Gene therapy trials for sickle cell disease halted after two patients develop cancer


A company has stopped its clinical studies of a promising gene therapy for the blood disorder sickle cell disease after two people who participated developed leukemia-like cancer. Bluebird bio is now investigating whether a virus it uses to deliver a therapeutic gene caused the cancers, reviving old concerns about the risks of this approach.

It’s also possible the cancers stemmed from chemotherapy the patients received to prepare their bodies for the gene’s delivery. “This is really a sad development whatever the cause,” says Donald Kohn of the University of California, Los Angeles, who has led gene therapy trials for sickle cell and other diseases.

In the bluebird bio trials, scientists remove a patient’s blood stem cells and treat them in a dish with a modified virus related to HIV. It carries DNA encoding the oxygen-carrying protein hemoglobin and is intended to compensate for the patient’s defective gene for this molecule. After this step, called “ex vivo” because a patient’s cells are treated outside the body, doctors infuse the cells back into the person. Fourteen people who have received the latest version of the bluebird bio therapy are now virtually free of the pain crises their sickled red blood cells once caused.

But today came the news that a patient treated 5 years ago in one of the studies has developed acute myeloid leukemia (AML). Another has myelodysplastic syndrome (MDS), which can develop into AML. A previous patient in the same study developed MDS in 2018, but tests showed it had likely resulted from the DNA-damaging chemotherapy that wipes out a patient’s bone marrow cells to make room for treated cells.

Still, the gene therapy could play a more direct role. In past small clinical trials, several boys with an inherited immune disorder who received similar ex vivo gene therapy developed leukemia. In those cases, a mouse virus ferrying a curative gene into cells landed its genetic cargo in a location that turned on a cancer gene. Researchers then switched to a potentially safer delivery system, a lentivirus that also inserts the genes it carries into the host’s DNA but in sites less likely to trigger a cancer gene. A 2019 report that a monkey treated with a lentiviral gene therapy had developed a leukemia-like condition suggested, however, that the cancer risk had not been eliminated.

Bluebird bio told investors today that although its scientists have found the virus inserted DNA into the chromosomes of the leukemia cells of the treated sickle cell patient with AML, they don’t yet know its location. They’ll look to see whether the viral DNA landed near a known cancer-promoting gene, perhaps driving its activity. The company says these tests should take a matter of weeks.

Meanwhile, bluebird bio has also halted sales in Europe of an approved treatment that uses the same vector to treat the blood disorder beta-thalassemia. The company’s stock price plunged 38% today.

Another sickle cell disease clinical trial that uses the CRISPR gene-editing tool to turn on a fetal form of hemoglobin reported promising results last year. That treatment doesn’t rely on a virus to deliver CRISPR; instead, it uses a zap of electricity to get CRISPR editing molecules into cells in a dish. However, CRISPR itself can make off-target effects and rearrange chromosomes, and whether that can trigger cancer may not be known for several years.

The bluebird bio news comes on the heels of a December 2020 report that a patient in a gene therapy trial for hemophilia had developed a liver tumor. The company, uniQure, planned to explore the possible role of its vector, an adeno-associated virus (AAV). Even though AAVs are supposed to be safer than lentiviruses for gene therapy because they are not designed to insert their cargo into a cell’s genome, animal studies have found they sometimes can., 18 February 2021