“An effective safety switch is needed in a rising spectrum of cell therapies in order to protect against an array of toxic effects.”
Transplanted stem cells can cure patients with leukemia, lymphoma and rare genetic disorders but such procedures can trigger a potentially deadly response known as graft-versus-host disease as the immune cells that the transplanted cells give rise to can attack the patient’s healthy tissue.
Now researchers may have a way to halt and reverse this complication, which occurs in 30 to 80 percent of patients, depending on how well the transplanted cells are matched to the patient.
During stem cell transplantation, a patient’s own stem cells are eradicated with drugs or radiation. They then receive an infusion of blood-forming stem cells along with the immune system workhorses known as T-cells from a related donor. These T-cells help to kill any remaining cancer and to fight infections.
Researchers at Baylor Center for Cell and Gene Therapy at Baylor College of Medicine, Texas Children’s Hospital and The Methodist Hospital report in a study published in The New England Journal of Medicine that they were able insert a so-called “suicide gene” into the transplanted T-cells that are given to a patient along with stem cells. If a patient had an adverse response to the transplanted cells and the T-cells began attacking the patient’s own healthy tissue, a drug could be administered that would trigger the gene to activate and cause the cells creating the problem to self-destruct.
The researchers introduced into the T-cells a gene called iCasp9, which produces a process known as apoptosis or programmed cell death. By using a specific and otherwise inert drug called AP1903 that joins together two single molecules of iCasp9 to make it active —a process known as dimerization— it rapidly triggers the death of the cell.
“The patients come in with a severe itchy rash all over their bodies,” says Malcolm Brenner, director of the Baylor Center for Cell and Gene Therapy. “We give them the drug and we can literally watch the rash melt away."
In the study, the investigators gave the genetically modified T-cells to five patients who had received a blood stem cell transplant for relapsed leukemia. The transplanted T-cells divided in the patients’ blood over time and helped their immunity recover.
Four patients developed the potentially fatal graft-versus-host disease and received the special activating drug. Within 30 minutes, 90 percent of the T-cells were dead and their graft versus host disease began to disappear. The T-cells continued to decrease in number over the next 24 hours and their graft-versus-host disease went away completely. The small number of T-cells that remained were able to expand and were able to fight infections, but did not cause further graft versus host disease.
Michel Sadelain of the Center for Cell Engineering at Memorial Sloan-Kettering Cancer Center, said in an accompanying editorial that “An effective safety switch is needed in a rising spectrum of cell therapies in order to protect against an array of toxic effects.” He called the results of the study “compelling.”
The researchers said the rapid cellular braking medicine would extend to other T-cell therapies and may ultimately be applicable to other forms of stem cell therapy in general accelerating their safe introduction to the clinic. Houston-based Bellicum Pharmaceuticals has licensed the technology and is developing it as CaspaCIDe.
November 11, 2011
http://www.burrillreport.com/article-suicide_switch_.html