Dose intensification of TRAIL-inducing ONC201 inhibits metastasis and promotes intratumoral NK cell recruitment
Jessica Wagner, … , Mark Stein, Wafik S. El-Deiry
Jessica Wagner, … , Mark Stein, Wafik S. El-Deiry
Published March 13, 2018
Citation Information: J Clin Invest. 2018;128(6):2325-2338. https://doi.org/10.1172/JCI96711.
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Research Article Oncology

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

Abstract

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–/– 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–PD-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.

Authors

Jessica Wagner, C. Leah Kline, Lanlan Zhou, Kerry S. Campbell, Alexander W. MacFarlane, 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

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Figure 1

ONC201 dose intensification negatively impacts tumor growth and metastasis.

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ONC201 dose intensification negatively impacts tumor growth and metastas...
(A) Mouse cohorts received 25 mg/kg or 100 mg/kg weekly, every 2, 3, or 4 weeks. Shown is the percent tumor growth of both dose and frequency of ONC201 over time in athymic female nu/nu mice using HCT116 p53–/– colorectal cancer xenografts. (B) Final HT29-luciferase tumors harvested after 4 weeks from cohorts administered weekly vehicle or 100 mg/kg ONC201 treatment. Blue arrows indicate metastatic tumors. (C) Final HT29-luciferase bioluminescence of cohorts administered 100 mg/kg at different frequencies and harvested after 4 weeks, with corresponding RLU for the whole cohort. n = 6 HT29 and HCT116 p53–/–. Percent tumor calculated by diving each tumor volume by the average tumor volume in the vehicle-treated group and multiplying by 100. *P < 0.05, **P < 0.01 compared with vehicle using 2-sided Wilcoxon’s rank-sum test. Data represent mean ± SD.