A novel compound screen for enhancing T-cell based immunotherapy identifies aurora kinases as a targetable mechanism for tumor immune escape in pancreatic ductal adenocarcinoma preclinical models

Harnessing a patient’s immune system by attenuating endogenous immune checkpoints on T-cells has led to dramatic, durable tumor rejection for multiple tumor types. Nonetheless, many cancers, including pancreatic ductal adenocarcinoma (PDAC), still do not respond to immunotherapy. PDAC remains largely resistant to all therapies, leading to its notoriety as one of the most lethal malignancies, with a 6% 5-year survival rate. We aimed to find novel, targetable mechanisms by which tumors escape the adaptive immune system and resist immunotherapy. We conducted a high throughput screen of 1280 compounds producing a synergistic effect with T-cell killing to assess differences and similarities among distinct pathways inclusive between PDAC and melanoma. These screens identified several aurora kinase inhibitors as synergistic with autologous T-cell killing of tumor target. Here we present results underlying the mechanism by which aurora kinase inhibition enhances autologous T-cell mediated killing and may improve T-cell-mediated cancer immunotherapy. These findings may contribute to the design of new therapeutic combination strategies for enhancing immunotherapy treatment of melanoma, PDAC, and other “immunologically cold” tumors. Note: This abstract was not presented at the meeting. Citation Format: Emily L. Ashkin, Deborah Silverman, Simone Punt, Soraya Zorro Manrique, Leila Williams, Yunfei Wang, Patrick Hwu. A novel compound screen for enhancing T-cell based immunotherapy identifies aurora kinases as a targetable mechanism for tumor immune escape in pancreatic ductal adenocarcinoma preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3956.