Humanized Ovarian Cancer Patient-Derived Xenografts for Improved Preclinical Evaluation of Immunotherapies.

Abstract

Simple SummaryEpithelial ovarian cancer (EOC) is a heterogenous disease and new combination therapies are employed to improve treatment, decrease disease recurrence, and avoid the development of treatment resistance. Immunotherapy has been suggested to boost the immune system and improve the prognosis of EOC patients. However, overall low response rates and missing reliable biomarkers to stratify patients to their best-suited personalized treatment regime hinder the successful implementation. Our aim is to advance the development and characterization of humanized patient-derived xenograft models aiding to unravel the function and interaction of the unique tumor microenvironment and the immune system in EOC. These developed and clinically relevant humanized models of EOC have the potential to test various immune cell-targeting combination therapies and identify mechanisms in heterogenous EOC cohorts to ultimately allow patient stratification.High-grade serous ovarian cancer (HGSOC) has poor prognosis and new treatment modalities are needed. Immunotherapy, with checkpoint inhibitors, have demonstrated limited impact. To evaluate the suitability for immunotherapeutics, contextualized preclinical models are required to secure meaningful clinical translation. Therefore, we developed and characterized humanized patient-derived xenograft (hu PDX) murine models of HGSOC, which were established by orthotopic implantation of tumor cell suspensions and intravenous injection of CD34+ cells isolated from umbilical cord blood samples. The developing human immune system in NSG and NSGS mice was followed longitudinally by flow cytometry and characterized by mass cytometry with a panel of 34 surface markers. Molecular imaging of tumor burden, survival analysis, and characterization of tumor-infiltrating immune cells was performed to assess the treatment response to anti-PD-1 (nivolumab) monotherapy. Successful generation of hu PDX models was achieved. Mice treated with nivolumab showed a decrease in tumor burden, however no significant survival benefit was identified when compared to untreated controls. No correlation was seen between PD-L1 expression and CD8 T cell infiltration and response parameters. As the characterization showed an immune infiltration of predominantly myeloid cells, similar to what is observed in HGSOC patients, the models may have the potential to evaluate the importance of myeloid cell immunomodulation as well.