International Funding

Chemical ARX degraders

Targeting mannosylation for regenerating beta cell mass

Knock out oncogenic drivers and curing kids (KOODAC)

GoE

Genome of Europe

Innate-ImmunomeTabolIsm as Antiviral Target

Immunosep

Personalized immunotherapy in sepsis: a precision medicine based approach

Understanding and exploiting epigenetic regulation in CAR T cell therapy

The dramatic efficacy of CAR T cell therapy in certain hematopoietic malignancies provides clinical validation of a groundbreaking paradigm: Human cells can be engineered into purpose-built therapeutic agents by genetically introducing artificial regulatory programs. The EPI-CART project will focus on epigenetic regulation in CAR T cell therapy – an important but underappreciated aspect of all cell-based therapies.
We will investigate the regulatory dynamics during CAR T cell therapy in unprecedented molecular detail, by following 40 patients who will receive treatment for two blood cancers (Aim 1). Using single-cell epigenome/transcriptome profiling of CAR T cells and sequential biopsies, clonal tracking, monitoring of immune regulation, and liquid biopsies, we will bioinformatically reconstruct patient-specific trajectories, identify molecular markers for therapy monitoring, and uncover epigenetic drivers of CAR T cell response.
To engineer the first “epigenetically boosted” CAR T cells for hard-to-treat cancers (CAR-T-resistant blood cancers, solid tumors), we developed a CAR T cell screening/engineering platform that enables us to functionally test thousands of potential regulators in cellular assays and mouse tumor models (Aim 2). The in vivo experiments leverage our CRISPR single-cell sequencing method (CROP-seq), supporting rational optimization of CAR T cells and quantitative modeling of the underlying regulatory mechanisms.
The EPI-CART project will uncover key roles of epigenetic regulation in CAR T cells, advance our understanding of existing CAR T cell therapies, and establish new approaches for areas with unmet clinical need. We will establish preclinical proof-of-concept for the efficacy of “epigenetically boosted” CAR T cells and provide a compelling rationale for subsequent first-in-human clinical trials. More generally, this project will demonstrate the biological roles and translational potential of epigenetic programs in cell-based therapy.

Translating Tudor domain splicing inhibitors for oncological applications

Therapeutic hijacking of E3 Ligases

Traditional drug design relies on inhibition of enzymes or receptors with accessible hydrophobic pockets. The concept of proteolysis targeting chimeras (PROTACs) promised to overcome this limitation. Following our discovery of the first PROTAC that induced selective protein degradation in vivo, this technology has seen a boost in academia and industry. Despite global research efforts, advances are so far incremental: (i) most focus is on degrading targets that can be liganded and are druggable with conventional inhibitors; (ii) currently, only 3 out of 600 E3 ligases can be exploited. Glue2Degrade aims to transform the pharmacologically targetable space of the proteome. The project is built on the hypothesis that molecular glues (MGs), non-chimeric small molecules that degrade target proteins by inducing cooperative binding to E3 ligases, are much more prevalent than anticipated. Lenalidomide and related immunomodulatory drugs (IMiDs) are prime examples of the potential of MGs. Without a specific targeting moiety, IMiDs induce cooperative binding of the E3 ligase CRBN to undruggable proteins like IKZF1/3, thereby inducing their degradation. However, no technologies exist to rationally develop MGs that hijack other E3 ligases. ERC-funding would allow us to address this limitation. Based on data generated in my laboratory, we will systematically identify novel MGs and their E3 ligases by innovating (i) phenotypic discovery strategies, and (ii) an orthogonal chemical genetics pipeline. To elucidate the mechanisms of novel MGs, we will (iii) conduct target identification via unbiased proteomics followed by (iv) chemical optimization and initial translational characterization. Glue2Degrade, if successful, will transform the engageable E3 space and identify novel MGs, thereby opening up the potential for therapeutic development of cell-, tissue-, and cancer-type specific chemical degraders for undruggable proteins.

Rewire the lymph node niche to instruct T cell immunity

Lymph nodes (LN) are communication centers within the lymphatic network that instruct T cell priming and differentiation in homeostasis and disease. Multiple layers of control are achieved by a complex network of signals from stromal and immune cell compartments. As a result, spatially segregated LN niches coexist that foster diverse T cell lineages. In the context of cancer, T cell differentiation is pushed towards the lineage of exhaustion, with a progenitor exhausted T cell population arising in the LN. Hence, LN are central anatomic sites where T cell exhaustion can be controlled and reversed to eliminate cancer. The key question of REWIRE is: What microenvironmental factors determine the differentiation and maintenance of progenitor exhausted T cells in the LN?

Tumor-derived signals reprogram stromal and immune cells within tumor-draining LN. Thus, a premetastatic niche is formed that supports future metastatic seeding while establishing an immunosuppressive microenvironment. I hypothesize that signals guiding T cell differentiation are altered by premetastatic remodeling of the LN niche, resulting in the generation of exhausted T cells.

In this project, I aim to (1) decode spatial determinants of the progenitor exhausted T cell niche; and to (2) manipulate the tumor-draining LN ecosystem to control T cell immunity. The overarching goal is to dissect how tissue architecture directs molecular responses within the LN niche to regulate T cell exhaustion. We will use high-dimensional imaging technologies to chart the spatial context of progenitor exhausted T cells following tumor progression; as well as a novel myeloid cell-based in vivo delivery platform to specifically target tumor-draining LN.

REWIRE will uncover basic mechanisms of communication between the LN microenvironment and differentiating T cells in the LN; as well as explore the novel concept of controlling T cell responses via manipulating key-features of the LN niche.

T cell regulation by fed state bacterial metabolites

Intestinal microbial communities expand the functional capabilities of the host via their metabolic attributes. From energy harvest to the production of vitamins, the gut microbiota shapes mammalian physiology and is often considered a postnatally developed “organ”. Yet, the microbiome poses a formidable challenge to the immune system: How can we host trillions of bacteria without mounting an inflammatory response?
Gut immune homeostasis relies on the balanced action of suppressive and inflammatory T cell subsets. I discovered that bacterial metabolism of bile acids and dietary fibers promotes the differentiation of suppressive T cells. Given the complexity of the microbiome, finding other immunoregulatory cues deployed by gut bacteria and their mechanisms of action remains a major challenge, and the logic behind these tolerance mechanisms is not understood. I will use a novel conceptual framework to bridge this gap: based on my previous findings, I postulate that immunoregulatory bacterial molecules are produced in response to food intake. Within this emerging paradigm, I selected two new groups of bacterial molecules for immediate investigation and developed a strategy to identify novel putative immunoregulatory candidates based on a careful examination of microbial metabolism after food intake. I will find the molecular targets of active molecules using chemical screening and chemoproteomic methods and test metabolites in vivo by colonizing germ-free mice with genetically manipulated bacterial strains.
The proposed work is grounded on my strong expertise in host-microbe interactions and takes advantage of the state-of-the-art biochemistry facilities at my hosting institution and of the complementary skillsets of my collaboration network. This synergistic combination will allow for a comprehensive interrogation of immunological tolerance to gut commensals: from metabolites and their molecular targets to their functional relevance for intestinal health.

EpiTargetkids

Studying epigenetic heterogeneity and phenotypic plasticity of pediatric high-grade gliomas for the development of novel strategies in precision medicine

Metabolic adaptation during helminthic infection

RESOLUTE - Research Empowerment on Solute Carriers

RESOLUTE is a public-private partnership funded with a grant from the Innovative Medicines Initiative (IMI) and coordinated by CeMM and Pfizer, with 13 partners from academia and industry.

RESOLUTE’s goal is to goal to trigger an escalation in the appreciation and intensity of research on solute carriers (SLCs) worldwide and to establish SLCs as a tractable target class for medical research and development.

Add medical genetic solutions to RESOLUTE (REsolution)