By Michael Smith, North American Correspondent, MedPage Today
Published: May 03, 2012
Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner
- This report evaluates results from three clinical trials designed to use retroviral-modified chimeric antigen receptor T cells for treatment of HIV.
- Note that genetically modified immune cells were still present and active 11 years after they were infused without any obvious toxicity.
A gene therapy approach to HIV treatment is long-lasting and safe, researchers reported.
In long-term results from three small clinical trials, genetically modified immune cells were still present and active 11 years after they were infused, according to Carl June, MD, of the Perelman School of Medicine at the University of Pennsylvania, and colleagues.
And there have been more than 540 patient-years of follow-up without any toxicity related to the gene therapy, suggesting that the adverse event rate is extremely small, June and colleagues reported online in Science Translational Medicine.
The findings are in contrast to many other studies of gene therapy, in which modified cells lasted only weeks or months, the researchers noted. As well, in some high-profile studies, gene therapy led to serious adverse effects, including leukemia.
Those results had cast a shadow over gene therapy, but there has been renewed interest in the approach recently among HIV researchers, after a stem cell transplant apparently cured an HIV-positive patient by making his immune cells resistant to the virus.
Earlier this year, researchers reported that gene therapy with the same aim was both safe and well tolerated, with at least some hints of efficacy.
The findings don't bear directly on current gene therapy research in HIV, because investigators are mainly trying to modify stem cells, according to John Rossi, PhD, of City of Hope in Duarte, Calif.
"HIV doesn't infect just T cells," Rossi told MedPage Today. By modifying stem cells, he and other investigators hope to create an immune system in which all cells are resistant to HIV infection.
But he said it is good news that modified T cells can be safely used and made to last.
"If you have a safe way to modify cells in patients with HIV, you can potentially develop curative approaches," June said in a statement.
In the current study, he and colleagues report on what happened to 43 patients treated from 1998 to 2005 with infusions of their own CD4-positive T cells, genetically modified so they would bind specifically to envelope protein of HIV.
The so-called chimeric antigen receptor -- dubbed CD4-ζ (zeta) -- included native CD4 cells, linked to the CD3-ζ signaling chain, which is involved in antigen recognition.
As part of the study protocols, the researchers took yearly peripheral blood mononuclear cell samples, as well as monitoring the patients for toxicity related to the infusions.
The researchers reported that of 221 samples tested over 11 years, 212 still contained modified T cells. A mathematical model indicated that the half-life of the cells was greater than 16 years, suggesting they could persist for decades.
Continued observation of the patients has not turned up any sign of toxicity and the researchers said their analysis suggests an adverse event rate of less than 0.0068 per person-year.
That works out, they said, to about one event every 145 years.
They cautioned that the safety profile might not apply to all gene transfers; it might be specific for T cells or for the specific modification used in these studies.
The modified cells remain active against HIV, they added.
The studies were small and patients received a relatively small number of the cells, so the researchers did not observe a significant treatment effect, although viral loads did fall in the wake of the therapy, according to co-author Bruce Levine, PhD, also of the University of Pennsylvania.
But in the light of the safety and durability information, he told MedPage Today, it might be useful to try the approach again, this time with more modern techniques.
Among other things, he said, gene transfer techniques have improved and researchers would want to try to engineer a better chimeric receptor, as well as increasing the dose of engineered cells.
"If we gave [patients] more, we might well see an effect," Levine said.
While the gene transfer approach has been criticized as an expensive "boutique therapy," he said, if it could be done once or twice and result in control of HIV, it might be cost-effective compared with life-long anti-retroviral therapy.
One sidelight of the original studies is that the durable effect was achieved without having to destroy and re-seed the immune system, as has been needed in stem cell therapies and T cell treatment for cancer.
The study had support from the NIH, the University of Pennsylvania Center for AIDS Research, and the Department of Defense. The journal said June reported no competing interests.
Primary source: Science Translational Medicine
Scholler J, et al "Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells" Sci Transl Med 2012; 4: 132ra53; DOI: 10.1126/scitranslmed.3003761.