UF Scientists Find Immune System Cells Fight Cancer's Return, Predict Outcome So

March 10, 2004

GAINESVILLE, Fla. — By measuring levels of cells crucial to marshaling the forces of the immune system, University of Florida researchers have been able to predict with greater accuracy the likelihood cancer patients who have received a blood stem cell transplant will go into remission or suffer a relapse and die.

Known as dendritic cells, these captains of the immune system normally initiate the body’s response to infection or disease, ordering a veritable molecular military of soldier-like cells to the front lines. Remarkably, when dendritic cells are produced in large enough numbers after blood stem cell transplantation, they appear to single-handedly launch the body’s fight against the return of blood-borne cancers, without attacking a patient’s healthy tissues.

Until recently, doctors largely presumed that successfully battling leukemia and related cancers would require the use of powerful drugs or infusions of cells altered to trigger recognition of malignant cells, enabling the immune system to better target them. The new findings, reported in the journal Blood, raise the hope of someday using patients’ own naturally occurring dendritic cells to attack their cancer.

“This is the first study to demonstrate that dendritic cells by themselves can fight off cancer,” said the study’s lead author, Dr. Vijay Reddy, an assistant professor of hematology and oncology at UF’s College of Medicine. “It’s the first study in any cancer patient to show that if you don’t have enough dendritic cells the cancer comes back. And it’s the first study in the bone marrow transplant arena that shows that large numbers of dendritic cells are important to having a good immune system after transplant to avoid death after transplant.

“Essentially, if you have dendritic cells in your blood it’s good for you; if you don’t have them it’s bad,” said Reddy, who also is affiliated with the UF Shands Cancer Center.

Each year, an estimated 30,000 patients undergo a bone marrow or peripheral blood stem cell transplant for a diagnosis of leukemia or another blood disease. Both types of transplantation aim to restore patients’ blood stem cell counts after their own stem cells have been wiped out by high-dose chemotherapy or radiation therapy used to treat cancer. After they are infused into the bloodstream, stem cells take up residence in the bone marrow, where they give rise to the immune system’s infection-fighting white blood cells, red blood cells or platelets.

An increasing number of researchers have become interested in dendritic cells, evaluating their use in the development of cancer vaccines and assessing their effectiveness in priming the immune system to fight prostate, breast and other cancers. But the UF study was the first to discover that in and of themselves they are highly predictive of outcome, and thus presumably powerful in their own right.

“Up to now, to gauge prognosis the most important things we’ve been looking at are how well the donor and recipient are matched, the kind of disease they’re receiving the transplant for and how well the treatments given before the transplant have led to cancer control,” said study co-author Dr. John Wingard, a professor of medicine at UF’s College of Medicine and director of the Bone Marrow Transplant Program at Shands at UF medical center.

In the study, UF physicians took blood samples from 50 patients within two to four weeks after they received a bone marrow or peripheral blood stem cell transplant from a donor. Most were being treated for leukemia, lymphoma or multiple myeloma. Patients with a low dendritic cell count were nearly 12 times more prone to cancer relapse in the study period, which lasted on average nearly a year and a half. They also were more than three times as likely to develop graft-versus-host disease and ultimately were nearly four times more likely to die.

Researchers are still puzzled why some patients boasted high levels of dendritic cells, whereas others had low levels. They evaluated how many cells of various types – including dendritic – were in the donor graft, but found no correlation with the number of dendritic cells produced after transplantation. Learning more about the phenomenon will help them discover ways to optimize dendritic cell counts after transplantation.

“If we measured the levels of dendritic cells in the person’s blood at the time of engraftment and discovered they were low, then perhaps we could boost with additional cells from the donor,” Wingard said. “That could have enormous therapeutic importance.”

Interestingly, patients who had large numbers of dendritic cells also were less likely to suffer a deadly complication of transplantation, graft-versus-host disease, in which transplanted cells – the graft – don’t discern between healthy tissues and cancer and attack both.

“Essentially, when the immune cells from the donor in the transplant graft get into the patient, these cells look at the patient and say ‘Hey, this is not my body. I’m Joe Smith but this is Joe someone else,’” Reddy said. “The cells can literally attack the body, causing graft-versus-host disease. The same cells, however, also look at the cancer and say, ‘Hey, this doesn’t belong here.’ They can fight the cancer, therefore causing graft-versus-leukemia, which is a beneficial effect. So what we need to do is identify these cells that can have the graft-versus-leukemia and not have this negative effect of fighting the rest of the body, because we want the cells to live in harmony in the patient except for fighting off the leukemia. This is our biggest problem as well as the most exciting area of research.”

Dr. Edmund Waller, director of the Bone Marrow Stem Cell Transplant Center at Emory University, said the UF findings represent “important observations regarding the role of dendritic cells in transplant outcomes.”

“These studies will lead to a better understanding of how relapse is controlled by allogeneic (from a genetically matched or similar donor) transplantation,” Waller said. “The increasing evidence that dendritic cell subsets are critical in the regulation of immune responses suggests novel approaches to improve allogeneic transplantation.”