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The use of base editing to generate universal off-the-shelf chimeric antigen receptor (CAR) T cells in patients with relapsed T-cell acute lymphoblastic leukemia (ALL) should be further investigated based on promising interim results from a phase I study.

In one of three patients -- a 13-year-old girl who had relapsed T-cell ALL after allogeneic stem cell transplantation -- molecular remission was achieved within 28 days after infusion of a single dose of base-edited CAR7 (BE-CAR7), reported Waseem Qasim, MBBS, PhD, of the Great Ormond Street Hospital for Children in London, and colleagues.

This allowed the patient to receive a reduced-intensity (nonmyeloablative) allogeneic stem cell transplant from her original donor, with successful immunologic reconstitution and leukemic remission that was confirmed by an analysis of bone marrow at 9 months, which showed normal morphologic characteristics and ongoing remission, they noted in the .

BE-CAR7 cells also showed "potent activity" in two other young patients, Qasim and colleagues said. A 15-year-old boy was able to undergo allogeneic stem cell transplantation while in remission. However, fatal fungal complications developed in the other patient, a 13-year-old boy.

"The interim results of this phase I study support further investigation of base-edited T cells for patients with relapsed leukemia," the authors wrote, adding that the data "are consistent with the antileukemic effects of allogeneic CAR T cells, effects that are sufficient for securing remission and deep clearance of T-cell ALL."

However, they noted that the strategy "is not without risk: the immunosuppressive and cytopenic effects of the trial protocol are substantial, and immune-cell manipulation carries risks."

Each patient developed fever, rash, and other manifestations of cytokine release syndrome (CRS) within the first week of treatment, and levels of interleukin-6 and ferritin were elevated in the two boys.

The 13-year-old boy was considered at particular risk for CRS due to his high disease burden. He developed biphasic CRS along with overlapping sepsis and fungal lung disease, leading to treatment in intensive care and death.

All three patients had multilineage cytopenia, which Qasim and team pointed out has been seen in other CAR7 studies and is a condition that "probably exacerbated infectious complications, including invasive fungal disease."

"In this study, subsequent allogeneic transplantation ensured donor-derived immune reconstitution and also limited the persistence of engineered cells," they wrote. "Additional safety measures could include the incorporation of a drug-inducible safety switch (or elimination system) to enable the controlled removal of infused cells once the useful therapeutic effects are derived or in the event of serious toxic effects."

Overcoming T-Cell Fratricide

Children with T-cell ALL who relapse after allogeneic stem cell transplantation have an extremely poor prognosis, with a long-term survival rate of less than 15%. For the teens in this study, further treatment with allogeneic stem cell transplantation had been ruled out and all faced palliation for their leukemia.

CAR-T strategies against T-cell cancers have been challenging, Qasim and colleagues noted, because targeting T-cell antigens "can trigger CAR T-cell fratricide (in which CAR T cells target one another because each expresses the protein that it is engineered to target) and have damaging effects on the broader T-cell population."

To address this challenge, 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 (CAR7), a protein that is expressed in T-cell ALL.

Qasim and colleagues then used base editing "to inactivate three genes encoding CD52 and CD7 receptors and the β chain of the αβ T-cell receptor to evade lymphodepleting serotherapy, CAR7 T-cell fratricide, and graft-versus-host disease (GVHD), respectively."

The began at Great Ormond Street Hospital in April 2022, with a protocol specifying a study population of 10 children ages 6 months to 16 years with relapsed or refractory CD7+ T-cell cancer that is quantifiable in bone marrow (>10⁻⁴ as measured with the use of flow cytometry or polymerase chain reaction assay).

Exclusion criteria included active, uncontrolled infections; pre-existing GVHD; or the detection of anti-human leukocyte antigen antibodies against BE-CAR7 cells.

Patients in the study received lymphodepletion with fludarabine (150 mg/m² of body-surface area), cyclophosphamide (120 mg/kg of body weight), and alemtuzumab (Lemtrada; 1 mg/kg) followed by infusion of 0.2×10⁶ to 2.0×10⁶ BE-CAR7 T cells/kg, with a maximum of 5×10⁴/kg of T-cell receptor αβ+ T cells, to limit the risk of GVHD.

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