TOPLINE:

In a phase 1 study, anti-CD7 chimeric antigen receptor (CAR) T cells induced complete remission in children and adults with relapsed or refractory T-cell acute lymphoblastic leukemia (ALL), with 82% achieving deep remission that enabled stem cell transplant.

METHODOLOGY:

• Relapsed or refractory T-cell ALL often requires allogeneic stem cell transplant, but the risk for relapse is high unless deep remission is achieved. CAR T-cell therapy is a potential strategy for achieving such remission, and the antigen CD7 is considered a prime target because of its high expression in T-cell ALL blasts. However, targeting T-cell antigens can trigger fratricide. To address that and other barriers, the study used multiplex base editing, a next-generation genome editing technique, to create universal anti-CD7 CAR T cells, derived from a single donor.
• Nine children (aged 16 years or younger) and two adults with relapsed or refractory CD7-positive T-cell ALL received a single infusion of base-edited anti-CD7 CAR (BE-CAR7) T cells, following lymphodepletion. The adults were treated under compassionate use arrangements.
• Patients were assessed using flow cytometry and polymerase chain reaction assays on day 28, and those achieving deep remission (minimum residual disease of less than 1 disease cell per 10,000 normal cells) proceeded to allogeneic stem cell transplant.
• The primary outcome was safety, and secondary outcomes were frequency and duration of remission, disease-free survival, and overall survival.

TAKEAWAY:

• All patients achieved complete morphologic remission with incomplete count recovery at day 28. Nine patients (82%) achieved deep remission and proceeded to stem cell transplant, with either reduced-intensity or standard conditioning regimens.
• Seven patients maintained ongoing remission at 3-36 months post-transplant. Overall survival at cutoff was 73%, and disease-free survival was 64%. The first child treated in the study has been disease-free for more than 3 years.
• Complications included cytokine release syndrome of grades 1 or 2 in 82% of patients, with two pediatric patients experiencing grade 3 or 4. Erythematous maculopapular rashes and multilineage cytopenia were common, and three patients had grade 1 immune effector cell-associated neurotoxicity syndrome.
• Viral reactivations were universal, with adenovirus, Epstein-Barr virus, cytomegalovirus, human herpes virus 6, and BK virus frequently detected. Three patients had clinically significant posttransplant virus-related complications requiring substantial support. One pediatric patient developed a CD7-negative relapse approximately 3 months after transplant.

IN PRACTICE:

“Data from this early-phase study support the further investigation of BE-CAR7 T cells for the treatment of relapsed or refractory T-cell ALL in both children and adults in extended trial cohorts,” the study authors wrote. Among the open questions, they noted, are the molecular basis for CD7-negative relapse and whether the preparative regimen can be altered to reduce viral reactivations without diminishing anti-tumor efficacy.

SOURCE:

The study, led by Robert Chiesa, MD, Great Ormond Street Hospital for Children NHS Trust, London, England, was published online in The New England Journal of Medicine.

LIMITATIONS:

The study to date has drawn only on a single donor for all patients who received a dose of the investigational therapy; this situation may have contributed to the consistency of responses, the study authors wrote.

DISCLOSURES:

The study received support from the Medical Research Council, the Wellcome Trust, the National Institute for Health Research, and the Great Ormond Street Hospital Children’s Charity. Full disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.