Improvement of the Merkel Cell Carcinoma treatment through the combination of different immune therapies
Merkel Cell Carcinoma (MCC) is a rare but highly aggressive skin tumor caused by the usually non-oncogenic Merkel Cell Polyomavirus. This virus can integrate into the host cells` genome and express a truncated form of one of its proteins, the large T antigen (truncLT). Until recently, metastatic MCC was treated with surgical excision as well as radio- and chemotherapy but the treatment with checkpoint inhibitors such as anti-PD-1/PD-L1 (programmed death 1 receptor/PD-ligand 1) and anti-CTLA-4 (cytotoxic T-lymphocyte-associated Protein 4) has shown outstanding clinical response rates of over 50%. These antagonistic antibodies target inhibitory receptors on T cells and their ligands to enhance anti-tumor immune responses. However, this treatment strategy can only release an existing but inhibited immune response, while a de novo induction of tumor-specific T cells requires an active immunization. One possible option to accomplish this is dendritic cell-based therapeutic vaccination. In general, dendritic cells (DCs) process and present antigens and are the only cells capable of inducing new T-cell mediated immune responses.. Therefore, ex vivo generated DCs loaded with viral target antigens can be used to treat virally induced cancers, as it is already evaluated in several clinical trials.
The aim of this project is to evaluate whether a combination of checkpoint inhibitors and therapeutic DC-based vaccination against MCC and other virally induced cancers is feasible. Improving the response rate to checkpoint inhibition by increasing the number of tumor-specific T cells by DC-based vaccination could lead to a better MCC treatment but this strategy could also be applied to other virally induced malignancies.
The previous PhD student Dr. Tatjana Sauerer performed T-cell stimulation experiments with DC presenting the truncLT antigen in presence of checkpoint inhibitors. These experiments showed that a simultaneous application of a DC-based vaccine with Avelumab, the only approved checkpoint inhibitor for metastatic MCC, seems unfeasible due to an observed Avelumab-mediated antibody-dependent cellular cytotoxicity (ADCC) against the DCs during the T-cell priming in our ex vivo cell culture system.
To relate more to the in vivo situation we will characterize the PD-L1 expression in different DC subpopulations in primary blood from healthy donors as well as from patients under Avelumab treatment and test their susceptibility to this observed ADCC. This will be done in collaboration with Prof. Dudziak (project B2). This project will also investigates alternative strategies to combine checkpoint blockade and DC-based vaccination. For this, a sequential application of Avelumab and the vaccine will be examined. Furthermore, a combination with other PD-L1 checkpoint inhibitors like Durvalumab and Atezolizumab, which are modified to inhibit FC-receptor binding, as well as PD-L1-negative DCs as the base of the vaccine will be considered. To analyze the immunogenicity of DCs to autologous T cells, we will use our established ex vivo cell culture system and evaluate the influence of the different checkpoint-blockade antibodies and alternative timing of application. 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. With the acquired knowledge, the therapeutic options for treatment of MCC may be improved and patients initially not benefitting to checkpoint inhibition may be rendered from non-responders to responders.
