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 with dendritic cells (DCs). This strategy is especially promising for virally induced cancers, because they express viral target antigen, which is absent in healthy tissue. On the other hand, the virus has evolutionary learned to escape the immune response, so here the combination of checkpoint blockade and therapeutic vaccination seems reasonable.
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 an initial trial with a checkpoint-blockade antibody against PD-1 has shown very positive effects, currently MCC-patients receive checkpoint blockade. However, only part 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 therapeutic vaccination. In our already established human ex vivo cell culture systems, in which the immunogenicity of DCs towards autologous T-cells is elucidated, the influence of the different checkpoint-blockade antibodies alone and in combination will be analysed. 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. From the expanded T-cells, a truncLT-specific TCR will be cloned as tool to reprogram T-cells for short-term stimulations. After possible combinations and concentration ranges have been narrowed, we will switch from healthy donor blood to that of MCC patients, because the T-cells, which were preconditioned by the tumour, may behave differently. In parallel, we will examine the expression of the inhibitory receptors targeted by checkpoint-blockade on truncLT-specific patient-derived T-cells.