Innovations in cord blood transplantation may make this option more successful in children and much more widely available to adults, which is good news for the many people who need a hematopoietic cell transplant but cannot find a matched donor. Doctors at Fred Hutchinson Cancer Research Center, a founding organization of Seattle Cancer Care Alliance (SCCA), are leading the way in cord blood transplant research. As this source of stem cells expands, the transplant donor pool expands as well, making stem cell transplants available to a greater number of patients.
Only minutes old, counting from the moment of birth, the immune cells in cord blood haven’t yet seen the world or its many pathogens. This makes cord blood a good match for virtually any transplant recipient—even when it isn’t a good match.
It Pays to Be Naïve
Cord blood is the blood that remains in the umbilical cord when a mother and newborn are separated. Most cord blood is discarded. But some is collected in banks so that people who need stem cell transplants can use it. This is one possible source of stem cells for a hematopoietic cell transplant. The other sources are bone marrow and peripheral blood, the blood that circulates around your body.
The stem cells from cord blood are more versatile than those from bone marrow or peripheral blood, simply because the infant donor’s immune system is immature. The immune cells in cord blood are naïve. They aren’t yet educated against foreign invaders, such as bacteria and viruses. So there’s less likelihood of an adverse interaction between the transplanted cells and the recipient’s cells. As a result, they don’t need to be such a close match to a recipient’s tissue in order to be transplanted successfully.
“Cord blood transplant has the advantage of allowing greater tissue-matching disparity,” says Colleen S. Delaney, MD, MSC, a researcher at the Hutchinson Center. By using cord blood, she says, “you open up transplantation to patients who need it but can’t get it.”
This is especially important for patients who belong to ethnic minorities or have mixed ethnicity, because they often have trouble finding a donor whose tissue type closely matches their own.
There is a greater risk with cord blood transplants that the recipient’s body will reject the transplanted cells, which may be too naïve to defend themselves. But doctors have treatments to help prevent rejection, and fewer than 10 percent of recipients experience it, estimates Dr. Delaney.
The process surrounding a cord blood transplant is not much different than the process surrounding a bone marrow or peripheral blood stem cell (PBSC) transplant using a donor who is not related to the recipient. With thousands of births each day in the United States, cord blood is a readily available source of stem cells for transplantation, and collecting it poses no risk to the donor.
Wanted: A Few (More) Good Stem Cells
According to Dr. Delaney, the number of stem cells per unit of cord blood is much smaller than the number per unit of donated bone marrow or peripheral blood—about 10 percent of what a patient receives in a conventional transplant. So cord blood provides a smaller cell dose. The cell dose is the number of transplanted stem cells per kilogram of body weight of the recipient. This means the same unit of cord blood provides a greater cell dose in a smaller recipient than it does in a larger recipient.
“The cell dose is the main predictor of how someone will do post-transplant,” Dr. Delaney says. A lower cell dose usually means a poorer outcome.
Why? When there are fewer stem cells transplanted, these cells take longer to engraft—to establish themselves in the recipient’s body and begin producing blood cells. The average time to engraftment is about 15 days for a PBSC transplant, 20 days for a bone marrow transplant, and 21 to 35 days for a cord blood transplant. Longer time to engraftment means a longer time without the white blood cells that guard against infection.
Though some recipients of a cord blood transplant may engraft in just a few weeks, some may take nearly two months. So a transplant of cord blood carries a higher risk of infection and poorer chance of survival than a transplant of PBSCs or bone marrow. In cord blood transplants there’s also a higher risk that the transplanted cells will not engraft at all.
Engrafting faster means reducing your risk of infection, recovering faster, being able to return home from the hospital sooner, and enjoying a better quality of life. Delayed engraftment is more of a problem for adults than children; larger people, by virtue of their greater size, need a greater cell dose. Even though a single unit of cord blood stem cells provides an adequate cell dose for most children, especially smaller children, they do experience delayed engraftment compared to a PBSC or bone marrow transplant. So doctors are still looking to improve children’s outcomes with cord blood transplants, too.
Dr. Delaney is developing a promising method to increase the number of stem cells available from a single cord blood sample so the sample is even more effective in children and is useful in larger recipients too. Read more about Dr. Delaney’s research into cord blood transplantation at the Hutchinson Center.
Are Two Units Better Than One?
The question then is: How do we increase the cell dose in cord blood transplants so that recipients get the advantages with fewer disadvantages? Dr. Delaney and other researchers are developing two solutions.
One solution is to give recipients two units of cord blood—especially larger recipients for whom the cell dose from a single unit is likely inadequate. In a double transplant, the recipient gets one unit each from two different umbilical cords, so two different donors.
Doctors wondered at first whether giving cells from two donors would increase the risk of graft-versus-host disease (in which transplanted cells see the recipient’s cells as foreign and attack them) or whether the two sets of transplanted cells would attack each other. But so far they are pleased with the results of clinical studies.
In a study in which patients receive either a single-unit or double-unit transplant based on their weight and the cell dose of the available units, overall survival has been improved and the risk of rejection is now lower. Results of the study helped doctors establish a cell-dose threshold, or minimum number of cells required for transplant, and showed that patients who meet this threshold—whether this means they receive one unit or two—have less risk of rejection. However, it still takes longer than doctors would like for the transplanted cells to engraft.
Expanding Immature Stem Cells
This leads us to the second solution: Culturing stem cells from cord blood in the lab before the transplant in order to expand the cell dose and spur faster engraftment. “This has been tried before, but never has it been shown to be clinically effective,” says Dr. Delaney. She hopes her upcoming studies in humans will change all that.
The activity in our own bones provides a model for Dr. Delaney’s experiments. Healthy bone marrow is an inexhaustible source of stem cells. The marrow constantly makes new stem cells, each of which takes one of two courses: either it divides into two stem cells or it matures into whichever type of blood cells the body needs at the time. The idea behind culturing stem cells in the lab is to place the cells in a dish on a growth medium that will prompt the same division that normally happens in our bodies.
Up until now, when researchers tried to culture stem cells, the cells tended to mature into blood cells, which rendered them useless for transplant. The trick has been to find a way to prevent this maturation. “We want to give them the right signal to say ‘Stay a stem cell! Stay a stem cell!’” says Dr. Delaney.
She seems to be onto something. Dr. Delaney is using a special protein that is known to regulate stem cell choices in the bone marrow and other hematopoietic tissues. When she cultures the cells in the presence of this specially manufactured protein, the stem cells do tend to stay young and to divide—and they seem primed for quicker engraftment than a typical unit of cord blood. In animal experiments at the Hutchinson Center, mice receiving transplants of cord blood that was expanded using Dr. Delaney’s method have engrafted in only 10 days.
Banking on a Breakthrough
In a clinical study that opened in the summer of 2006, researchers made the protein and cultured the cells in facilities at the Hutchinson Center. All patients in the study received two units of cord blood: one unit of cells that were expanded in the lab (expanded) and one unit of cells that were not manipulated (normal).
The clinical study was designed to test the hypothesis that the expanded unit will engraft sooner, providing a first wave of defense against pathogens more quickly than an unexpanded unit. "After several weeks, the cells from the expanded unit may begin to burn out, but by then the unexpanded unit should have engrafted and be ready to take over,” says Dr. Delaney. “This is a way of providing someone with protection against infection early on.”
“If it works, it’s going to be the first time anyone’s done this,” according to Dr. Delaney, though researchers at other facilities are exploring other ways to expand cord blood, so far no one has found a technique that’s shown benefit to patients.
In 2010, results of the study showed that on average it took 14 days for the expanded cells to engraft, compared to an average of four weeks for the normal cells. And 70 percent of patients were still alive with no evidence of disease and with sustained, complete engraftment. Tests revealed that the recovery of white blood cells early post transplant were derived predominantly from the expanded cells.