HIV patients given gene therapy more than a decade ago are healthy and the altered DNA they received remains stable in their bodies, according to a study that scientists say proves the treatment may safely be tested as a way to attack other illnesses.
All except two of 43 people treated with genetically-altered versions of their own infection-fighting T cells were healthy as many as 11 years later, according to the research reported today in the journal Science Translational Medicine.
Previous uses of gene therapy in experiments have suggested that leukemia caused by the viruses that transfer the genes to the cells might be a risk. Today’s finding allays that concern, enabling researchers to move beyond immediately life-threatening illnesses, such as HIV and cancer, said Bruce Levine, a study author and researcher at the University of Pennsylvania.
“We turned those cells into heat-seeking missiles directed against HIV-infected cells,” said Levine, head of the Clinical Cell and Vaccine Production Facility at the Philadelphia university’s Perelman School of Medicine. “What really surprised us was when we got those samples, not only could we detect the gene-modified cells but they appeared to be present at relatively stable levels.”
Because the therapy has been found to work safely over a significant period of time, the designer cells should be considered a platform technology that can also be used by scientists researching other diseases besides HIV, Levine in a telephone interview.
Designer T Cells
Each patient in the study cited today received at least one transfusion of their own immune cells between 1998 and 2005. The T cells were designed to look for an HIV protein and kill any infected cells they encountered, before the virus has a chance to mature.
“It’s like a controlled burn,” Levine said.
The U.S. Food and Drug Administration required the patients be followed for 15 years to see if any late-developing side-effects, such as cancer, might arise from the therapy. The patients were followed every year after their initial dose.
No gene therapy has been approved by the FDA. The field almost halted in 1999, when 18-year-old Jesse Gelsinger died within hours of being injected. Earlier, in a French trial, two of 10 patients acquired leukemia following gene therapy for “Bubble Boy disease,” or severe combined immunodeficiency.
Last year, Levine and co-author Carl June, also at the University of Pennsylvania, published research that used modified T cells to fight off leukemia in two patients. Both patients remain in remission 18 and 19 months after getting the treatment, Levine said.
‘No Good Options’
“In the case of our leukemia patients, they had no good options,” Levine said. “How do you do drug development if you’re always and only testing in the most-advanced patients? There has to be a point where there’s enough experience with the drug, in this case, the T cells, where you can test them with a less-advanced disease.”
Levine and June began working together when Levine joined June’s Navy research lab as a post-doctoral researcher on the HIV research. When June’s wife, Cynthia, was diagnosed with ovarian cancer in 1996, June was galvanized to see how his experience with the immune system might help cancer patients. He moved to the University of Pennsylvania in Philadelphia, where Levine joined him.
Today’s finding suggests the altered immune, or T cells, could continue killing HIV for decades, assuming the cells continue to decay at the same rate and depending on the dosage of the infusion, Levine said. It’s difficult to pinpoint the duration of effectiveness beyond nine years because of the limited numbers of samples, the study concluded.
When the cells were taken out of the patients and studied in the lab, they were still able to proliferate in the presence of HIV targets and attack, he said.
There are some limitations on the data, according to Michel Sadelain, director of the Center for Cell Engineering at Memorial Sloan-Kettering Cancer Center in New York.
First, the cells weren’t shown to be functioning in the patients, merely in the lab dishes. That doesn’t mean they aren’t functioning in the patients; it means that researchers should be cautious in interpreting that finding, said Sadelain, who wasn’t involved in the study.
Second, while the therapy was found to be safe, it didn’t bring HIV in the bodies of the patients studied down to undetectable levels, possibly because the dosage of T cells wasn’t high enough, Sadelain said. An ideal safety finding would be in a highly effective therapy, he said.
“It’s nonetheless encouraging,” said Sadelain, who also works with designer T cells.
His group is focused on leukemia, and he is collaborating with the Penn researchers to determine the most-effective way of treating patients.
“This adds to the rise of this approach,” he said of the latest finding. “It’s been over a decade in the making and it’s been met with relatively broad skepticism.”
Levine and June are also working with Sangamo Biosciences Inc., a Richmond, California-based biotechnology company that develops gene-regulation factors, on designer white-blood cells that mimic a mutant gene that blocks HIV from entering the cells
In September, Sangamo presented data at a scientific conference showing that its gene therapy helped six patients fight off HIV without use of other drugs. The most common side effect for patients was a persistent smell of garlic, the study found.
Today’s study was funded by the National Institutes of Health in Bethesda, Maryland, the University of Pennsylvania Center for AIDS Research, and the Infectious Diseases Clinical Research Program, a U.S. Department of Defense project. Some of the study patients were recruited by Cell Genesys, now a unit of BioSante Pharmaceuticals Inc.