Terminating 'Serial Killers' makes cell therapy safer
Cancer treatment with stem cell transplantation and specially modified immune system components called T-cells can enhance the chance of recovery from diseases such as leukemia or lymphoma because each T-cell can act as a serial killer of many cancer cells. Despite their benefits, however, the T-cells are uncontrolled and can produce severe and even lethal side effects. Now these treatments can be made safer by using a new termination system that almost immediately controls the therapy if things go wrong, said researchers from the Center for Cell and Gene Therapy at Baylor College of Medicine, Texas Children’s Hospital and The Methodist Hospital in a report in the current issue of the New England Journal of Medicine.
Dr. Malcolm Brenner, director of the Center for Cell and Gene Therapy, and his colleagues have been developing special anti-tumor cells called T-cells that harness the body’s immune system to fight cancer. Although they and other investigators have successfully developed ways of targeting these cells to attack cancer, the T-cells can grow in number in the patient and survive many years, which make any side effects severe, long-lived and often uncontrollable. These treatments would be much safer if researchers could turn the cells off if patients suffered a bad reaction. However, no effective technology existed to rapidly accomplish this outcome.
New safety switch
The Cell and Gene Therapy researchers tested the new safety switch in patients who developed graft versus host disease after they received a stem cell transplant as part of their cancer therapy. 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 T-cells from a related donor, which help to kill any remaining cancer and to fight infections. However, sometimes the transplanted T-cells attack the patient’s own tissues. The result is graft versus host disease, which is disabling and often fatal. Turning off the T-cells in the transplant would stop the disease. The new treatment accomplishes just that – killing more than 90 percent of the cells within 30 minutes after a single treatment.
To make the safety switch, the researchers introduced into the T-cells a gene called iCasp9, which produces programmed cell death. When the patient receives a specific drug, it joins together two single molecules of iCasp9 (a process called dimerization) and makes it active – rapidly triggering the death of the cell.
"The patients come in with a severe itchy rash all over their bodies," said Brenner, also a member of the NCI-designated Dan L. Duncan Cancer Center at BCM. "We give them the drug and we can literally watch the rash melt away."
Helps immunity recover
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 (a blood cancer). 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.
This kind of rapid cellular braking medicine would extend to other T-cell therapies, he said, such as that recently reported in the New England Journal of Medicine, and may ultimately be applicable to other forms of stem cell therapy in general, hastening their safe introduction to the clinic.
Others who took part in this work include Dr. Antonio Di Stasi, Dr. Siok-Keen Tey, Dr. Gianpietro Dotti, Yuriko Fujita, Dr. Alana Kennedy-Nasser, Dr. Caridad Martinez, Dr. Karin Straath, Enli Liu, April G. Durett, Bambi Grilley, Dr. Hao Liu, Dr. Conrad R. Cruz, Dr. Barbara Savoldo, Dr. Adrian P. Gee, Dr. Robert A. Krance, Dr. Helen E. Heslop, Dr. David M. Spencer, and Dr. Cliona M. Rooney, all of BCM and Dr. John Schindler of The University of Texas Southwestern Medical School.
Funding for this work came from the National Heart, Lung, and Blood Institute and the National Cancer Institute, both part of the National Institutes of Health. The dimerizing drug was supplied by Bellicum Pharmaceuticals.
Dr. Brenner holds the Fayez Sarofim Chair. Dr. Spencer holds the Roger D. Rossen, M.D. Endowed Professorship.