Multi-Dimensional Biomarker Analyses Identify Pembrolizumab Responders In Advanced Stage, High Grade Endometrial Cancer.

Objectives: The recent FDA approval of pembrolizumab for the treatment of recurrent, tissue agnostic cancers with Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) has led to the treatment of a selected cohort of endometrial cancer (EC) patients. Methods: We designed a study to ascertain tumor immune modulatory effects of pembrolizumab in the front-line setting for advanced stage III/IV surgically-resectable endometrial cancers regardless of MSI-H or dMMR status. The primary objectives were to determine the safety of treatment with pembrolizumab by radiographic imaging and to determine progression-free survival at 6 months. Exploratory objective was to compare the immune response before and after treatment. In an open label, single-arm Phase I trial, 8 EC patients were treated with 2 doses of preoperative pembrolizumab IV prior to surgery followed by carboplatin and paclitaxel and 4 doses of pembrolizumab 200mg/kg q3 weeks IV. Peripheral blood was collected from EC patients at baseline level before treatment and post 2 doses of pembrolizumab treatment. Blood from healthy controls (HC) was also collected. Both were processed for high-dimensional single-cell mass cytometry (CyTOF) using an optimized lymphoid and myeloid panel. Results: Patients who responded to therapy showed lower frequency of circulating CD8+ naïve T cells but higher frequency of CD8+ effector T cells after the treatment than the poor responders. We observed post-therapy expansion of populations of CD8+ and CD4+ T cells expressing co-stimulatory receptor ICOS in responders but not in poor responders. Granzyme+CD8+ and Granzyme+CD4+ T cell populations were expanded after pembrolizumab treatment in responders but were decreased in poor responders. Higher frequency of CD27+Fas- CD4+ T cells at baseline and increased frequency of CD27-Fas+CD4+ T cells post-treatment were observed in responders but not in the poor responders. Furthermore, we identified that circulating MDSCs were reduced after pembrolizumab treatment in responders. Conclusions: Our results suggest that peripheral blood analysis may provide valuable insights into responses to anti-PD-1-targeted therapies in patients with endometrial cancers. The recent FDA approval of pembrolizumab for the treatment of recurrent, tissue agnostic cancers with Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) has led to the treatment of a selected cohort of endometrial cancer (EC) patients. We designed a study to ascertain tumor immune modulatory effects of pembrolizumab in the front-line setting for advanced stage III/IV surgically-resectable endometrial cancers regardless of MSI-H or dMMR status. The primary objectives were to determine the safety of treatment with pembrolizumab by radiographic imaging and to determine progression-free survival at 6 months. Exploratory objective was to compare the immune response before and after treatment. In an open label, single-arm Phase I trial, 8 EC patients were treated with 2 doses of preoperative pembrolizumab IV prior to surgery followed by carboplatin and paclitaxel and 4 doses of pembrolizumab 200mg/kg q3 weeks IV. Peripheral blood was collected from EC patients at baseline level before treatment and post 2 doses of pembrolizumab treatment. Blood from healthy controls (HC) was also collected. Both were processed for high-dimensional single-cell mass cytometry (CyTOF) using an optimized lymphoid and myeloid panel. Patients who responded to therapy showed lower frequency of circulating CD8+ naïve T cells but higher frequency of CD8+ effector T cells after the treatment than the poor responders. We observed post-therapy expansion of populations of CD8+ and CD4+ T cells expressing co-stimulatory receptor ICOS in responders but not in poor responders. Granzyme+CD8+ and Granzyme+CD4+ T cell populations were expanded after pembrolizumab treatment in responders but were decreased in poor responders. Higher frequency of CD27+Fas- CD4+ T cells at baseline and increased frequency of CD27-Fas+CD4+ T cells post-treatment were observed in responders but not in the poor responders. Furthermore, we identified that circulating MDSCs were reduced after pembrolizumab treatment in responders. Our results suggest that peripheral blood analysis may provide valuable insights into responses to anti-PD-1-targeted therapies in patients with endometrial cancers.