Among them are Yiouli Ktena, MD at the Johns Hopkins University in Baltimore (USA) and Esteban Arrieta-Bolaños, PhD at the University Hospital in Essen (Germany). They received the award in 2020 and 2021, respectively, based on their promising research projects in the field of hematopoietic stem cell transplantation (HSCT).
Dr. Yiouli Ktena is a specialist in pediatric hematology and oncology and conducts research at the renowned Johns Hopkins University. "For some of my patients, stem cell transplantation, which involves replacing the patient's immune system with a donor's immune system, is the only chance for a cure. These include children and young adults with cancer who have certain types of aggressive leukemia and lymphoma, or non-malignant diseases such as bone marrow failure," she explains. Although the procedure is life-saving for many diseases, it also carries the risk of serious complications - one of which is graft-versus-host disease (GVHD).
GVHD is a severe immunological reaction in which the graft turns against the recipient. Each graft contains immune cells from the donor in addition to the actual stem cells. While the donor stem cells settle in the patient's bone marrow and create a new, healthy blood and immune system, the foreign immune cells migrate through the recipient's body after transplantation. Ideally, they destroy cancer cells and prevent the cancer from returning, a process known as the graft-versus-tumor effect. However, if the donor's immune cells attack the patient's healthy cells because they recognize them as foreign, GVHD will occur.
"The current treatments available for GVHD put patients at increased risk of infection and cancer recurrence," says Dr. Ktena. "This is a big problem: If you curb the immune response of the transplanted donor cells, GVHD decreases, but the patient also becomes more susceptible to infection and cancer recurrence." Her research approach therefore goes in a different direction: she wants to epigenetically manipulate the donor cells responsible for GVHD in favor of the patient. "Our goal is to contain GVHD while maintaining the potency of the new immune system, or the graft-versus-tumor effect."
To accomplish this, she is studying the role of epigenetics in the development of GVHD. Epigenetics is a scientific area of interest that encompasses the changes that determine the expression of certain genetic traits independently of the DNA sequence - on the smallest level, this would be the decision whether a gene is "switched on" in the cell or not. In the field of epigenetics, the enzyme DNMT3A (DNA (cytosin-5)-methyltransferase 3A) plays an important role. The enzyme is able to mark the DNA by a chemical bond. This labeling makes the DNA practically invisible to the cell and it is no longer actively used by the cell. DNMT3A thus regulates important cellular processes. It has been observed that patients who have received a stem cell transplant from a donor carrying a mutation in DNMT3A are more likely to suffer from GVHD – at the same time they are less likely to experience a relapse. Interestingly, DNMT3A mutations are not rare. According to one study from 2020, 6.2% of the total population carried a DNMT3A mutation, with an age-related increase in prevalence.
Using genetically modified T cells, Ktena was able to successfully recreate the DNMT3A phenomenon in the laboratory. She was thus able to examine these cells for their epigenetic characteristics. In particular, she looked at which DNA segments were chemically modified and how they differed from normal T cells. Interestingly, these cells were overall very similar to normal cells, with the exception of very localized differences that were surprisingly specific. The altered DNA regions are located within genes that are directly related to the activation, proliferation, and differentiation of T cells.
Dr. Yiouli Ktena
"These data are significant in three ways. They demonstrate the importance of epigenetic regulation in modulating T cell activation after stem cell transplantation and provide us with a basis for studying epigenetic signatures of donors to predict the risk of GVHD in recipients. Second, they also allow us to consider epigenetic modifications as a therapeutic tool. Finally, the data can be used as a platform to discover new gene pathways that could potentially also be used as therapeutic targets," says Dr. Ktena. “Now going through all this data and sorting through all the pathways that we have identified is truly a labor of love – but we are getting there!”
One interesting target has already emerged from the data: CCR9, a chemokine receptor that directs T cells to the gut - one of the main areas where GVHD starts and manifests. CCR9 has been targeted in patients with inflammatory bowel disease and could now potentially be targeted in the context GVHD as well. "We have already started some of these experiments targeting CCR9, and our lab is looking forward to the promising results," says Dr. Ktena.
Another successful young researcher is Dr. Esteban Arrieta-Bolaños from University Hospital Essen working in the lab of Prof. Dr. med. Katharina Fleischhauer. The group is specialized on human leukocyte antigens (HLA) and their recognition by T cell receptors especially important in the context of HSCT and CAR-modified immune cells.
Although the search for a hematopoietic stem cell donor usually aims at a complete HLA match between donor and patient, most transplants with unrelated donors are performed with mismatches at the HLA-DPB1 locus. Although HLA mismatches in general have negative consequences, it is also known that some HLA-DP mismatches are permissive and hence better tolerated by the patient. In addition, these well-tolerated HLA-DP mismatches have been shown to provide effective leukemia control without significantly increasing transplant-related mortality. This was the starting point for Dr. Arrieta-Bolaños’ research project. He wanted to know what modulates T cell alloreactivity in permissive mismatches, and to do so he and his colleagues examined the immunopeptidome of HLA-DP, i.e. the repertoires of DP-bound peptides.
"We found that permissive HLA-DPB1 mismatches have significantly higher peptide repertoire overlaps compared to their non-permissive counterparts, resulting in a lower frequency and diversity of alloreactive T cell receptor clonotypes," Dr. Arrieta-Bolaños explains. "Moreover, we found that this permissiveness depends on the peptide editor HLA-DM. This intracellular protein helps selecting the peptides to be loaded onto membrane-bound major histocompatibility complex (MHC) class II proteins. These loaded MHC proteins may then be recognized by CD4+ T cells. In the absence of HLA-DM, the peptide repertoire changes and expands, which means that recognition by T cells increases and consequently permissiveness decreases." The research group’s findings were published last year in Blood.
Based on the results, HLA-DM has become one of Dr. Arrieta-Bolaños’ main proteins of interest. One of his goals is to find HLA-DM polymorphisms to study how they influence peptide editing and thereby T cell alloreactivity. Another goal is to identify T cells that show alloreactivity only when HLA-DM is not functional. These T cells would then react specifically against the membrane-bound HLA-DP when its immunopeptidome is deregulated. This type of T cell could theoretically be directed specifically against B cell leukemia cells, since B cells naturally have lower HLA-DM activity. An even bigger step being actively investigated would be the application of CRISPR-Cas9, which could delete HLA-DM from tumor cells completely, maximizing alloreactivity against them. HLA-DM-sensitive, HLA-DP-specific T cell therapy could then be applied to target the malignant cells.
These various approaches mean a lot of work for the young scientist. Fortunately, he is now receiving support from Kulvara Kittisares, a new PhD student who joined the lab and who is actively working on his project. Together, they are in the process of starting many new experiments that will yield interesting results in the near future.
From left to right: Kulvara Kittisares , MD, PhD student; Esteban Arrieta-Bolaños, PhD; Joana Peters, Technical Assistant; Anastasiia Stoianova, MD student
When asked what led him to the HSCT field, he explains, "I first heard about stem cell transplantation when I was still in high school; my dad, who did some work in this field, explained to me that this therapy could cure people of their blood cancer. I was impressed by that and became very interested in this field ever since. It's such a crazy therapy when you think about it: you take one person's immune system and put it into another human being. And the amazing thing is that it gives very sick patients a chance to be cured – it is really rewarding to work on it."
Are you a passionate researcher in the field of hematopoietic cell transplantation and cell therapy? Or do you know someone who is? Outstanding young researchers are encouraged to apply for the John Hansen Research Grant 2023. Interested applicants can submit their documents until December 2, 2022. For more information, please visit https://professional.dkms.org/research-grant or email email@example.com.