Projects

Principal Investigator: Eline Menu

Participants: Inge Oudaert, Yanmeng Wang, Chenggong Tu

Multiple Myeloma cells develop drug resistance, partially through interactions with the bone marrow (BM) microenvironment. In the team of Eline, we focus on the cross-talk between the tumor cells and the surrounding BM cells. Two interwoven topics are studied: metabolic changes induced by the BM environment in the tumor cells AND the involvement of extracellular vesicles, termed exosomes, in the cross-talk between BM stromal cells and MM cells. The team has access to a Zeta View particle analyzer to quantify exosomes and has published multiple papers demonstrating the involvement of exosomes not only in MM drug resistance but also in modulation of the BM environment. Since the BM is a naturally hypoxic region, MM cells need to adapt their metabolism to their surroundings. Moreover, the BM can induce a metabolic symbiosis by providing necessary metabolites to the tumor cells. The Menu team is now examining whether exosomes also play a role in this process.

Principal Investigator: Eline Menu

Participants: Arne Van der Vreken; Ellen Vennix

The bone marrow of multiple myeloma is an immune suppressive environment. Metabolites and secreted proteins contribute herein. By modulating these molecules we aim to create a less suppressive environment. Next to that, we are developing and  testing either passive or active anti-myeloma immunotherapies. The former will be done by generating nanobody-based chimeric antigen receptor (nanoCAR) T-cells against different myeloma cell antigens. We are also evaluating the latter by testing mRNA-based galsome vaccination. Galsomes are nanoparticles coated with a-GalCer, which can activate iNKT cells. In the past, we already showed the importance of iNKT cells in an anti-myeloma immune response. The included mRNA in these nanoparticles will trigger a specific CD8⁺ T-cell response towards the myeloma cells.  

Another objective is to improve the function of nanoCAR T-cells. (nanoCAR) T cells in a myeloma setting will be characterized via multi-omics to evaluate their exhaustion profile during disease development. We will evaluate new targets and test whether they can be usefull to overcome exhaustion, thereby extending T cell proliferative capacity. 

Principal Investigator: Kim De Veirman

Despite significant therapeutic advances, multiple myeloma remains incurable for the majority of patients as they inevitably relapse due to an incomplete eradication of residual cancer cells. In collaboration with the lab of Prof. Peter Croucher (Garvan Institute of Medical Research, Sydney, Australia) we recently demonstrated for the first time the presence of dormant myeloma cells by longitudinal intravital two-photon imaging. These quiescent cells were resistant to chemotherapy and demonstrated differences in gene expression compared to dividing cancer cells. Importantly, myeloma cell dormancy was a reversible state controlled by the endosteal niche containing osteoblasts and osteoclasts. Furthermore, gene array analysis identified some specific genes (e.g. Axl, CS1 and VCAM1) that were significantly upregulated in quiescent cells compared to proliferating cells. Importantly, these upregulated genes can serve as potential therapeutic targets to eradicate the remaining cancer cells after initial treatments and prevent relapse of myeloma patients.

The objective of this project is to specifically target residual cancer cells by the use of nanobodies. Compared to conventional antibodies, camelid-derived nanobodies are extremely small, very stable and easy to manufacture. Nanobodies are directed against tumor-specific antigens CS1 and Axl. Anti-CS1 nanobodies will be charged with beta- and alfa-emitting radionuclides killing both bulky and neighboring dormant cells. Antagonistic Axl-targeting nanobodies will be developed to reverse myeloma cell dormancy and subsequently increase chemosensitivity. This may provide a complementary approach to current treatments (e.g. chemotherapy, proteasome inhibitors), which target only the rapidly dividing myeloma cells.

Principal Investigator: Elke De Bruyne

Participants: Michiel De Coster, Lien Van Hemelrijck, Catharina Muylaert

The need for biomarker-driven personalized cancer treatment to improve patient outcome is becoming increasingly apparent. While cancer is typically considered a genetic disease, epigenetic lesions are well-known to also contribute to most, if not all, hallmarks of cancer. Moreover, an increasing number of non-recurrent mutations in epigenetic modifiers (epiplayers) has been reported in cancer cells, with the mutation frequency increasing upon relapse. Also in MM, numerous epigenetic defects, including locus-specific DNA hypermethylation of cancer-related and B cell specific genes, genome-wide DNA hypomethylation and somatic mutations, copy number variations and/ or abnormal expression patterns of a large variety of epiplayers, are linked with genomic instability, high risk disease, drug resistance and relapse. Epigenetic reprogramming of the MM cells using epigenetic modulating agents (EMAs) or so-called epidrugs holds promise to delay/overcome relapse, but the knowledge-gap in which epiplayers are key and the lack of selective inhibitors to target them severely hampers clinical implementation. Over the past 10 years, the De Bruyne team has gathered ample expertise in the field of MM epigenetics and has become highly skilled in working with murine 5TMM and xenograft models and applying gene-editing tools to manipulate MM cell biology and drug sensitivity within the context of the MM-BM niche. The De Bruyne team is now using this expertise to identify novel, clinically-relevant (epi)genetic defects involved in multiple myeloma progression and relapse and design new therapeutic (exosome-based) modalities correcting for these defects, to not only counter the drug resistance but also overcome the current EMA-related toxicity issues.

Principal Investigator: Ivan Van Riet

Participants: Marleen Bakkus, Rik Schots, Wouter De Brouwer, Robbe Heestermans

During the last decade, an impressive progression has been made in the treatment possibilities and clinical outcome of multiple myeloma. However, the availability of new drugs and additional therapeutical options cannot prevent that most patients relapse and become refractory to treatment at a certain stage in their disease evolution. Multiple myeloma is characterized by a patchy tumor distribution pattern in the bone marrow, implicating that single bone marrow sampling during diagnostic working up, can lead to underestimation of the true tumor heterogeneity. Moreover, a better disease follow-up during and after treatment requires a more frequent analysis of minimal residual disease as well as genetic profiling at the moment of relapse or refractory disease. Therefore, there is much interest in the development of peripheral blood-based monitoring methods that could allow more frequent sampling without the discomfort of repeated bone marrow aspirations. This project aims to identify and characterize different circulating markers for diagnosis and disease monitoring in multiple myeloma. In particular we focus on circulating tumor cells, cell-free DNA and exosomes-derived DNA for their potential and clinical value in mutation profiling and disease monitoring. It is important that such markers are fully validated in relation to the biology and clinical features of this disease, before they can be finally used in clinical practice.

Principal Investigator: Ivan Van Riet

Participants: Rik Schots, Ann De Becker

Autologous and allogeneic stem cell transplantations (from bone marrow, peripheral blood and cord blood) became through the last three decades a standard therapy for various hematological, (mostly) malignant disorders. Over the years, there has been besides the evolution in the pre-transplantation conditioning regimens and the control of clinical complications also further progress in the graft collection and processing technology. In parallel there is increasing interest to use peripheral blood–derived cells for immune effector cell therapy in different types of hematological and solid cancers. The department Hematology UZ Brussel has a JACIE-accredited stem cell transplantation program and a FAGG-licensed bank for hematopoetic stem cells, donor lymphocytes and dendritic cells. All technologies are available for research and clinical scale cell isolation, cell cryopreservation and graft quality testing. Research (and research collaboration) is focused on characterization of in vitro expanded mesenchymal stem cells and cell processing  for new immune effector cell therapies.

Principal investigator: Prof. Dr. Kristin Jochmans

Participants: Dr. Christelle Orlando

Inherited antithrombin (AT) deficiency is a very rare thrombophilic condition that is associated with thrombosis at young age, familial history of VTE, recurrent events and the presence concomitant risk factors. Over the past 20 years, our center has become a reference center for inherited antithrombin deficiency. Besides phenotypical characterization, we are the only Belgian center performing molecular analysis to unravel the genetic background of inherited AT deficiency. This has revealed that thrombotic complications are linked to the genotype of the patients, emphasizing the added value of performing the genetic studies to provide better patient care. More surprisingly, some mutations seem to be associated with arterial thrombosis. The exact mechanism is currently unknown and will be further the explored. By studying unreported mutations in recombinant in vitro experiments, novel pathogenic mechanisms can be identified, leading to a better understanding of the disease

Principal investigator: Prof. Dr. Kristin Jochmans

Participants:

The research topic is that of the small B-cell clones in the peripheral blood, the so called monoclonal B-cell lymphocytosis (MBL), a relatively benign entity that is detected with flow cytometry. It is a new research domain with still lots of opportunities for exploration. Most MBL studies up until now describe MBL with a chronic lymphocytic leukemia immunophenotype (C-MBL) because they are the most common and easiest form of MBL to detect. MBL with a lymphoma-like immunophenotype (L-MBL) is largely unexplored, presumably because it is harder to detect. Its clinical course especially, i.e. evolution towards B-cell non-Hodgkin lymphoma, remains unknown. The goals of this project are threefold. First off, it is the intention to better characterize L-MBL by studying its biology and clinical outcome in a hospital population. Secondly, we wish to study the immunological aspects in MBL (C-MBL and L-MBL) subjects, such as the T-cell response and the serum immunoglobulin secretion. Lastly, we want to ameliorate the detection rate of B-cell lymphoproliferative diseases (and thus of L-MBL) by implementing a new flow cytometer into the laboratory together with improved and expanded antibody combinations and novel gating strategies. By doing so, it will be possible to have a more accurate estimate of the frequency of MBL in healthy subjects and patients with a B-lymphoid related ailment such as myeloma and possibly idiopathic thrombocytopenic purpura, while also acquiring more information regarding the antigen expression of these clones.

Principal Investigator: Marleen Bakkus

The detection of residual disease after initial chemotherapy determines the prognosis for children with ALL. If MRD can be detected, these children will receive a more intense treatment strategy, thereby improving their survival rates. It is therefore important to have the most sensitive method possible to determine MRD. In this project, a specific PCR technique has been developed and optimized to detect MRD. Currently, this PCR technique is now recognized as the golden standard. However, this techniqe is labor-intensive and can only be used in a number of reference laboratories. To improve this technique, we are now investigating the use of NGS to improve sensitivity, specificity and efficiency.

Principle Investigator: Barbara Depreter

Participants: Ann De Becker, Kristin Jochmans

Although the majority of patients with COVID-19 are thought to have mild symptoms, some of them will have severe illness that progress to acute respiratory distress syndrome (ARDS). This lung inflammation would be mediated by immunological reactions. It is well known that genetic differences contribute to different immune response to pathogens. The Human Leucocyte Antigen (I-ILA) molecules, encoded by the most polymorphic genes in the human population, are cell surface glycoproteins responsible for the presentation of foreign peptides for immune surveillance. Such life-threatening hypersensitivity reaction was observed by HIV patients treated by Abacavir who were positive for HLA-B*57:01 allele. Furthermore, Killerlg-like (KIR) receptors regulate the NK cells in a HLA-dependent manner that are important in the immune defense against viral infection.