Prior exposure of pancreatic tumors to [sorafenib plus vorinostat] enhances the efficacy of an anti-PD-1 antibody

摘要

Checkpoint immunotherapy antibodies have not shown efficacy in pancreatic adenocarcinoma. Pre-clinical studies and subsequently an on-going phase I trial have demonstrated the safety and efficacy of combinatorial radio-chemotherapy plus surgery in this malignancy, including the combination of sorafenib and vorinostat. The lethality of [sorafenib + vorinostat] was enhanced by gemcitabine. Exposure to [sorafenib + vorinostat] reduced the expression of beta-catenin, ERBB1, BCL-XL and MCL-1, and the phosphorylation of AKT T308, AKT S473, GSK3 S9/21, mTORC1 and mTORC2. The drug combination increased the expression of Beclin1 and the phosphorylation of eIF2 alpha S51. The drug combination rapidly reduced the levels of multiple HDAC proteins that was directly associated with the previously noted changes in tumor cell biology, as well as with alterations in the expression of biomarkers predictive for a response to checkpoint inhibitor antibodies. In vivo studies using the PAN02 model in its syngeneic mouse demonstrated that an anti-PD-1 antibody had no impact on tumor growth whereas a transient exposure to [sorafenib + vorinostat] significantly suppressed growth. The combination of [sorafenib + vorinostat] with an anti-PD-1 antibody caused a significant further reduction in tumor growth compared to the drug combination alone. Tumors transiently exposed three weeks earlier to [sorafenib + vorinostat] contained elevated levels of CD8+ cells, M1 macrophages and natural killer cells. Drug exposure plus an anti-PD-1 antibody further significantly enhanced the levels of these immune cells in the tumor. Our data argue for performing a new phase I trial in pancreatic cancer combining immunotherapy with [sorafenib + vorinostat]. Abbreviations: ERK: extracellular regulated kinase; PI3K: phosphatidyl inositol 3 kinase; ca: constitutively active; dn: dominant negative; ER: endoplasmic reticulum; AIF: apoptosis inducing factor; AMPK: AMP-dependent protein kinase; mTOR: mammalian target of rapamycin; JAK: Janus Kinase; STAT: Signal Transducers and Activators of Transcription; MAPK: mitogen activated protein kinase; PTEN: phosphatase and tensin homologue on chromosome ten; ROS: reactive oxygen species; CMV: empty vector plasmid or virus; si: small interfering; SCR: scrambled; IP: immunoprecipitation; VEH: vehicle; HDAC: histone deacetylase.