Developing next-generation cancer immunotherapies by unraveling the mechanism of T-cell exhaustion

• Applicant: Dr. David Digomann
• Subject Area: Hematology, Oncology ; General and Visceral Surgery
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 568650851

Cancer is still a leading cause of death worldwide and accounts for nearly a sixth of all deaths. During the last decades, an essential improvement in cancer therapies has been made by implementing immunotherapies into treatment approaches. However, the benefits are still limited, and further improvements are awaited. The broad majority of current immunotherapies aim for immune checkpoints trying to reactivate a sufficient immune response. Another immunotherapeutic approach directly aims for the effector cells. For this purpose, tumor-infiltrating lymphocytes (TILs) are collected, expanded, and in some cases, engineered to enhance their natural abilities to eliminate cancer. These cells are then reinfused for therapy. This so-called adoptive cell therapy (ACT) is still in its infancy, and further developments are ongoing. To expand TILs and make them persist in patients, most protocols use non-myeloablative lymphodepleting chemotherapy and high doses of Interleukin (IL)-2. This comes with unintended side effects and economic downsides. Another essential factor for weak immune response and ACT treatment failure is the exhaustion of T lymphocytes due to chronic activation of CD8+ T cells. Recent data from the Coukos Lab support the hypothesis that TILs expanded under high-dose canonical IL-2 temporarily acquire a non-exhausted, highly functional effector state. This project aims to develop a deeper understanding of this effect. First, we will apply CRISPR library screening combined with single-cell sequencing, focusing on epigenetic perturbations that abrogate the IL-2 mediated reprogramming in the context of sustained antigen stimulation. Based on these results, CD8+ T-cells will be gene-engineered to resist exhaustion and have superior antitumor effector potential. To assess the translational potential of the best candidates, tumor-reactive human TILs will be gene-engineered and tested both in vitro (exhaustion assay) and in vivo using patient-derived xenograft (PDX) models. Overall, we expect to discover the molecular mechanisms of the reinvigoration of TILs upon IL-2 in-vitro expansion and anticipate finding therapeutic interventions that mimic the IL-2-mediated effect but prevent the reacquisition of TIL exhaustion upon cell transfer. The research project could enable a cheaper and more efficient approach of ACT and may even lead to a novel immune-modulating drug outside the field of ACT.

• DFG Programme: WBP Fellowship
• International Connection: Switzerland
• Host: Professor Dr. George Coukos