Graft-vs-host disease is a common and potentially deadly complication following bone marrow transplants, in which immune cells from the donated bone marrow attack the recipientâ€™s body.
Winship Cancer Instituteâ€™s Ned Waller and researchers from Childrenâ€™s Healthcare of Atlanta and Yerkes National Primate Research Center were part of a recent Science Translational Medicine paper that draws a bright red circle around aurora kinase A as a likely drug target in graft-vs-host disease.
Aurora kinases are enzymes that control mitosis, the process of cell division, and were first discovered in the 1990s in yeast, flies and frogs. Now drugs that inhibit aurora kinase A are in clinical trials for several types of cancer, and clinicans are planning to examine whether the same type of drugs could help with graft-vs-host disease.
Leslie Kean, a pediatric cancer specialist at Seattle Childrenâ€™s who was at Emory until 2013, is the senior author of the STM paper. Seattle Childrens’ press releaseÂ says that Kean wears a bracelet around her badge from a pediatric patient cured of leukemia one year ago, but who is still in the hospital due to complications from graft-vs-host. Read more
As a followup to yesterday’s post on following troublemaker cells in patients with lupus, we’d like to highlight a recent paper in Blood that takesÂ a similar approach to studying how the immune system comes back after bone marrow/blood stem cell transplant.
Leslie Kean, MD, PhD
The paper’sÂ findings have implications for making this type ofÂ transplant safer and preventing graft-versus-host disease.Â In a bone marrow/blood stem cell transplant, to fight cancer, doctors are essentially clearing out someone’s immune system and then “planting” a newÂ oneÂ with the help of a donor. What this paper shows is how much CMV (cytomegalovirus) distorts the new immune system.
CMV is often thought of asÂ harmless — most adults in the United States have been infected with CMV by age 40 and don’t get sick because of it. But in this situation, CMV’s emergence from the shadows forces some of the new TÂ cells to multiply, dominating the immune system so much that it creates gaps in the rest of the T cell repertoire, which canÂ compromise protective immunity. Other seemingly innocuous viruses like BK cause trouble in immunosuppressed patients afterÂ kidney transplant.
The senior author, Leslie Kean, moved from Emory to Seattle Children’s Hospital in 2013, and her team began these studies here in 2010Â (a host of Emory/Winship hematologists and immunologists are co-authors).Â This paperÂ is sort of a mirror image of the Nature Immunology paper on lupus because it also uses next-generation sequencing to follow immune cells with DNA rearrangements — in this case, T cells. Read more
Low doses of the anti-cancer drug imatinib can spur the bone marrow to produce more innate immune cells to fight against bacterial infections, Emory and Winship Cancer Institute researchers have found.
The findings suggest imatinib, known commercially as Gleevec, or related drugs could help doctors treat a wide variety of infections, including those that are resistant to antibiotics, or in patients who have weakened immune systems. The research was performed in mice and on human bone marrow cellsÂ in vitro, but provides information on how to dose imatinib for new clinical applications.
â€œWe think that low doses of imatinib are mimicking â€˜emergency hematopoiesis,â€™ a normal early response to infection,â€ says senior author Daniel Kalman, PhD, associate professor of pathology and laboratory medicine at Emory University School of Medicine.
Imatinib, is an example of a â€œtargeted therapyâ€ against certain types of cancer. It blocks tyrosine kinase enzymes, which are dysregulated in cancers such as chronic myelogenous leukemia and gastrointestinal stromal tumors.
Imatinib also inhibits normal forms of these enzymes that are found in healthy cells. Several pathogens â€“ both bacteria and viruses â€“ exploit these enzymes as they transit into, through, or out of human cells. Researchers have previously found that imatinib or related drugs can inhibit infection of cells by pathogens that are very different from each other, includingÂ tuberculosis bacteriaÂ andÂ Ebola virus. Read more
Before all the excitement about embryonic stem cells, doctors were using hematopoetic â€“ that is, blood-forming — stem cells. Hematopoetic stem cells can replenish all the types of cells in the blood, and are the centerpiece of transplantation as treatment for diseases such as multiple myeloma or leukemia. They can come from two different places: directly from the marrow of a donorâ€™s hip bone, or indirectly from the donorâ€™s blood after a drug nudges the stem cells out of the bone marrow.
Most hematopoetic stem cell transplants in the United States now use the indirect method of obtaining the stem cells. Until this fall, gold-standard randomized clinical trial results were not available to say which method is best for patient outcomes. Winship Cancer Institute hematologist Ned Waller was a key co-author of a study that was published in October in the New England Journal of Medicine addressing this question.
The trial involved 48 centers enrolling 551 patients as part of the Bone Marrow and Clinical Trials Network (BMT CTN).Â Waller helped design the study, and his lab at Winship analyzed the cells in each type of graft as the central core lab for the trial.
The study found no significant difference in the overall Ray Ban Italia survival rate at two years, and no difference in relapse rates or in acute graft-versus-host-disease (GVHD). However, there was a significantly higher rate of chronic GVHD with the use of blood stem cells.
GVHD, a difficult and sometimes life-threatening complication for this type of transplant, involves damage inflicted by the transplant recipientâ€™s new immune system upon the liver, skin and digestive system.
This finding will generate serious discussion among leaders in the transplant field about whether bone marrow or peripheral blood stem cell transplantation is a better treatment option, Waller says. A text Q + A with him follows.
What was surprising about the results of this study?
The equivalent survival was expected, and the increased chronic GvHD in recipients of blood stem cell grafts was suspected. What is surprising is that the relapse rate was similar between the two arms, in spite of the PBSC arm having more chronic GvHD.
The accompanying editorial argues bone marrow should be the standard for unrelated-donor transplants. Do you agree?
Yes, with the exceptions that Fred mentioned: patients with life-threatening infections and patients at high risk for graft rejection.
What are the differences, procedurally, between bone marrow and peripheral blood as sources for hematopoetic stem cell transplant?
Donating bone marrow involves a two or three hour surgical procedure requiring general anesthesia, in which bone marrow is removed from the hip bone with a needle and syringe.Â For peripheral blood stem cells, the donor undergoes five days of injections of granulocyte colony-stimulating factor and then a four-hour apheresis procedure to harvest stem cells from the blood. Blood stem cell donors have bone pain during the 5-day period of cytokine treatment, and bone marrow donors have more discomfort early after donation, but symptoms for both BM and PBSC donors have typically resolved by four weeks after donation.
What proportion of each is now in use here?
Marrow is the graft source in about 25% of recipients of grafts from unrelated donors, 10% in recipients of grafts from related donors.
What proportion of HSCT is unrelated donor?
For allogeneic transplants, about 60% receive grafts form unrelated donors (33% matched related donors and 7% mis-matched related donors).
What kind of information does this study provide oncologists/hematologists about which option to use in which situation?
Marrow should be preferred in recipients of grafts from unrelated donors when the conditioning regimen is myeloablative [substantially damages the patient’s existing bone marrow].
Does it depend on the type of leukemia/myeloma, the age or other conditions of the patient etc?
This study only enrolled patients with acute leukemia and MDS [myelodysplastic syndrome]. It excluded patients with myeloma or lymphoma. Ages included children, adults up to 60.
What other types of studies in this area are being conducted at Winship?
We are studying the role of different constituents in the graft (BM and PBSC) to determine which are most important in shaping transplant outcomes (relapse, GvHD). We have an active pre-clinical research program utilizing mouse models to address specific questions related to engraftment cell homing and specific pathways related to immune activation. In addition, we will participate in a clinical trial of a new way of mobilizing blood stems that avoids the need for five days of G-CSF and uses a CXCR4 antagonist called plerixafor to mobilize PBSC. The properties of the plerixafor-mobilized PBSC may be more similar to BM cells with respect to GvHD.
This title for a 2008 paper in Journal of Immunology, from pathologist Andrew Gewirtz’s laboratory, is astounding. Flagellin can protect against all those things (in mice, of course)? What about bullets or heartbreak? What is flagellin?
Flagellin is a structural feature many bacteria have in common — courtesy of iGEM via Creative Commons
Flagellin is the main structural component of flagella, the miniature whips bacteria use to propel themselves.Â Several Emory scientists are investigating how flagellin could be used as a protective agent to strengthen the body’s innate defenses and also as a vaccine component.
Encouraged by Emory’s success, Edmund Waller, MD, PhD, director of Emoryâ€™s Bone Marrow and Stem Cell Transplant Center says, “While 3,000 is a nice round number, it’s the middle of a growing and successful program. After 3,000 procedures, I know we all look forward to the future of this program.â€