A transplant of healthy bone marrow stem cells may be the only hope for many patients with acute myeloid leukemia, a cancer affecting the production of healthy white blood cells. But after cancerous cells and a patient’s immune system have both been knocked out by radiation and chemotherapy, rebuilding that person’s immune capacity is a delicate, and potentially deadly, balancing act.
Mature donor immune cells provide short-term protection in the weeks after the operation. But these immune cells can also attack the host’s body, causing deadly graft-versus-host (GVH) disease. Now a novel way of preventing this reaction in bone marrow recipients, while protecting them from dangerous infections, has been developed by Italian and Israeli scientists.
The key is adding special immune-calming cells to the transplant material to prevent the donor immune cells from attacking the host, without compromising their ability to fight off dangerous infections. The researchers behind the work presented their findings this week at the Annual Meeting of the American Society of Hematology in New Orleans.
The problem of GVH disease is aggravated by the fact most transplants are provided by partially matched donors, because perfect matches–those with compatible proteins, called human leukocyte antigens–are usually unavailable.
When a patient and donor are not perfectly matched, high doses of stem cells, which mature into immune cells, can overcome rejection. The principle has been successfully pioneered in animal models by the coauthor of the new study, Yair Reisner of the Weizmann Institute of Science in Rehovot, Israel.
Following successful work in mice, Reisner joined forces with researchers at University of Perugia, Italy, to test the approach in more than 300 patients. The success rate for these partially matched transplants was found to be similar to that of transplants from matched donors picked from international bone marrow donor registries. To reduce the risk of GVH, mature immune T-cells have to be removed, meaning that post-transplant levels of life-threatening infection are high.
In the latest study, the Italian researchers infused 28 leukemia patients with a type of regulatory immune cell called CD4/CD25+ that had been selected from the donors’ own blood. These cells lessen T-cells’ tendency to attack host tissue, and have been shown to prevent GVH in animal studies. The “calming” immune cells have also been shown to keep other immune responses in check, including autoimmune attacks on the body’s own cells, but without hindering immune cells’ ability to fight infection.
The CD4/CD25+ cells were injected after the patients’ cancer cells and immune system had been knocked out by total-body radiation and chemotherapy. Next the patients were given transplants of bone marrow containing stem cells plus mature T-cells to help the depleted immune systems fight off viral and fungal infections in the short-term.
Of all the patients who received the entire treatment, only one developed GVH. In addition, the researchers claim that the reconstitution of the hosts’ immune systems appeared to occur more quickly than normal.
Study leader Massimo Martelli, head of hematology and clinical immunology at the University of Perugia, says the study shows that “T-regulatory cell-based therapy may be an innovative strategy to improve the outcome of patients who undergo bone marrow transplants.”
“We hope that this new method will reduce infection-related mortality and thus improve overall survival,” he adds.
Armand Keating, the director of hematology and a professor of medicine at the University of Toronto, says the new method is “an interesting and potentially important way of regulating T-cells” in stem cell transplants given to leukemia patients.
Keating adds that the method, if eventually validated, might prove particularly important for ethnic minorities who need marrow transplants. “The vast majority of donors on the registers are white people of northern European extraction. But with this method it might become possible to accept more partial matches from close family members such as siblings, or parents, if they are young enough,” he says. “With these kinds of transplants you need to move fast. Sometimes a day can make all the difference, so there isn’t time to find perfect matches on the register.”
However, Keating stresses that bigger, longer studies are needed. “With these patients, relapse is always a concern,” he says.