Abstract 5193: Assessing the efficacy of immune checkpoint blockade as part of a combination therapy in a zebrafish model of rhabdomyosarcoma

Abstract

Abstract Rhabdomyosarcoma (RMS) is a rare and devastating pediatric soft tissue cancer. There is urgent need to identify more effective therapy options for children suffering from RMS. Immune checkpoint blockade (ICB) has shown promise in several sarcoma types including RMS. In some cancer types, ICB shows enhanced efficacy in combination with a chemotherapeutic agent or an inhibitor against the epigenetic modifiers. Selective chemotherapeutic agents and epigenetic inhibitors (e.g. histone deacetylase inhibitors) have also been shown to increase tumor immunogenicity and sensitize tumor cell response to immune checkpoint inhibitors. However, it remains to be further investigated in RMS how chemotherapy and epigenetic inhibitors modulate immune cell landscape and function and whether the efficacy of ICB combined with either a chemotherapeutic agent or an epigenetic inhibitor is enhanced compared to ICB monotherapy. There is currently no tractable mammalian model for assessing the efficacy of immunotherapy in RMS. Taking advantage of the conserved immune and cancer biology, short tumor onset, high-throughput capability of the zebrafish RMS model, our ongoing research is assessing 1) the efficacy of ICB combined with either a chemotherapeutic agent or an epigenetic inhibitor (histone deacetylases [HDACs] or DNA methyltransferases [DNMTs]) compared to ICB monotherapy on inhibiting RMS tumor growth; 2) effects of chemotherapy and epigenetic inhibition on the make-up and function of tumor-infiltrating immune cells. Our preliminary data so far showed that treatment of zebrafish RMS tumors with the combination of the standard-of-care chemotherapeutic agent, temozolomide, and the immune checkpoint inhibitor, nivolumab, showed increased T cell infiltration. By expression profiling, both temozolomide and nivolumab decreased expression levels of markers for immune checkpoint (pdl1, havcr2) and regulatory T cells (foxp3a) and increased expression levels of markers for inflammatory response (tnfa and infg1). By developing an immune-competent animal model for large-scale testing of important immunotherapy targets and characterizing the immune cell types in the tumor microenvironment of RMS in response to therapy, our research will establish the zebrafish model as a pre-clinical screening tool for testing promising immunotherapeutic agents in vivo, which will facilitate the process of prioritizing promising immunotherapy targets for testing in pre-clinical models and clinical trials and in turn provide therapeutic benefits to children with RMS. Citation Format: Madeline Fritzke, Andrea Largent, Eleanor Chen. Assessing the efficacy of immune checkpoint blockade as part of a combination therapy in a zebrafish model of rhabdomyosarcoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5193.