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The most dangerous side effect of allogeneic blood stem cell transplantation, graft-versus-host disease (GvHD), has still not been sufficiently researched. The world's largest blood stem cell donor center DKMS wants to change that - it is the declared goal of the non-profit organization to improve the survival and healing chances of blood cancer patients. In the fight against GvHD, DKMS research teams have now launched two new scientific studies.
Every year, around 70,000 people worldwide are looking for a non-related matching blood stem cell donor. For them, an allogeneic stem cell transplant is often the only chance of survival and cure. Most of those affected suffer from a malignant disease of the hematopoietic system, for example leukemia. However, not all stem cell transplants lead to the desired success. Up to 50 percent of patients develop graft-versus-host disease, a side effect of stem cell transplantation. Symptoms may include skin rashes, abdominal pain, fatigue, or even damage to the mucous membranes of the gastrointestinal tract (see also mediacenter.dkms.de/news/world-science-day-2021/). GvHD can even be fatal.
How does graft-versus-host disease develop?
GvHD is an immune reaction. Each graft contains immune cells from the donor in addition to the actual stem cells. While the donated stem cells settle in the bone marrow of the recipient and build up the new hematopoiesis, the immune cells migrate through the recipient’s body. Ideally, they destroy cancer cells in the process and prevent the cancer from returning. However, if the donor's immune cells attack the patient's healthy cells because they recognize them as foreign, GvHD is the result. This is why it is so important that patient and donor are genetically compatible, i.e. that their HLA markers match as closely as possible: The closer the "match," the more likely it is that the transplanted immune cells will recognize the recipient's cells as the body's own "material".
With regard to how GvHD can be prevented or treated, many questions are still open. The DKMS Clinical Trials Unit (CTU), together with top research centers, now wants to address two of these questions in studies.
Study 1: Are there genetic variants on the donor side that could influence the risk of GvHD?
The goal of this study is to find genetic markers in donors that predict the severity of GvHD after transplantation. If the researchers find that transplants from donors with certain genetic variants are significantly less likely to result in severe GvHD in patients, these genetic markers could be considered in future donor selection.
The researchers are looking for immune response genes that carry such genetic variants - so-called single nucleotide polymorphisms (SNPs). A team of DKMS researchers analyzed more than 200 scientific publications and selected 35 promising SNPs. To find out whether there is a connection between the SNPs and the patient's disease course, the researchers are now analyzing donor samples from the Collaborative Biobank (CoBi) and patient data.
The CoBi was founded by DKMS together with many partners, including several university hospitals. Donors and patients provide the biobank with samples and data in encrypted form. This valuable information can then be used for blood cancer research and to optimize stem cell transplantation.
During the study, researchers will sequence a total of 6,000 samples in the regions of the 35 selected candidate variants. This way, they will to determine whether specific SNPs are present in the immune response genes of the donor samples studied. Subsequently, the results will be correlated with the occurrence and severity of the patient's GvHD symptoms. The scientists expect first results by the end of 2022.
Study 2: Comparison of two drugs against GvHD - do PTCY and ATG work equally well?
This study compares the efficacy of the two drugs, anti-thymocyte globulins (ATG) and cyclophosphamide. Both have been used for years to prevent GvHD in transplanted patients. The drugs work in different ways.
Anti-thymocyte globulins are antibodies that bind to T lymphocytes and other immune cells. This neutralizes these cells and weakens defense reactions. The antibodies are administered immediately before the upcoming transplant. They are intended to reduce the number of immune cells that trigger inflammation. This is how GvHD can be prevented.
Cyclophosphamide is given after transplantation. Therefore, it is referred to as "post transplant cyclophosphamide", abbreviated PTCY. Cyclophosphamide is a chemotherapeutic drug given on the third and fourth day after transplantation. The drug slows down inflammatory responses of immune cells. The administration reduces the likelihood of developing GvHD.
Both drugs have a significant anti-GvHD effect. However, to date, it has not been thoroughly investigated whether they are both equally effective against GvHD. To fill this scientific gap, DKMS will collaborate with 17 top research centers to conduct a joint clinical trial over a period of four and a half years. "After all participating clinics have been appropriately trained and the contracts have been signed, we will recruit the first patient," announces Sarah Trost, Team Lead of DKMS CTU's Clinical Research Team. The research team expects around 540 study participants. "If it turns out that both drugs have the same positive effect, physicians will be able to better tailor their treatment plans to individual patients," explains Sarah Trost. "If, on the other hand, we find that the therapies are not equally effective, the inferior therapy will subsequently no longer be offered."
For further information, this study can also be found on the ClinicalTrials.gov website using the identifier (NCT number): NCT05153226.
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