The Schlenner lab broadly follows five research tracks. In our research, we employ a variety of approaches and analysis techniques in vitro and ex vivo, transgenic mouse strains for in vivo research, and collaborate (inter-)nationally with academic, clinical and industry partners e.g. for drug development research in the context of immune-related diseases and immuno-oncology. Naturally, there is methodological overlap between the different research tracks and each requires expertise in several scientific and technical areas; hence each research line greatly benefits from team work and collaboration to warrant success for every PhD student and postdoctoral researcher.

Fundamental Research

RNA modifications in functional differentiation of immune cells

The epitranscriptome is the sum of RNA modifications. >170 modifications to all types of RNA have been described and while highly conserved we are only beginning to understand their regulatory roles in mammalian cells. Important functions of RNA modifications are transcript stability and translation fidelity. Hence, they can impact cellular development, homeostasis and function.

Our lab focuses on the isomerization of uridine to pseudouridine, a process catalyzed by 13 non-redundant synthases. Pseudouridylation is the most common RNA modification, yet, its role in immune cells remains unexplored. An accumulating number of case reports demonstrate causative mutations in pseudouridine synthases in neurological and metabolic disorders, highlighting the importance of this regulatory mechanism. In our lab, we study the role of pseudouridylation in T cells and dendritic cells. We employ CrispR/Cas9 screening, in vitro differentiation, RNAseq and flow cytometry to dissect the potential role of these 13 synthases in T cell functional polarization and dendritic cell development and maturation.

Differential expression of pseudouridine synthases (PUS) along T cell differentiation and activation suggests regulatory roles.

Translational Research

Novel antibody-based immuno-oncology therapies (RETROFIT consortium)

In the last decade or so, anticancer immunotherapy has revolutionized treatment of cancer patients, especially immune-checkpoint blocking antibodies (ICBs) against solid tumors. This has been primarily driven by broad immuno-oncology targets like PD1/PD-L1 or CTLA4. The success of these ICBs has been severely hampered by multi-factorial immuno-resistance in patients. This is especially applicable to “immune cold” tumors resistant to all ICBs.

Starting 2026, we are proud to be a partner in the KU Leuven RETROFIT consortium together with Prof Abhishek Garg, PharmAbs – Dr Nick Geukens and Prof Maarten Dewilde, and Prof Naulaerts. Our consortium aims to create a next-generation platform to discover, validate and valorize novel immunological targets and their combinations in oncology. Target discovery will drive the creation of first/best-in-class bi- or multi-specific antibodies. Using advanced computational and AI methods, the consortium will identify and validate drugable immune pathways in cancer and develop antagonistic/agonistic multi-specific antibodies to modulate these pathways. Our lab will be strongly involved in the development and application of wet lab tools for functional validation of new antibodies designed and produced by the consortium.

Development of agonistic compounds for targeted Treg migration in inflammatory diseases

Regulatory T cells (Treg) can be found in all organs where they regulate immune homeostasis and prevent excessive immune activation. Chemokine receptors guide the selective migration of Treg to different organs. In collaboration with the Rega institute and the Department of Chemistry at KU Leuven, we are developing agonistic chemical compounds to promote the migration of highly immunosuppressive Treg to specific sites such as the skin or lung in contexts of immune-related diseases. In clinical applications, the topical application of these compounds as drugs shall ameliorate diseases such as dermatitis, proriasis or asthma.

Fig. CCR8 expression is high in inflammatory contexts such as in vivo in PBMC-transplanted NSG mice.

IL-2R agonists for selective Treg expansion and selective IL-2 targeting of Treg vs effector cells in different disease settings

To establish and maintain immune tolerance, IL-2 signalling is indispensable for Treg development, homeostasis and function. Treg are hence characterized by high expression of the trimeric (high-affinity) IL-2 receptor (IL-2R) consisting of the three receptor chains CD25 (IL-2Ra), CD122 (IL-2Rb) and CD132 (common g chain). Many strategies for targeting the IL-2 pathway have been developed, however, various immune cells other than Treg express the intermediate-affinity IL-2R (CD122 + CD132). IL-2R agonists therefore must possess high selectivity for Treg when applied in inflammatory contexts to prevent activation and/or expansion of effector cells such as CD8 T cells or NK(T) cells, or even non-immune cells such as endothelial cells.

Fig. A novel trispecific IL-2R agonist is compared for avidity-driven Treg selectivity with different formats of the same subunits along with an additional CD25-binding subunit. Treg selectivity is increased via 2:1 anti-CD25:anti-CD122/CD132 antibody format in functional ex vivo assays. (αVHH in blue, βVHH in green, γVHH in yellow)

On the other hand, IL-2 can support anti-cancer immune responses (in fact, it was the first FDA immunotherapy and then in cancer). Selective targeting of IL-2 to effector T cells is hence the flipside application and another research line in our lab.

In T cell tolerance context and in collaboration with industrial partners, we developed agonistic tri-specific antibodies to activate human Treg with high selectivity. We employed nanobody development, in vitro activation and expansion assays, as well as murine humanized (disease) models. (link to preprint).

Further, and with potential applications in both T cell tolerance as well as cancer, we develop IL-2 targeting strategies in collaboration with KU Leuven PharmAbs and the lab for Biomolecular Modelling and Design (Prof Aernout Voet). This research involves protein design and production, in vitro cell line and primary cell experiments as well as humanized in vivo mouse models.

Fig. Application example: selective targeting of IL-2 to CAR-T cells to enhance viability, expansion and function.

Clinical research

Our clinical research is focused on CAR-T cell therapy in hematological diseases – the development of novel CAR-T cell therapies but also understanding why CAR-T cell infusions lead to substantial patient-to-patient variation in toxicity severity, why some patients enter long-term remission while others relapse due to inefficient CAR-T cell efficacy, and how these can be forecasted by clinical biomarker assays across the CAR-T treatment path to support clinical guidance and monitoring.

            Development of a novel CAR-T cell therapy for NPM1-mutant AML

Approximately, 25% of acute myeloblastic leukemias is caused by a mutation in the NPM1 protein. In this research line, we aim to specifically target cancer cells by novel CAR-T cells that recognize and eliminate cells that express mutant NPM1 and present neoantigens at the cell surface. This novel ATMP will be developed in close collaboration with clinicians at the University Hospital Leuven (UZ Leuven) and with VIB Leuven.

iCARe study: Linking CAR-T cell potency and efficacy with functional and phenotypic immune signatures throughout the treatment

Several CAR-T products for B cell malignancies have been FDA/EMA-approved. Yet, only ~half of the patients receiving this powerful ATMP enter long-term remission. In a multi-centric study involving 5 clinical sites in Belgium, we aim to describe

• protein immune signatures in apheresis T cells that correlate with CAR-T cell potency,
• CAR-T cell functional and phenotypic characteristics that correlate with adverse effects and in vivo efficacy,
• and in vivo CAR-T cell markers that correlate with persistence and memory.

We are employing e.g. high-parametric flow cytometry, single cell multi-omics, and single cell secretomics for functional analyses. By employing computational analyses and machine learning we aim provide viable biomarkers to be integrated into clinical practice to facilitate guidance of treating clinicians and to reduce response times.

Funding Institutions

• KU Leuven BOF and KU Leuven IOF
• FWO (Fonds voor Wetenschappelijk Onderzoek, Research Foundation Flanders)
• Fred and Thea Philips FTBO (ATMP research – NPM1/AML study)
• University Hospital Leuven / UZ Leuven
• VLAIO (Agentschap Innoveren & Ondernemen, Flanders Innovation & Entrepreneurship)
• Kom Op Tegen Kanker (KOTK, ‘Fight Against Cancer’ Foundation)
• Chinese Scholarship Council (CSC)