Immunomodulation of malignant rhabdoid tumors

• Applicant: Dr. Juliane Buhl, Ph.D.
• Subject Area: Hematology, Oncology ; Immunology ; Pediatric and Adolescent Medicine ; Clinical Immunology and Allergology
• Term: from 2020 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 458375005

Although the prognosis of children with cancer has improved significantly during the last decades, malignant rhabdoid tumors (MRTs) remain one of the big challenges. MRTs arise during embryonal development through a block in cell differentiation and occur in the brain, the kidneys and soft tissues. Even with aggressive treatment regimen the 4-year overall survival is only 23%.Recently, cytotoxic T-cell infiltration and expression of immunomodulatory markers such as PD-L1 have been reported for MRTs. Although initial clinical studies indicate that checkpoint inhibition may be a potential treatment option for MRT, patients relapsed under monotherapy. Therefore, more effective combination or novel tumor-specific therapies need to be developed. We hypothesize that the block in differentiation during fetal development underpinning MRTs could preserve unique embryonic antigens, which are no longer present in matured tissues. Such antigens could serve as tumor-specific therapeutic targets. With this proposal, I aim to develop immunotherapeutic treatment strategies for MRT patients using a cutting-edge proteomics approach in combination with unique patient-derived organoid and immune cell co-culture models. To do so, I have defined the following objectives:1. Identify MRT-specific cell surface antigens and generation of therapeutic monoclonal antibodies.I will perform cell surface proteomics on MRT as well as patient-matching healthy tissue organoids to identify MRT-specific cell surface antigens. MRT-specific antigens will be validated in primary tissue samples and several pediatric tumor and healthy tissue-derived organoid models with repurposed or newly developed therapeutic monoclonal antibodies generated in our in-house antibody production platform. 2. Develop an antibody-based therapy for MRT patients.The anti-tumor activity and mechanism of action of the therapeutic monoclonal antibodies will be assessed with viability assays and antibody-dependent cellular toxicity assays using MRT and healthy tissue-derived organoids.3. Investigate the response of MRTs to immunotherapeutic treatment approaches in a co-culture system.A co-culture system of patient-derived MRT organoids and patient-matching tumor infiltrating lymphocytes will be used to test different immunotherapeutic strategies such as mono- or combination therapy with the established monoclonal antibodies, checkpoint inhibitors as well as CAR T-cells directed against MRT-specific targets. Viability assays, flow cytometry and live-cell imaging will serve read-out for therapeutic response.Ultimately, the unique co-culture model will allow the establishment of a patient-tailored platform to evaluate different immunotherapeutic treatment strategies and develop a targeted, more effective treatment approach for MRT patients.

• DFG Programme: WBP Fellowship
• International Connection: Netherlands
• Host: Dr. Jarno Drost, Ph.D.