CRISPR-edited, donor-derived CAR-T shows early promise for T-cell acute leukemia
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Key takeaways:
- Two of the first three base-edited CAR7 recipients achieved complete molecular remission by day 28 after infusion.
- The preliminary safety profile appeared similar to that of other CAR T-cell therapies.
Two teenagers with T-cell acute lymphoblastic leukemia achieved complete molecular remission after receiving a donor-based investigational chimeric antigen receptor T-cell therapy, phase 1 study results showed.
The patients — a 13-year-old girl and a 15-year-old boy — were among three study participants in the United Kingdom to receive the experimental CAR T-cell therapy as part of a first-in-human trial evaluating the use of base-edited T cells for the treatment of T-cell malignancies.
Data from an interim analysis published in The New England Journal of Medicine suggested the treatment has been safe.
“It is really crucial that children affected by cancer who failed standard of care have access to innovative strategies in the context of clinical trials such as this,” Robert Chiesa, MD, consultant in pediatric bone marrow transplantation and cell therapy at Great Ormond Street Hospital for Children, said in a press release. “A research hospital such as Great Ormond Street Hospital offers the ideal setting for developing experimental approaches that might offer hope to children with otherwise very poor prognosis.”
Background and methodology
Researchers from Great Ormond Street Hospital, in cooperation with colleagues at University College London Great Ormond Street Institute of Child Health, developed a novel method for base editing of donor T cells.
The approach uses CRISPR-based gene editing technology and avoids “double-stranded breaks in DNA that can trigger translocations and other chromosomal aberrations,” investigators wrote.
The process used healthy donor T cells that were transduced with a lentivirus to express a CAR specific to the CD7 protein (CAR7), a known antigen expressed in high proportion on the surface of T-cell ALL cells.
Investigators then used base editing techniques to inactivate genes encoding CD52 to prevent lymphodepleting serotherapy, CD7 to prevent CAR7 T-cell fratricide, and the beta chain of the alpha-beta T-cell receptor to prevent graft-versus-host disease.
“Base editing involves making changes to single letters of DNA code to change signals and stop genes being expressed, without having to make a cut to the chromosomes,” Waseem Qasim, MD, PhD, professor of cell and gene therapy at University College London, said in the release. “It works really well for engineering T cells.”
Study participants underwent preconditioning lymphodepletion followed by a single infusion of CAR7 at a dose of 0.2 × 106 to 2 × 106 CAR T cells per kg. Protocol called for patients who achieved molecular remission by day 28 to undergo allogeneic HSCT.
Safety and feasibility served as the study’s primary outcome measurements.
Key findings
The first patient — a 13-year-old girl with relapsed T-cell ALL who underwent previous allogeneic HSCT — achieved molecular remission by day 28 after infusion with a single dose of base-edited CAR7.
She then received nonmyeloablative allogeneic HSCT that resulted in successful immunologic reconstitution, and she remained in ongoing remission as of the study’s data cutoff date.
A second patient — a 15-year-old-boy with disease that switched from mixed-phenotype acute leukemia to CD7+ T-cell ALL — received intrathecal treatment with base-edited CAR7. He achieved molecular remission by day 28 and was awaiting allogeneic HSCT as of the data cutoff date.
The third study participant — a 13-year-old boy with cortical T-cell ALL — died of opportunistic infection following treatment with based-edited CAR7.
Investigators reported treatment-related toxicities like those seen with other CAR T-cell therapies, including cytokine release syndrome, cytopenia and opportunistic infections.
Clinical implications
Results thus far show anti-leukemia efficacy from base-edited CAR7 with no unanticipated toxicities, according to researchers. The findings support further evaluation of the investigational therapy, they added.
“It’s nice to be able to see the fruits of a long period of work coming together from multiple teams and being brought into play for new treatments,” Qasim said in the release. “It’s still early, and we need more follow up and to treat more patients to know how it might impact treatments long term.”
References:
Chiesa R, et al. N Engl J Med. 2023;doi:10.1056/NEJMoa2300709.
University College London. Further hope for base-edited T-cell therapy to treat resistant leukaemia (press release). June 14, 2023.
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