Title
Optimizing (CAR) T cell stemness and persistence through metabolic engineering
Research Area
Microbiology, Immunology, Clinical Immunology, Hematology, Oncology
Project Summary
Chimeric Antigen Receptor (CAR) T cell therapy has revolutionized cancer treatment, particularly in hematologic malignancies. However, its effectiveness in solid tumors remains limited due to challenges in maintaining the functionality and persistence of tumor-infiltrating CAR-T cells. Solid tumors generate a hostile tumor microenvironment (TME), characterized by hypoxia, immunosuppressive cytokines, and metabolic stress, which collectively impair T cell persistence and effector function. To address these challenges, engineering metabolically optimized CAR-T cells capable of coping with these adverse conditions in the TME has emerged as a promising strategy to enhance the efficacy of CAR-T cell therapy. This project aims to augment the stemness, persistence, and longevity of T cells through metabolic, epigenetic and thermodynamic engineering strategies. By preventing T cell exhaustion and augmenting the resilience of (CAR) T cells, our approach seeks to develop an efficient and durable antitumor immunotherapy to overcome the (metabolic) barriers of solid tumors. The goal of this project is to enhance the stemness, persistence, and efficacy of (CAR) T cell products through innovative metabolic-epigenetic engineering strategies, structured into the following four work packages:
Aim 1. Optimizing T cell stemness and longevity via metabolic-epigenetic remodeling
WP#1.1. Enhancing (CAR) T cell stemness by modulating ACLY-mediated protein acetylation. We will investigate how acetyl-CoA generation controls the glycolytic programming, signal transduction and metabolic-epigenetic rewiring to enhance the stemness of engineered T cells.
WP#1.2. Preventing (CAR) T cell exhaustion by optimizing amino acid utilization capacity. We will overexpress natural and synthetic amino acid transporters to improve the stemness and effector function of engineered (CAR) T cells during chronic viral infection and cancer.
Aim 2. Increasing persistence of TILs by targeting ROS and death receptor signaling
The accumulation of dehydroascorbic acid (DHA) in the tumor microenvironment induces the functional exhaustion and apoptosis of T cells. In this aim, we will target death receptor and ROS signaling pathways to enhance the resistance and survival of intratumoral T cells.
Aim 3. Thermic modulation as an engineering procedure to improve CAR-T cell products
Eukaryotic cells adapt to cold-stress to ensure energy homeostasis and survival. We will characterize the metabolic, transcriptional and translational changes in T cells during CAR-T cell production at defined hypothermic conditions aiming to optimize the final CAR-T cell product regarding cellular fitness, subset composition and functionality.
Aim 4: Translational analyses of metabolic programs in CAR-T cell immunotherapy
To define the translational importance of metabolic targets and their dynamic changes associated with patient specific metabolic factors such as obesity and diabetes mellitus for the function and toxicity of CAR-T cell therapy we will analyze serum and tissue specific (bone marrow) metabolome, metabolic gene expression and the metabolic phenotypes of T cells in cancer patients.