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Grant Projects (ongoing in the year 2026)
View ongoing grants in the year: 2009, 2010, 2011, 2012, 2013, 2014, 2015, 2016, 2017, 2018, 2019, 2020, 2021, 2022, 2023, 2024, 2025, 2026, 2027, 2028.
Advanced genomic characterization of secondary myeloid malignancies: implications for diagnostics and prognostication
AZV NU23-03-00401 [2023 – 2026]
RNDr. Monika Beličková, Ph.D.
Mgr. Jana Kotašková, Ph.D., Fakultní nemocnice Brno
Therapy-related myeloid neoplasms (t-MNs) are secondary malignancies that occur after chemotherapy and/or radiation therapy of a previous cancer. The t-MN category accounts for approximately 10-20% of newly diagnosed patients with myeloid neoplasms (MNs) and the latency between treatment and development of t-MN ranges from a few months to years. The prognosis of these patients is generally poor, and unlike primary MNs, there are no specific prognostic scoring systems for this group nor a defined complex genomic background. We hypothesized that the combined effect of acquired somatic mutations and numerous germline variants, including common and rare variants, which underlie the multistep molecular pathogenesis, contributes to t-MN development. Thus, we propose an advanced analysis of the t-MN genome, which will include the examination of somatic and germline mutations using whole-genome and targeted sequencing. Furthermore, transcriptome analysis of protein-coding and noncoding RNAs at the level of bone marrow CD34+ cells will be performed to determine the signaling pathways involved in t-MN development. Genomic data along with cytogenetic findings will be correlated with clinical parameters. Relevant molecular markers will be incorporated into the diagnostic and prognostic evaluation of t-MN patients. Knowledge of the molecular background of secondary malignancies will lead to a more detailed subclassification of patients, determination of a more accurate prognosis and selection of an appropriate treatment, ultimately strengthening personalized approaches for patients.
Next generation CAR-T cells for the therapy of hematological malignancies
AZV NU23-03-00188 [2023 – 2026]
doc.MUDr. Pavel Otáhal, Ph.D.
Prof. MUDr. Pavel Klener, Ph.D., 1. LF UK Praha
The proposed project deals with new methods of cell therapy of hematological malignancies such as AML, B-ALL and B-NHL using CAR-T T lymphocytes. The aim of the project is to build on the ongoing clinical study with CD19-specific CAR-T lymphocytes, which are produced in IHBT for therapeutic purposes (UHKT CAR19) and are tested in a clinical trial in patients with refractory/relapsing B-ALL/B-NHL. Treatment with commercial CD19 CAR-T products cures about 20-30% of patients indicated for this treatment, the remaining patients either do not respond to treatment or relapse even when complete remission is achieved. The causes of CAR-T treatment failure are being intensively studied. One of the ways to prevent lies in the development of so-called next-generation CAR-T cells that have enhanced antitumor activity, e.g. by co-expression of cytokines (IL-12, IL-15, IL-18, IL-21) or—by secreted bi-specific antibodies. The first goal of this project is to develop such modified CD19-specific CAR-T lymphocytes. The second goal is the development of CD123-specific CAR-T lymphocytes, for the treatment of acute myeloid leukemia. These new types of CAR-T products will be analogically to the UHKT CAR19 T cells that are now being produced at UHKT. During the solution of the project, we will establish GMP-certified production of both CAR-T products in the Clean Rooms of the IHBT, prepare pharmaceutical documentation and submit an application for two clinical trials with these products - one for AML and the other for refractory/relapsing B-ALL/B-NHL.
Changes in expression of adhesion molecules: a tool for prediction of extramedullary relapse of B cell acute lymphoblastic leukemia following blinatumomab treatment
AZV NU23J-03-00033 [2023 – 2026]
Blinatumomab (Blincyto ®) is a bi-specific therapeutic antibody mediating the connection of the CD19 receptor on malignant B-cells to CD3 on effector T-lymphocytes. This enables the formation of a cytolytic synapse and effective elimination of the tumor. According to current knowledge, however, the relapse into extramedullary disease (EMD) is unusually common in blinatumomab-treated patients with B-cell acute lymphoblast leukemia (B-ALL). The main hypothesis of the project assumes that blinatumomab affects leukemia cell adhesion properties and thereby homing of B-ALL cells to tissues where blinatumomab is not effective. This may eventually lead to EMD. The sole interaction of blinatumomab with CD19 can affect the signaling of several adhesion-related molecules (integrins, Lyn). Furthermore, immune synapse formation can lead to changes in the expression of surface cell adhesion molecules (CAM) on both involved cells. Additionally, cytoskeleton changes induced by B-cell receptor (BCR), a vital component of the immune synapse, are dependent on Lyn kinase signaling. The project aims to analyze the effect of blinatumomab on B-cell adhesion processes. Mechanisms of blinatumomab-induced changes in adhesion signaling will be studied on B-cell leukemia (B-ALL) cell lines, both in the absence and in the presence of model T-lymphocytes. We will assess changes in the cell affinity to proteins of the extracellular matrix and to model stromal cells and, on a molecular level, changes in the activation status of selected proteins to find a clinically useful marker of the changes induced by blinatumomab. In primary samples (B-ALL, ~60 patients and up to 250 samples during the project course), changes in expression and activation of relevant CAMs (integrins, CD44, CD62L), as well as selected intracellular markers (Lyn) after blinatumomab treatment, will be evaluated, and correlated with the treatment results.
VEXAS syndrome; characterization and clinical consequences of individual UBA1 genetic variants among patients with rheumatic and hematologic disorders
AZV NU23-10-00160 [2023 – 2026]
MUDr. Heřman Mann, Ph.D., Revmatologický ústav, Praha
RNDr. Monika Beličková, Ph.D.
VEXAS (vacuoles, E1 activating enzyme, X-linked, auto-inflammatory, somatic) syndrome is a clinically serious and potentially fatal adult-onset disease caused by somatic mutations in the UBA1 (Ubiquitin-like modifier activating enzyme 1) gene in hematopoietic progenitor cells. It was first described in 2020 therefore data regarding its clinical manifestations, genetic associations, prognosis and treatment efficacy are limited. UBA1 missense mutations in VEXAS syndrome patients cause activation of inflammatory pathways, which clinically present in older patients with systemic inflammation and a potential to progress into myelodysplastic, myeloproliferative, or lymphoproliferative disease. Patients may meet diagnostic criteria for several rheumatic and/or hematological disorders. Given its heterogeneous clinical manifestations a high degree of clinical suspicion is required for pursuing the diagnosis of VEXAS syndrome. Demonstration of known pathogenic variants in hot spot sites of p.Met41 in exon 3 in UBA1 sequencing analysis of hematopoietic cells is currently required to establish the diagnosis of VEXAS syndrome. However, this approach may not be sufficient since an extended analysis of all coding regions of the UBA1 gene may uncover other mutations with putative functional consequences as we have shown. VEXAS syndrome is associated with high morbidity and mortality. There is currently no information regarding the impact of VEXAS syndrome on patients’ quality of life. Many patients experience partial response to treatment with glucocorticoids and/or immunosuppressive therapy. Limited evidence suggests that hematopoietic stem cell transplantation may be curative in some cases. More data from careful clinical observations is clearly needed to provide much evidence regarding the optimal diagnostic approach, impact of the disease on patients’ quality of life, prognosis and value of individual treatments.
