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 2

ONC201 triggers dual ERK/Akt inactivation, ISR signaling, and TRAIL upregulation in tumor cells.

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ONC201 triggers dual ERK/Akt inactivation, ISR signaling, and TRAIL upre...
(A) HT29 tumor xenograft protein lysates analyzed by Western blots treated with (left) 25 mg/kg at varying frequencies and (right) increasing dose up to 100 mg/kg and varying frequency of administration as indicated. (B) Induction of ATF4, CHOP, and TRAIL mRNA in HT-29 xenografted tumors following (left) increasing dose with weekly administration of ONC201 or (right) frequency of ONC201 dosing at 50 mg/kg. (C) Serum TRAIL levels measured by nonspecific ELISA compared following administration of ONC201 at a 25 mg/kg dose at different frequencies in MDA-MB-231 xenograft–bearing mice. Treatments are indicated by arrows. AUC values are shown above. For Western blots and qRT-PCR: n = 6, run twice in triplicate of each sample. For ELISA, n = 4 run in duplicate, samples were frozen until end of mouse experiment and then run through the assay. All samples were harvested 4 weeks after treatment began, unless otherwise indicated. *P < 0.05, **P < 0.01, ***P < 0.005, compared with vehicle unless indicated, 2-sided Wilcoxon’s rank sum test; for C, only the last time point was analyzed for statistical significance. Data represent mean ± SD.