Genome-edited stem cells support safer targeted therapy in blood cancers

A transplant of genome-edited stem cells designed to protect healthy donor cells from cancer therapy has shown promise in patients with aggressive blood cancers.

The Phase 1/2 multicentre clinical trial involved thirty adults with acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS) at high risk of relapse. Researchers used CRISPR/Cas9 to remove a protein called CD33 from donor stem cells before transplantation. This modification protects the transplanted cells from CD33-targeted cancer therapies, which would otherwise damage both malignant and healthy blood-forming cells. All patients achieved successful engraftment, with blood cell production returning at similar rates to standard transplants.

'We are encouraged by the results of this study showing that a CD33-deleted stem cell transplant looks very similar to the outcomes of standard stem cell transplantation,' said Professor John DiPersio, director of the Centre for Gene and Cellular Immunotherapy at Washington University School of Medicine in St Louis, Missouri, who led the research published in Nature Medicine.

CAR-T cell immunotherapy has transformed treatment for some lymphoid cancers but has struggled to treat myeloid malignancies like AML and MDS. The challenge stems from target proteins on cancer cells also appearing on healthy blood stem cells. When immunotherapy attacks these shared targets, it can trigger severe toxicity and dangerous inflammatory responses while limiting the intensity of treatment that can safely be delivered.

The genome-edited stem cell product, tremtelectogene empogeditemcel (trem-cel), was manufactured by Vor Biopharma, which funded the study. Patients received a CD33-targeted antibody-drug conjugate after transplantation. While this therapy may help prevent relapse, its use following transplantation has previously been limited by liver toxicity and prolonged suppression of healthy blood cell production.

Nineteen patients received at least one cycle of maintenance therapy, maintaining healthy blood counts across all doses – confirming the genome edit successfully protected donor cells. Side effects mirrored standard transplants and included anaemia, low platelet counts, fever, infections, and graft-versus-host disease. Seven patients died during the study – four from cancer progression and three from transplant-related complications including kidney failure, liver toxicity, and sepsis. Median overall survival was just over 14 months.

The research team also published a case study of one patient with particularly aggressive AML who received the genome-edited transplant and subsequently underwent CAR-T cell therapy targeting CD33 after relapsing. That patient achieved complete remission and remained cancer-free at follow-up more than a year later.

'In the future, we are hopeful we will be able to combine this with CD33-targeted immunotherapies, such as CAR-T cells, and improve treatment options for patients with these very aggressive blood cancers,' said Professor DiPersio.

The study provides proof-of-concept that genome-edited transplants could enable the safer use of intensive CD33-targeted therapies in patients with high-risk blood cancers.