%0 Journal Article
%T Dose intensification of TRAIL-inducing ONC201 inhibits metastasis and promotes intratumoral NK cell recruitment
%A Alexer W. MacFarlane
%A Andrew Zloza
%A Anthony J. Olszanski
%A C. Leah Kline
%A Charles B. Chesson
%A Eric A. Ross
%A Harvey H. Hensley
%A Howard Kaufman
%A Jenna H. Newman
%A Jessica Wagner
%A Joseph Bertino
%A Kathy Q. Cai
%A Kerry S. Campbell
%A Lanlan Zhou
%A Marie D. Ralff
%A Mark Stein
%A Wafik S. El-Deiry
%J The Journal of Clinical Investigation
%D 2018
%R 10.1172/JCI96711
%X ONC201 is a first-in-class, orally active antitumor agent that upregulates cytotoxic TRAIL pathway signaling in cancer cells. ONC201 has demonstrated safety and preliminary efficacy in a first-in-human trial in which patients were dosed every 3 weeks. We hypothesized that dose intensification of ONC201 may impact antitumor efficacy. We discovered that ONC201 exerts dose- and schedule-dependent effects on tumor progression and cell death signaling in vivo. With dose intensification, we note a potent anti-metastasis effect and inhibition of cancer cell migration and invasion. Our preclinical results prompted a change in ONC201 dosing in all open clinical trials. We observed accumulation of activated NK+ and CD3+ cells within ONC201-treated tumors and that NK cell depletion inhibits ONC201 efficacy in vivo, including against TRAIL/ONC201-resistant Bax¨C/¨C tumors. Immunocompetent NCR1-GFP mice, in which NK cells express GFP, demonstrated GFP+ NK cell infiltration of syngeneic MC38 colorectal tumors. Activation of primary human NK cells and increased degranulation occurred in response to ONC201. Coculture experiments identified a role for TRAIL in human NK-mediated antitumor cytotoxicity. Preclinical results indicate the potential utility for ONC201 plus anti¨CPD-1 therapy. We observed an increase in activated TRAIL-secreting NK cells in the peripheral blood of patients after ONC201 treatment. The results offer what we believe to be a unique pathway of immune stimulation for cancer therapy
%U https://www.jci.org/articles/view/96711