Pinpointing causality
At bluebird bio, investigation into the possible “genetic gymnastics” of the lentivirus vector is focusing on where it integrates into the genome – whether it harpoons an oncogene like the gamma retroviral vectors, or affects genome stability, Dr. Gregory explained. To be causative, the affected gene must be a “driver” of the cancer, and not just a “passenger.”
Another suspect is busulfan, a drug used to “condition” the recipient’s bone marrow, making room for modified stem cells. “It’s possible that busulfan is the main problem, as it is a carcinogen unto itself,” said Paul Knoepfler, PhD, a stem cell researcher at the University of California, Davis.
In addition to the two more recent reports of complications, a third trial participant, who had participated in a phase 1/2 trial, developed MDS in 2018 and died of AML in July 2020. The cancer cells from that patient did not contain viral vectors and the MDS was attributed to busulfan conditioning.
Nick Leschly, chief of bluebird, pointed out the importance of clinical context in implicating the vector. Because SCD itself stresses the bone marrow, patients already face an increased risk of developing blood cancer, he said. “Now layer on other risks of the gene therapy. It’s challenging because we’re dealing with patients who have life expectancy in the mid 40s.” Previous treatments, such the antisickling drug hydroxyurea, may also contribute to patient vulnerability.
A patient’s view
SCD affects more than 100,000 people in the United States, and about 20 million globally. Charles Hough is one of them. He can attest to the severity of the disease as well as the promise of gene therapy
Mr. Hough was diagnosed at age 2, and endured the profound fatigue, pain crises, and even coma characteristic of severe cases. He cited his “rebirth” as Sept. 25, 2018, when he received his first modified stem cells at the National Institutes of Health. Mr. Hough told his story a year ago in a webinar for the National Organization for Rare Disorders. This news organization caught up with him in light of the clinical trial hold.
Although the preparative regimens for the gene therapy were tough, his sickle cell symptoms vanished after gene therapy. Even hearing about the current hold on the clinical trial, Mr. Hough doesn’t regret his participation.
“I had a lot of friends who passed because of the complications from sickle cell. I was always worried that I wouldn’t live to see the next day. Now I don’t have that stress hanging over my head and I feel like I can live a normal life. Becoming sickle cell free was my dream.”
A version of this article first appeared on Medscape.com.