Research units – Blood Cancer Research Group

Simicek Lab

The Simicek Lab applies state-of-the-art genomic, proteomic, biochemical, and cell-based methodologies to investigate fundamental molecular mechanisms associated with immunoreceptors on T cells and tumor-associated surface proteins representing key targets for modern immunotherapy. A major focus of our research is the chimeric antigen receptor (CAR)-based immune synapse (IS). Our team is actively developing novel strategies to enhance the therapeutic potential of CAR T cells, with a particular emphasis on designing next-generation CARs, hybrid T-cell receptors, and other immune synapse-associated proteins. We employ cutting-edge techniques, including advanced imaging, protein engineering, CRISPR-based precise genome editing (knock-in/knock-out) in primary T cells, and preclinical testing in vivo models. Through close collaboration with the translation unit, we strive for the rapid translation of our findings into clinical applications, accelerating the path from discovery to patient treatment.

Team leader: Assoc. Prof. Michal Šimíček

Actual projects

Development of Highly Effective Allogenic CAR T-Cells Using Innovative Surface Proteome Analysis and Non-Viral Gene Editing

Current CAR T-cell therapies face significant challenges, including high production costs, lengthy manufacturing times, and risks associated with viral gene transfer. Our research addresses these challenges by integrating advanced proteomic analyses, CRISPR-based gene editing, and non-viral gene delivery approaches to improve the efficacy, safety, and scalability of CAR T-cell therapy.

In this project we aim to:
• Identify optimal T-cell subsets with superior persistence and anti-tumor activity
• Characterize the protein landscape of CAR-based immune synapse, using innovative protein proximity labelling to uncover key molecular interactions that drive CAR functionality
• Develop novel CAR constructs and hybrid T-cell receptors that enhance tumor recognition and immune activation
• Implement non-viral site-specific gene editing to create safer, off-the-shelf allogenic CAR T-cells, avoiding the risks of random integration associated with viral vectors

A key focus is on multiple myeloma (MM), where CAR T-cell therapy has shown remarkable success but remains limited by antigen escape and treatment resistance. By targeting multiple tumor-specific epitopes and optimizing CAR design, this project aims to develop highly effective CAR T-cell products with enhanced durability and broader clinical applications.

By combining cutting-edge molecular and cellular techniques with preclinical in vivo models, this research aims to pave the way for safer, more accessible, and more effective CAR T-cell therapies for cancer patients.

Jelinek Lab

Under the expert guidance of Assoc. Prof. Jelinek, the laboratory is dedicated to advancing multiple myeloma research through a multifaceted approach. Specializing in the processing of patient tumor samples, the lab employs cutting-edge techniques like spectral flow cytometry and single cell RNA sequencing. Driven by a commitment to precision medicine, the team conducts rigorous bioinformatic and biostatistical analyses, unraveling the molecular complexities of multiple myeloma. What sets this lab apart is its seamless collaboration between clinical and research teams. By leveraging this close partnership, Jelinek’s lab not only pioneers discoveries of novel predictive and treatment targets but also accelerates the translation of these findings into tangible benefits for multiple myeloma patients.

Team leader: Assoc. Prof. Tomáš Jelínek, M.D., Ph.D.

Actual projects

Extramedullary multiple myeloma: molecular pathogenesis and novel therapeutical targets
Multiple myeloma (MM) is the second most common blood cancer caused
by aberrant proliferation of plasma cells in bone marrow. Despite great advances in treatment, the disease usually progresses and repeated relapses are common. Advanced phases of MM are in some cases accompanied by the development of extramedullary disease (EMD) with a very poor prognosis. At the EMD stage, tumor plasma cells become independent on the bone marrow microenvironment and infiltrate other tissues and organs with fatal consequences for the patient. Due to the lack of deeper knowledge of EMD biology, there are no predictive biomarkers and effective treatment strategies are currently not available. Therefore, the main goal of the proposed project is identification of genetic and molecular features associated with the emergence of EMD with a particular focus on novel druggable targets. To fulfil these aims we plan to collect the world´s largest longitudinal cohort of EMD patients and characterise the genomic and transcriptomic changes using the state-of-the-art techniques. Further, we plan to unveil the composition of the cellular microenvironment of extramedullary lesions by single-cell transcriptomics and spectral flow cytometry, particularly focusing on the status and availability of immune cells and application of modern immunotherapies. Our previous research identified CD38 and SREBF1 pathways as potentially crucial for acquisition of EMD phenotype. To expand and validate these findings we will investigate detailed molecular mechanisms of CD38 and SREBF1 pathways using sophisticated in vitro and in vivo approaches. Our project is original, highly innovative and of unmet need as the genetic and molecular characteristics of EMD remain enigmatic. The outcomes of the proposed project will significantly contribute to the understanding of the EMD pathogenesis and provide important basis for novel selective treatment strategies for this prognostically extremely unfavourable group of myeloma patients
Link: https://starfos.tacr.cz/projekty/NU23-03-00374

Saving Lives Through Cancer Early Detection and Prevention Research: Molecular, Genomic and Social Factors (SALVAGE)
Malignant tumors are the second most common cause of death in the Czech Republic and the EU, while half of these deaths can be avoided through prevention. The SALVAGE project deals with the main challenges in research in the field of primary, secondary and tertiary oncological prevention. Its implementation will contribute to the fulfillment of the main goals of the European Plan to Fight Cancer and the Concept of Health Research of the Czech Republic 2030. At the same time, it will bring results applicable in clinical practice, strengthen international cooperation and reduce the research deficit in this area.
LINK: https://www.osu.cz/20316/projekty-a-granty/?g=6577

Efficacy of anti-CD38/BCMA therapies in extramedullary multiple myeloma
Unprecedented efficacy especially of daratumumab was demonstrated in all stages of multiple myeloma, nevertheless there are almost no data available regarding its effectiveness in EMD. Our group revealed, for the first time, that daratumumab monotherapy yielded significantly shorter progression free survival in MM patients with EMD compared to those without EMD. This observation could be explained by significantly lower expression of CD38 antigen on plasma cells from EM tumor compared to the bone marrow plasma cells (Jelinek et al., EHA, 2020). On the other hand, subgroup analysis of Icaria trial focusing on activity of isatuximab plus pomalidomide and
dexamethasone revealed that addition of isatuximab to pomalidomide and dexamethasone significantly improved the outcomes of patients with soft tissue plasmocytoma compared to pomalidomide and dexamethasone alone (Beksac et al., ASH, 2020).
The overall objective of the project is to comprehensively evaluate the efficacy of anti-CD38 therapies in EMD and comprehensively describe the constitution of EM tumor microenvironment.

Genomic analysis of residual clone in multiple myeloma: approach for targeted therapy
Multiple myeloma (MM) is a plasma cell dyscrasia causing damage of multiple organs with fatal consequences for patients. Despite the success of modern therapies eliminating a vast bulk of the aberrant cells, surviving residual clones eventually lead to the relapse of the disease. Accumulation of genomic alterations during the stage of minimal residual disease (MRD) likely contributes to a selective grow advantage and survival under the drug pressure. Identification of specific mutations in MM patients with MRD can provide unique opportunities to target the residual plasma cell clones. We aim to identify mutations and deregulated gene expression in residual aberrant plasma cell population and to pinpoint molecular targets for precision medicine using the combination of whole genome, bulk RNA and single-cell RNA sequencing.

Immuno-Biophysics Lab (Jung Lab)

Our research focuses on the biology of T cells and natural killer (NK) cells, using a combination of advanced imaging, optogenetics, cell engineering (e.g., CAR-T/NK), and synthetic biology to uncover the biophysical principles of immune cell signaling. Specifically, we investigate membrane organization, receptor clustering, and the spatial dynamics of signaling pathways. By integrating cutting-edge imaging techniques, biophysical manipulation, and synthetic biology, our goal is to precisely control immune cell activity and develop innovative strategies for immune modulation. We collaborate closely with research groups within BCRG as well as with international collaborators.

Team leader: Assist. Prof. Yunmin Jung, Ph.D.

Actual projects

Optogenetic control of T cell activation through light-Induced condensation of key signaling molecules
The formation of dynamic condensates of signaling molecules is a crucial regulatory mechanism in immune cell activation. This project aims to explore how key signaling protein condensates act as molecular switches to modulate T cell activation. Using an optogenetic system, we will precisely induce molecular condensation with light, allowing for high spatial and temporal control. We will characterize the phase transitions of these condensates and examine their role in regulating downstream signaling and T cell activation. This research will reveal the biophysical principles underlying the molecular condensation of key signaling proteins and provide new strategies for engineering light-controlled immune cell therapies.

Super-Resolution Imaging Analysis of Microvilli-Dependent Spatial Arrangement of Activating and Inhibitory Receptors on NK Cells
Microvilli are prominent structures on the surface of all nucleated hematopoietic cells, including NK cells. However, the molecular distribution of key receptors in relation to microvillar protrusions is still poorly understood, especially on NK cells. Since the balance between activating and inhibitory receptors critically regulate NK cell function, it is essential to understand how these receptors are spatially arranged and how they interact with target receptors relative to microvillar structures. In this project, we will use super-resolution imaging to map the spatial organization of activating and inhibitory NK cell receptors on the three-dimensional surface of NK cells, with a focus on microvillus-dependent patterns.

Alzubi Lab

We are developing next generation Chimeric Antigen Receptor (CAR) Immune cell therapies with improved activity and safety parameters with the ultimate goal to treat patients suffering from solid and hematological malignancies. We combine viral and non-viral gene delivery platforms with CRISPR editors to produce allogenic CAR T cell products at clinical stage without lossing their persistance. Our modern gene editing tools facilitate the generation of different flavors of CAR immune cell products such as exhaustion-free and enhanced CAR theraputics.

Team leader: Jamal Alzubi, PhD

Actual projects

Combine safe multiplex base editor streatgy with non-viral sleeping beaty platform to develop cost-effictive “non-alloreactive “ CAR T cell product at clinical scale.

Develop novel CAR T cells targeting alternative Multiple Myeloma (MM) antigens beyond the state-of-the art BCMA with the aim to buid focused CAR T cells with high on-target/low off-tumor activity.

Apply targeted genome editing streatgies to develop hybrid TCR like CAR T cells with “physiological“ immune cell responses.

Targeting the inhibitory metabolic pathways with CRISPR editors to generate inhibitory-resistance CAR T cells with enhanced anti-tumor activity within the inhibitory tumormicroenviroment (TME) for solid and advanced stage MM malignancies.

Develop ready to use γδ and NK based allogenic CAR immune cell products with enhanced anti-tumor activity