ROCKVILLE, Md. - In spite of the recently reported death of a gene therapy patient in France, an FDA advisory committee cautioned that issues arising from that study shouldn't cloud judgments on other gene therapy trials.
"It seems that, based on all the available data, there's an increased risk," Mahendra Rao, chairman of the FDA's Cellular, Tissue and Gene Therapies advisory committee, told BioWorld Today. "However, it seems that so far, the problems can't be related to a generalized problem that can be extended to all the trials."
The FDA meeting followed a halt in a French gene therapy study in patients with X-linked severe combined immunodeficiency disorder (X-SCID) after a third child developed cancer following treatment. Previously, one of the two prior children who had developed cancer after gene therapy died.
In response, the FDA's Center for Biologics Evaluation and Research in January called a halt to three U.S. studies testing gene therapy in patients with SCID, a fatal disorder if left untreated. Two were focused on X-SCID patients, while the third had been testing patients with adenosine-deaminase deficiency (ADA-SCID).
The FDA's Carolyn Wilson, also of the Office of Cellular, Tissue and Gene Therapies, told the committee that the latest French patient who developed cancer exhibited T-lymphocyte proliferation about 33 months after treatment. The patient had received gene transfer at 8 months of age, and she called it "eerily similar" that the three patients developed their cancerous effects about 30 months to 34 months after receiving gene therapy.
The latest "has responded well to steroid treatment and is in complete remission," Wilson noted, adding that among nine other patients who were treated, six have had no further intervention. She said that they continue to show a sustained clinical benefit following gene therapy.
Also of recent concern to the FDA was a report of a monkey that died from cancer six years after receiving gene therapy.
"The tumor had a vector," said Cynthia Dunbar, of the National Heart, Lung and Blood Institute, part of the National Institutes of Health. She added that "it's very likely that the gene transfer in some way precipitated the leukemia in this monkey."
Dunbar also said she has yet to uncover other reports of the same type of tumor, myeloid sarcoma, in other rhesus macaques, though she noted that most of the research animals are not allowed to sustain long lives.
There remain uncertainties as to the exact causes of the recent adverse events, though researchers postulated that side effects could arise from interactions caused by vectors used in gene transfers, as might be the case with the monkey, or related to the therapeutic genes themselves.
"I don't know how much clarity we have at this point," said panel member Daniel Solomon of the Scripps Research Institute, "because the mechanism is very confusing and complex."
Panel member Rebecca Buckley of Duke University Medical Center described findings that showed that SCID patients who are diagnosed and treated with bone marrow transplants at a very young age - not older than a few months - have a high rate of survival. As a result, she said she is lobbying for newborn screening of the disease.
Buckley, who has overseen bone marrow transplants in more than 100 SCID patients, added that "we have to think about SCID as 10 different diseases, because 10 different genes, when mutated, give you SCID."
But others on the panel noted that alternatives such as bone marrow transplantation aren't always effective options for SCID patients, and therefore further testing of the experimental gene therapy is warranted. The University of Southern California's Donald Kohn, who was testing ADA-SCID patients before the FDA stopped his study along with the two X-SCID trials, presented findings showing that ADA-SCID patients would benefit from continued gene therapy experiments. The committee members agreed.
"For patients who have failed bone marrow transplant, the risk-reward, despite the fact that there's much higher risk, is still reasonable," Rao said. "The basis for the problems when one thinks about X-SCID doesn't seem to extrapolate directly to ADA-SCID."
The committee members said that studies in ADA-SCID patients should move forward. They also stopped short of recommending that the FDA legislate limitations on further gene therapy studies, though they encouraged investigators to consider limiting doses based on the total vector copy number in transduced cells and the number of transduced cells, as well as redesigned retroviral vectors.
Others on the committee added that patient consent forms should clearly define patient risks. But in the end, the panel members were in consensus on careful monitoring of gene therapy trials going forward, especially a UK-based study in X-SCID patients.
"It seems that the highest concern should be for trials which are very similar to the trial that currently has the problem, the French trial," Rao said. "The closest to that is the British trial, over which we have no regulatory authority, but so far has not reported any problems. And they have been very good about sharing data."
A gene therapy conference is scheduled in Washington for next month.