Developing a way to safely transplant bone marrow represents one of the great success stories in treating blood cancers such as leukemia and lymphoma. Still today, however, many patients who receive a transplant with donor cells suffer complications such as graft-versus-host disease (GVHD) — when immune cells from the donor attack tissue in the recipient — or relapse, when the underlying cancer comes back.
Researchers have known for decades that the makeup of bacteria in the gastrointestinal tract can impact how a patient fares following a transplant. In recent years, advances in computing power and genetic sequencing technologies have allowed Memorial Sloan Kettering researchers to get a clearer picture of how specific bacterial types in the gut affect risk of GVHD.
Now a new study of MSK transplant patients has found a link between the presence of a particular bacterial group in the intestinal tract and a lower risk that the patient’s leukemia or lymphoma will return after stem cell transplantation. Patients harboring this bacterial group, made up primarily of the bacterium Eubacterium limosum, had their cancer come back at a significantly lower rate.
“If this association is confirmed, the bacteria could serve as a useful biomarker to guide patient treatment, and possibly point to targets for therapies to improve survival after transplant,” says MSK medical oncologist Jonathan Peled, who helped lead the study.
An essential next step will be to see whether this association holds true at other institutions that perform transplants.
The finding was reported in the Journal of Clinical Oncology by Dr. Peled along with Marcel van den Brink, Head of the Division of Hematologic Oncology, physician-scientist Robert Jenq (who recently joined the University of Texas MD Anderson Cancer Center), and additional researchers from MSK and other institutions.
Unclear Protective Process
The researchers studied all of the intestinal microbes (called the microbiota) contained in stool samples taken from 541 patients just before and just after an allogeneic transplant, which uses cells from a donor. They then examined the relationship between various bacterial types and whether the patients’ disease relapsed over the following two years. They found that only 19.8% of patients who had Eubacterium limosum in the gut relapsed during that period, while 33.8% of patients without Eubacterium limosum relapsed.
The researchers are unsure whether or how the bacteria may exert a protective effect or how directly that effect is imparted. It’s possible that the bacteria somehow interact with the host’s immune system or the immune cells within the transplant graft — or both.
Dr. van den Brink, who has helped lead much of the recent research at MSK on intestinal bacteria and transplant outcomes, says this finding provides more evidence that microbiota changes have a big impact. Patients undergoing bone marrow transplants have a major disruption in gut bacteria, both from receiving powerful antibiotics to relieve and prevent infection and from changes in diet and nutrition during the course of care.
“You can put this finding into a row of recent studies showing that bacteria in the gut can have a big impact on tumor growth and immunity against tumors,” he says. “The next question is: Can we find this association in other patient groups at other transplant centers? We might find that the same kind of association exists but with a completely different bacteria — that would not surprise me.”Back to top
An Immune Interaction
In addition to looking for the same bacteria–relapse link at other institutions, the researchers hope to shed light on the mechanism that might be responsible for this association. Does this bacterial group somehow influence the donor immune cells to hold cancer at bay so it does not rise again? Does it secrete a metabolite, such as a fatty acid, that is absorbed into the bloodstream that influences the immune response? If that metabolite is identified, could it be isolated and given to transplant patients?
Drs. Peled and van den Brink say these answers will be found mainly through conducting experiments in animals and performing a new, more sophisticated method of genetic analysis, called shotgun sequencing, on the bacteria itself. Shotgun sequencing decodes a genome by shredding it into smaller DNA fragments that are then assembled by computer programs that find which genes and synthetic pathways are present in the sample.
“This newer approach lets us find out quickly how many genes a bacteria has for making a different metabolite, which gives clues to what they may be secreting,” Dr. Peled says. “This will provide insight into the biology of what’s actually happening and how it may affect the immune response.”Back to top