T-cells that target common virus become tumor fighters
By Ruth SoRelle, M.P.H.
Crafting a tumor-fighter out of cells that fight a commonly occurring virus could improve the body's ability to fight off a devastating form of childhood cancer called neuroblastoma, said Baylor College of Medicine researchers in a recent report in the journal Nature Medicine.
"This is a way to convert a naturally occurring problem into a benefit in treating cancer," said Malcolm K. Brenner, M.D., Ph.D., director of the Center for Cell and Gene Therapy at BCM, Texas Children's Hospital and The Methodist Hospital, and professor of pediatrics and medicine at BCM.
Special virus-fighting T-cells
By using T-cells (special white blood cells in the immune system) that specifically target the Epstein-Barr virus that is commonly associated with mononucleosis), he and his colleagues extended the life of their cancer-fighting treatment.
They reported on using the new treatment in 11 patients with neuroblastoma that had come back.
"For the first time, we started to see tumor responses. We have one complete remission and others who have had stable disease for more than a year," said Brenner.
The patients responded after only the one infusion of cells because they last a long time in the body and their numbers can increase, said Brenner.
Receptor found in neuroblastoma cells
Brenner and his group added to these T-lymphocytes a particular receptor for a protein called diasialoganglioside GD2, which is found in human neuroblastoma cells.
Previous attempted to use T-lymphocytes with an artificial receptor directed to tumor cells proved disappointing because they disappeared from the body too quickly to have an anti-cancer effect. However, cytotoxic T cells that already have a natural receptor for the Epstein-Barr virus are continually activated by the presence of the virus, which is never eliminated from the body. Most people have been infected with Epstein-Barr at one time or another,
"We took the T-lymphocytes' with specificity for Epstein-Barr and added another receptor," said Brenner. "In effect they trampoline off the virus and onto the tumor."
Constant stimulations
These cytotoxic T-lymphocytes remain in the body because they are constantly stimulated by the ever-present virus. Their artificial antigen receptor enables them to latch onto and kill the cancer cells.
When the researchers put the artificial receptor into both ordinary T-lymphocytes and those that are stimulated by the virus into the 11 patients, they found that the cancer directed cells stimulated by the Epstein-Barr virus lasted as long as 18 months and at higher levels than the other cells.
Neuroblastoma
Neuroblastoma is a tumor of primitive cells that go on to form the sympathetic nervous system. Apart from brain tumors, it is the most common solid cancer of children, and accounts for 7 percent of all childhood cancers. In two-thirds of cases, it is not diagnosed until it has already spread to other parts of the body.
Brenner and his colleagues hope to improve the treatment to make the T-lymphocytes more potent cancer killers, he said. One way would be to add specific receptors for proteins that allow the T-lymphocytes to avoid the immune-dampening effects of the cancers.
After stem cell transplant
Another might be to give the treatment right after the patients receive a stem cell transplant. At that time, the number of tumor cells would be at its lowest and there would be a lot of signals telling the T-lymphocytes to increase in number.
Within the next year, they plan to add receptors for other cancers to the virus-specific T-cells and see if they get the same cancer-fighting effect.
The Cell and Gene Therapy Center is affiliated with the Dan L. Duncan Cancer Center at BCM.
Others who took part in this research include Martin A. Pule, Barbara Savoldo, G. Doug Myers, Claudia Rossig, Heidi V. Russell, Gianpietro Dotti,M. Helen Huls, Enli Liu, Adrian P. Gee, Zhuyong Mei, Eric Yvon, Heidi L. Weiss, Cliona M. Rooney and Helen E. Heslop, all of BCM.
Funding for this work came from the National Institutes of Health, the General Clinical Research Centers at BCM, and the Doris Duke Charitable Foundation.
