Immunotherapies have transformed the treatment of melanoma. However, many patients treated with immune checkpoint inhibitors, including dual checkpoint blockade, still do not achieve lasting responses. Growing evidence suggests that therapy resistance can emerge very early, within the DYNAMO Window. This highlights the need to understand and counteract immune escape mechanisms at their earliest stages.
Our project supports DYNAMO’s mission by combining hypothesis-driven T cell engineering, unbiased discovery approaches, and melanoma-focused disease models. Together, these strategies aim to prevent early T cell dysfunction and improve the translational relevance of new immunotherapies.
A central goal is to overcome early glucocorticoid-mediated immunosuppression in the tumor microenvironment. To achieve this, we will engineer melanoma-reactive CAR-T cells that are shielded from glucocorticoid-driven inhibition. These improved CAR-T cells are expected to maintain proliferation and cytotoxic activity under immunosuppressive conditions, while remaining controllable through synthetic dexamethasone administration as a built-in safety switch.
In parallel, we will use optimized CRISPR–Cas9 screening platforms in CAR-T cells to identify key regulators of T cell proliferation, persistence, trafficking, and cytotoxicity during the DYNAMO Window. These unbiased screens will help uncover druggable mechanisms that determine whether T cells remain effective or become dysfunctional at the earliest stages of therapy resistance.

Project Leaders

Hölzel, Michael, Prof. Dr. med.

• https://ieo.uni-bonn.de/

Reinhardt, H. Christian, Prof. Dr. med.

• https://www.lymphoma-lab.de/about-us/the-lymphoma-lab
• https://haematologie.uk-essen.de/