Around half of the patients undergoing HSCT develop some degree of GvHD. Symptoms may include skin rashes, damage to mucous membranes of the gastrointestinal tract, the eyes and more rarely the genital tract leading to discomfort or pain or joint and muscle pain. GvHD may be triggered by mismatches between the donor and patient HLA alleles. As a result, the donor's immune cells recognize the patient's cells as foreign and initiate an immunological response. However, even in fully-matched donor-patient pairs, GvHD can cause severe harm. This already shows that HLA mismatches are not the only cause of the disease.
Clinical and subclinical infections in the post-transplant period may elicit adaptive and innate immune reactions which may trigger GvHD manifestation. The severity of these immunologic processes may vary between patients independent of the degree of HLA compatibility match. Part of this variation may be explained by polymorphisms in the donor genome. Small genetic variations in relevant immune response genes, such as those encoding interleukins, may, for example, tune inflammation. Also, “self” peptides which differ between patient and donor and are displayed by antigen presenting cells may trigger immune reactions. Genetic disparities may therefore influence the course of inflammation and thus the severity and duration of GvHD.
There are still many open questions on this topic: not only which other genetic markers besides the HLA alleles influence the occurrence of GvHD but also which treatment before and after transplantation is more or less effective in preventing the disease.
To further investigate this complex disease, DKMS CTU has already started the first study in 2020 and has recently received approval for the second study. Both studies are completely different in their design. They also target distinct topics. However, both studies will address substantial questions concerning GvHD.
The goal of this study is to identify additional genetic markers in the donor genome that could predict the severity of GvHD after transplantation. CTU scientists reviewed more than 200 scientific publications to identify candidate genes - mostly immune response genes - carrying SNPs (single nucleotide polymorphisms). "We analyzed the studies for both statistical evidence and biological coherence and selected the most promising candidates for further investigation," says Katharina Kahnt, Scientific Project Manager at the CTU.
To find a positive or negative correlation of genetic variants with the patient's outcome, lots of data is needed. This is where the Collaborative Biobank (CoBi) comes into play. CoBi was established by DKMS together with many other partners – including several university hospitals. It gives scientists from all over the world access to DNA samples and health-relevant data of donors, patients and donor-patient pairs - pseudonymized only, of course. This valuable information can be used to study hematological cancer and optimize blood stem cell transplantation.
As of today, the DKMS research team already sequenced 2,000 donor samples at genomic locations of 35 selected candidate SNPs; 4,000 more samples are still pending. The data will show whether certain polymorphisms are present in immune response genes. Subsequently, the results will be correlated with the occurrence and severity of the patient's acute GvHD symptoms. If the researchers find that transplants from donors with certain genetic variants are significantly less likely to lead to severe GvHD in patients, these genetic characteristics could be further criteria for optimal donor selection in the future. First results are expected by the end of 2022.
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. Antibody binding 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 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.
“At DKMS, we take every opportunity to improve treatment options for blood cancer patients. To this end, we are ourselves active in research and development with our Clinical Trials Unit. As part of our commitment to scientific research, we also award international research grants to outstanding young scientists,” summarizes Prof. Dr. med. Johannes Schetelig, Head of the CTU. Every year, DKMS awards the John Hansen Research Grant to excellent young scientists working in the field of cell therapy and transplantation in order to secure medical progress in the field of stem cell transplantation and cell therapy for the future.