PITTSBURGH, August 26, 1996 — Transplant patients who develop cancers that are not responsive to standard treatment may benefit from an infusion of cells from their own immune system that have been activated to kill tumors, according to researchers from the University of Pittsburgh Medical Center (UPMC). Results of their preliminary study of this novel approach were presented today at the XVI International Congress of the Transplantation Society in Barcelona, Spain.
The complication of developing tumors following organ transplantation is called post-transplant lymphoproliferative disease (PTLD). Certain cells of the patient's own immune system, some of which may be associated with the Epstein-Barr virus, proliferate and tumors result. About 2 percent of transplant patients will eventually develop PTLD. Standard treatment involves temporarily reducing or eliminating the doses of drugs that are taken to suppress the immune system and prevent organ rejection; however, in only 30 to 50 percent of patients are tumors responsive to this therapy and shrink or disappear. PTLD can be fatal in as many as 80 percent of those patients affected with it, according to some reports.
Of the seven patients in the UPMC study -- individuals whose tumors were not responsive to a reduction in immunosuppression or in whom this intervention was not a clinical option -- four had complete remission of their tumors after single infusions of their own immune cells that the researchers manipulated to fight PTLD.
Researchers removed immune cells from blood taken from the patients and grew them in a culture for six to 10 days with Interleukin-2 (IL-2), a naturally occurring hormone that stimulates these cells to become lymphokine-activated killer (LAK) cells. The LAK cells, which can kill a variety of tumor cells while sparing normal ones, were then infused back into the patients' bloodstreams.
"We reasoned that the patient's own cells could be directly manipulated to increase the degree of anti-PTLD activity," said Michael A. Nalesnik, M.D., associate professor of pathology in the division of transplantation pathology at the UPMC's Thomas E. Starzl Transplantation Institute.
While cancer researchers have long known IL-2 to be a powerful anti-tumor agent, the UPMC team, led by Dr. Nalesnik, had to devise a way in which its transplant patients with PTLD could benefit from IL-2 without risking rejection of transplanted organs. Because IL-2 is a potent stimulator of immune cells, the researchers feared that delivering it directly into the body could trigger an immune attack not only against PTLD but also against the patients' organs.
"For this reason, we decided not to directly administer IL-2 to our patients, but rather let the IL-2 activate their immune cells in an isolated laboratory setting. The patients, by receiving an infusion rich in LAK cells, would still reap the benefits of IL-2," explained Dr. Nalesnik and his collaborators from theUniversity of Pittsburgh Cancer Institute.
The patients in the study were recipients of double-lung, liver, heart/lung, heart and kidney transplants and developed PTLD during the past year, one just 63 days after transplantation and one nearly 12 years later. Six of seven patients were considered candidates for the treatment with Il-2 activated LAK cells when, after being taken off their immunosuppressants for at least three weeks, their tumors continued to grow. The seventh patient had several episodes of rejection and could not risk being taken off anti-rejection medication.
The four patients whose tumors completely regressed included those whose tumors developed several years after transplantation. Three of the patients are alive between 11 and 14 months after the infusion therapy. One patient died three months after the treatment from pneumonia but had no evidence of PTLD at autopsy.
"Results are particularly encouraging since the responders included those with late-onset tumors. These late onset lesions are usually less responsive than many of the early-arising tumors," reported Dr. Nalesnik.
The three patients in the study who did not have complete regression of their tumors had aggressive cancers that also tested negative for the Epstein-Barr virus. Further study in at least 20 more patients will help researchers determine if the presence of Epstein-Barr virus or the type and stage of cancer more strongly contributes to a patients' success or failure with the promising treatment.
In addition to Dr. Nalesnik, the following researchers worked on the study: Abdul Rao, M.D., D. Phil; Adrianna Zeevi, M.D.; John J. Fung, M.D., Ph.D.; Hiro Furukawa, M.D.; Elaine Elder, Ph.D.; Wytold Rybka, M.D.; Si Pham, M.D.; Mark Jordan, M.D.; Albin Gritsch, M.D.; David Rowe, Ph.D.; Theresa Whiteside, Ph.D.; and Thomas E. Starzl, M.D., Ph.D.