Project B4: Jan Dörrie

A current and highly successful anti-cancer immunotherapy inhibits the natural brakes of the immune system with antagonistic antibodies. These checkpoint blockers have proved their efficiency in melanoma and other cancers, and their field of application is rapidly extending. However, many patients do not benefit since these antibodies cannot redirect but only release an existing but inhibited immune response. Such a redirection can be achieved by therapeutic vaccination. This strategy is especially promising for virally induced cancers, because they express viral target antigen, which is absent in healthy tissue, so here the combination of checkpoint blockade and therapeutic vaccination seems reasonable. RNA-based immunotherapies have long been pursued and received a booster due to the successful application during the Covid-pandemic. mRNA-transfection appears as an ideal strategy to deliver antigen and reprogram  immune cells in and ex vivo.

Merkel Cell Carcinoma (MCC) is an aggressive skin cancer, caused by the Merkel Cell Polyomavirus (MCV). Under certain circumstances, the virus integrates into the host cell genome and expresses a truncated form of its large T antigen (truncLT), while expression of other viral proteins is switched off. Until recently, no standardized therapy for MCC existed, apart from surgical excision, but since several clinical trials with checkpoint-blockade antibodies against PD-1 and its ligand PD-L1 have shown very positive effects, currently MCC-patients receive checkpoint blockade. However, only about half of the patients benefit from this treatment. We think that the efficacy of anti-PD-1 and other checkpoint-blocking antibodies can be further increased by active therapeutic vaccination against truncLT.

The aim of this project is to evaluate a possible combination of checkpoint inhibitors and RNA-based immunotherapy. In our already established human ex vivo cell culture systems, we will examine the interaction of T cells and NK cells with professional antigen-presenting cells and tumor cells. Using mRNA-transfection on the different players in this system, we will determine how immune responses against the tumor can be improved. In addition, possible synergistic influences of the different checkpoint-blockade antibodies will be evaluated. The expansion of CD4⁺ and CD8⁺ truncLT-specific T-cells, their phenotype, functional capacities concerning cytokine secretion and cytotoxicity, and repetitive expandability will be addressed, and the activation and functionality of NK-cells will be tested. In parallel, we examine the intracellular signaling within the tumor cells to find means of manipulating these by in mRNA transfection to become more immunogenic. After possible combinations have been narrowed, we will switch from healthy donor blood to that of MCC patients, because immune cells, which were preconditioned by the tumor, may behave differently.