Gene-edited stem cell transplant shows promise for blood cancers and immunotherapy

Researchers at Washington University School of Medicine have successfully tested a gene-edited stem cell transplant for aggressive blood cancers. This new approach shields healthy cells from immunotherapy, potentially improving survival rates for leukemia patients

Aggressive blood cancers such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) often require stem cell transplants as a curative measure, but recurrence remains a major issue.

While CAR-T cell therapy has revolutionized treatment for some cancers, it has struggled with myeloid malignancies. This difficulty arises because the target proteins used to identify cancer cells are also present in healthy donor stem cells.

When immunotherapy is used against these targets, it often destroys the healthy blood stem cells alongside the cancer. This leads to severe toxicity and dangerous inflammatory responses. Furthermore, the treatment’s effectiveness is reduced because the immunotherapy diverts energy to attacking healthy cells rather than focusing solely on the malignancy.

Gene editing to shield healthy cells

To address this problem, a team led by Dr. John F. DiPersio at WashU Medicine utilised CRISPR gene-editing technology to modify donor stem cells. The researchers removed a specific protein, CD33, from the donor cells. This protein is a common target for immunotherapy because it appears on the surface of myeloid cancer cells.

Crucially, CD33 is only found on blood-forming cells and is not necessary for their normal function. By removing this protein from the donor cells, the healthy immune system becomes invisible to CD33-targeted therapies.

This allows doctors to use aggressive immunotherapies to kill any remaining cancer cells without harming the transplanted immune system that the patient needs to survive.

Results of the clinical trial

The phase 1/2 multicenter clinical trial involved 30 adult patients with high-risk AML or MDS. These patients received the gene-edited stem cell product, known as trem-cel. The study found that all patients achieved successful engraftment by day 28, meaning the edited cells successfully populated the bone marrow and began producing blood. These timelines matched those seen in standard, non-edited transplants.

As a proof of concept, patients received a maintenance therapy called gemtuzumab ozogamicin, which targets CD33. In standard transplants, this drug causes significant damage to blood cells. However, patients with the gene-edited cells maintained healthy blood counts across various doses. This confirmed that the genetic modification successfully protected the healthy donor cells from the anti-cancer drug.

Future treatment implications for aggressive blood cancers

The success of this trial provides a foundation for more advanced combinations of gene editing and immunotherapy. The researchers also highlighted a separate case study involving a patient with highly aggressive AML. This patient received a CD33-deleted transplant followed by CAR-T cell therapy after a relapse. The patient achieved complete remission and has remained cancer-free for over a year.

The study concludes that gene-edited stem cell transplants could make immunotherapy a viable option for a wider range of aggressive blood cancers. By shielding healthy cells, researchers hope to improve the safety and effectiveness of treatments for patients who currently have very few options.