Aggressive blood cancers such as acute myeloid leukemia and myelodysplastic syndrome remain among the hardest cancers to treat successfully.
These diseases affect the bone marrow, where blood cells are made, and they can spread rapidly through the body. Many patients initially respond to chemotherapy, but the cancer often returns.
For people with high-risk disease, stem cell transplantation is frequently the best chance for survival. During this procedure, patients receive healthy blood-forming stem cells from a donor after their own diseased bone marrow is destroyed. The donor cells then rebuild the patient’s blood and immune system.
Although stem cell transplants can be lifesaving, they are also dangerous and complicated. Patients remain at risk for severe infections, organ damage, graft-versus-host disease, and cancer relapse even after the procedure appears successful.
In recent years, doctors have also become excited about CAR-T cell therapy, a form of immunotherapy that engineers immune cells to recognize and attack cancer. CAR-T treatments have shown remarkable success against some blood cancers, but they have been far less effective for cancers such as AML and MDS.
One major reason is that the target proteins found on cancer cells are also present on healthy blood stem cells. This creates a serious problem because the immune therapy may destroy healthy cells along with the cancer.
Researchers at Washington University School of Medicine in St. Louis believed they might have found a way around this obstacle. Their new clinical trial used CRISPR gene editing to remove a protein called CD33 from donor stem cells before transplantation.
The study, published in Nature Medicine, suggests the strategy may protect healthy donor cells and improve the safety of future cancer-targeting therapies.
The research involved 30 adult patients with AML or MDS considered at very high risk of relapse. The patients were treated at Siteman Cancer Center and several other medical centers in the United States and Canada.
CD33 was chosen because it appears on many AML and MDS cancer cells. However, healthy blood stem cells also carry the protein. This overlap has limited the usefulness of CD33-targeted treatments because the therapies can unintentionally destroy healthy blood production.
Researchers believed that deleting CD33 from donor cells could solve this problem. If healthy donor stem cells no longer carry CD33, therapies directed against CD33 might focus only on remaining cancer cells.
The donor stem cells were modified using CRISPR technology before transplantation. The engineered product is called trem-cel.
After the transplant, patients also received a CD33-targeted maintenance treatment called gemtuzumab ozogamicin. This treatment uses an antibody linked to a cancer-fighting drug to specifically target CD33-positive cells.
Normally, this therapy can damage healthy blood cells and cause severe side effects, limiting its use after transplantation. The researchers hoped the edited donor cells would be protected because they no longer carried CD33.
The results suggested the approach worked largely as intended. All patients achieved successful engraftment within about one month, meaning the donor stem cells settled into the bone marrow and began producing blood cells.
Researchers found that blood counts remained relatively stable during the maintenance therapy, suggesting the edited donor cells avoided much of the damage typically seen with CD33-targeted treatment.
The study also showed that platelet recovery occurred at rates similar to standard transplants. Overall survival averaged slightly more than 14 months.
However, the treatment still carried significant risks. Patients experienced side effects commonly seen after stem cell transplantation, including infections, fever, anemia, low platelets, and graft-versus-host disease.
Seven patients died during the trial. Four deaths were linked to the cancer progressing, while three were caused by transplant-related complications such as sepsis, kidney failure, and liver toxicity.
The researchers also reported a separate case involving a patient with extremely aggressive AML who relapsed after receiving the CD33-deleted stem cell transplant. The patient was later treated with CD33-targeted CAR-T cell therapy using immune cells from the same donor.
Remarkably, the patient entered complete remission and remained cancer-free for more than one year afterward. Blood production also recovered successfully using donor cells lacking CD33.
The researchers believe these results could open the door to a completely new treatment strategy for difficult blood cancers. By editing healthy donor cells before transplantation, doctors may eventually create safer environments for highly targeted immunotherapies.
The study also highlights the growing role of CRISPR gene editing in medicine. CRISPR allows scientists to remove or change specific genes with far greater precision than older technologies. Researchers hope this approach may eventually help treat many diseases beyond cancer.
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Source: Washington University School of Medicine in St. Louis.
