Dose intensification of TRAIL-inducing ONC201 inhibits metastasis and promotes intratumoral NK cell recruitment

• DOI: 10.1172/jci96711
• Publication Date: 2018-03-20T20:43:16Z
• Authors: Jessica Wagner; C. Leah Kline; Lanlan Zhou; Kerry S. Campbell; Alexander W. MacF...; Anthony J. Olszanski; Kathy Q. Cai; Harvey H. Hensley; Eric A. Ross; Marie D. Ralff; Andrew Zloza; Charles B. Chesson; Jenna H. Newman; Howard Kaufman; Joseph Bertino; Mark Stein; Wafik S. El-Deiry
• Keywords: 0301 basic medicine; Cell Death; Dose-Response Relationship, Drug; Cell Survival; Pyridines; Imidazoles; Mice, Nude; HCT116 Cells; Heterocyclic Compounds, 4 or More Rings; Xenograft Model Antitumor Assays; 3. Good health; Killer Cells, Natural; TNF-Related Apoptosis-Inducing Ligand; Mice; 03 medical and health sciences; Pyrimidines; Animals; Humans; Female; Neoplasm Metastasis; Colorectal Neoplasms; Cell Proliferation; Signal Transduction

ONC201 is a first-in-class, orally active antitumor agent that upregulates cytotoxic TRAIL pathway signaling in cancer cells. has demonstrated safety and preliminary efficacy first-in-human trial which patients were dosed every 3 weeks. We hypothesized dose intensification of may impact efficacy. discovered exerts dose- schedule-dependent effects on tumor progression cell death vivo. With intensification, we note potent anti-metastasis effect inhibition migration invasion. Our preclinical results prompted change dosing all open clinical trials. observed accumulation activated NK+ CD3+ cells within ONC201-treated tumors NK depletion inhibits vivo, including against TRAIL/ONC201-resistant Bax–/– tumors. Immunocompetent NCR1-GFP mice, express GFP, GFP+ infiltration syngeneic MC38 colorectal Activation primary human increased degranulation occurred response to ONC201. Coculture experiments identified role for NK-mediated cytotoxicity. Preclinical indicate the potential utility plus anti–PD-1 therapy. an increase TRAIL-secreting peripheral blood after treatment. The offer what believe be unique immune stimulation