculopapular skin rash between day 6 and 10. This rash was managed with topical or systemic glucocorticoids and resolved in all patients by day 21.
All patients experienced viral reactivation, and one patient with refractory disease died of progressive aspergillosis.
After lymphodepletion and CAR T-cell infusion, all patients experienced multilineage cytopenia and had documented viremia (adenovirus, Epstein-Barr virus, cytomegalovirus, and human herpes virus 6), with three patients developing clinically significant complications.
"Protracted lymphopenia and neutropenia clearly increase the risks of infectious complications, including with opportunistic pathogens and viral reactivations," the authors observed.
"Although intense surveillance and prophylaxis offered mitigations and the study was designed to reduce risk through transplant-derived and donor-derived reconstitution, virus-related complications extending into the post-transplantation period caused clinically significant complications in two children and an adult," they added. "Nonetheless, our experience suggests that the antileukemic effects of CAR7 therapy peak within 2 weeks, and once cytokine release syndrome has resolved, it is feasible to move rapidly to transplantation to secure prompt donor-derived reconstitution to address infectious complications."
Disclosures
The study was supported by grants from the Medical Research Council, the Wellcome Trust, the National Institute for Health Research, and the Great Ormond Street Hospital Children's Charity.
Qasim reported relationships with AstraZeneca, EsoBiotec, the Medical Research Council, the National Institutes of Health, ViroCell, the Wellcome Trust, and Wugen. Qasim and several co-authors also disclosed a patent related to T-cell therapy.
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