Memorial Sloan Kettering physician-scientists are investigating a novel way to wipe out a potentially devastating complication that commonly occurs in patients who have received a stem cell or organ transplant as part of their treatment. These transplants can weaken the immune system, allowing a dormant pathogen called Epstein-Barr virus (EBV) to awaken and trigger a new malignancy.
Epstein-Barr virus (EBV) is present in most people, but in those with a healthy immune system it may produce only mild symptoms or even go unnoticed. However, in someone whose immune system is not fully functional, EBV can cause infected cells to divide uncontrollably as a cancer in the lymph nodes, spleen, or even the liver, lungs, or brain. This can occur in both children and adults.
“This kind of transplantation complication is life threatening,” says Memorial Sloan Kettering pediatric oncologist Susan Prockop. “Historically, the life expectancy for somebody who developed an EBV lymphoma, the most common of these malignancies, was less than 30 days.”
A Third-Party Remedy
The new approach involves giving these patients T cells (a type of immune cell) from a healthy third-party donor — someone not related to either the patient or any donor who previously gave blood or tissue to the patient. Once infused, the third-party T cells attack all EBV-infected cells, cancerous or not, and destroy them.
The third-party donors need to have been exposed at some point to EBV so their T cells recognize the virus. They also are matched with the recipient based on human leukocyte antigen (HLA) type. HLAs are proteins that vary between people and function as the “fingerprint” of an individual’s immune system. The HLA match need not be perfect but should be close enough that the donated T cells attack EBV effectively in the recipient’s cells.
The T cells from the third-party donor’s blood are cultured in the laboratory in a way that expands them to sufficient numbers to be therapeutic after infusion, a process that takes about two months.
Using a third-party donor — rather than the person who donated stem cells for the original transplant — can offer several advantages, Dr. Prockop explains. “Some stem cell or organ donors have never had EBV, so their T cells wouldn’t recognize the virus in the recipient effectively,” she says. “Also, the patient may develop the EBV malignancy before cells from these donors have been collected and expanded in the laboratory, and the patient can’t wait two months for this to occur. Finally, EBV malignancies can develop in non-transplant patients — their immune systems may be weakened from other causes.”Back to top
The researchers have now characterized more than 300 cell lines that are frozen and stored, meaning they are available as a kind of “off-the-shelf” resource when needed. This is essential in treating EBV malignancies, which tend to progress very rapidly.
Dr. Prockop says the third-party T cells have so far shown no undesirable side effects and the researchers are conducting a phase II clinical trial establishing the treatment’s long-term safety and effectiveness. The new approach has been used on 53 patients, both children and adults, and results have been promising. “We’re now being referred patients from all over the country to treat these EBV malignancies,” she says.
On March 1, Dr. Prockop presented results at the 2014 BMT Tandem Meeting in the Dallas area focused specifically on the treatment of EBV lymphoma using third-party T cells. Of 35 patients treated for this aggressive malignancy, 17 had complete remission, six had partial remission, and two had stable disease — meaning the lymphoma did not progress.
“These patients have absolutely no other recourse, so it is very striking to have such an effective therapy with no side effects,” she says.
Dr. Prockop adds that caring for patients allows her to see the clinical problem first-hand and drives home the urgency of finding a solution for patients who have already been through an ordeal and now have a terrible complication. “It’s the best version of oncology — the excitement of seeing our efforts make these children better while studying these EBV-directed T cells, trying to figure out how they work, why they work, and how we can make it better to help patients with no other options.”Back to top