International Funding

Chemical ARX degraders

Knock out oncogenic drivers and curing kids (KOODAC)

GoE

Genome of Europe

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

A quantitative tissue architecture framework to understand human aging and disease

Aging is a complex biological process that manifests across diverse anatomical scales, from molecules and cells to organs and organisms. Despite the significance of age-associated diseases in affecting quality of life and mortality, our understanding of how cellular-level changes result in tissue-specific loss of function remains incomplete. Several limitations persist: the inability of animal models to fully mirror human physiology, the restricted scope of longitudinal human studies to easily accessible organs, and a prevalent cell-centric focus that overlooks the broader microanatomical context. Additionally, the challenge of uncoupling aging from pathology is exacerbated by the absence of baselines defining healthy aging, hindering the accurate interpretation of alterations. To address these challenges, the proposed project leverages large-scale human tissue imaging datasets and machine learning techniques. Specifically, Aim 1 employs unsupervised learning to systemically quantify and categorize microanatomical structures across 40 human tissues. In a parallel stream, Aim 2 aims to detect and characterize the manifestation of age-associated pathologies in tissue, pinpointing the molecular changes associated with them, across spatial scales. Aim 3 integrates the insights from previous aims, seeking to identify how they contribute to the process of aging and onset of age-associated diseases. Ultimately, this will unearth early predictors of pathology, providing a transformative approach to disease detection and management. This project will not only offer a novel, comprehensive view of human tissue complexity in the context of aging but also challenge the traditional notion that age-associated pathology is merely an aggregation of cellular dysfunctions. By quantifying the interconnected aspects of tissue architecture changes with age, and the manifestation of pathology, we aim to redefine our understanding of the onset of age-associated diseases.

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