Dose intensification of TRAIL-inducing ONC201 inhibits metastasis and promotes intratumoral NK cell recruitment
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
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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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 5

ONC201 induces NK accumulation and activation and CD4/CD8+CD3+ T cell accumulation.

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ONC201 induces NK accumulation and activation and CD4/CD8+CD3+ T cell ac...
(A) Analysis of NK and T cells in MC38 xenografts in NCR1-GFP mice. (B) Immunofluorescence analysis of GFP expression of MC38 xenograft tumors from BL6/129-NCR1-GFP mice and DAPI at ×20 and ×100 magnification. (C) Comparison of T cell and NK cell populations in CT26 tumors in BALB/c mice. (D) Analysis of NK cells and NK cell granzyme expression and MFI in CT26 tumors in BALB/c mice. (E) Relative CT26 tumor volume after 4 weeks in BALB/c mice treated with vehicle, 100 mg/kg ONC201, PD-1, or ONC201+PD-1. (F) Final CT26 tumor volume after 4 weeks in BALB/c mice treated with vehicle, 25 mg/kg ONC201, PD-1, or ONC201+PD-1. For mouse studies: NCR1-GFP mice, n = 4; CT26 PBMC experiment, n = 7; CT26 PD-1 100 mg/kg experiment in E, n = 7; CT26 PD-1 25 mg/kg experiment in F, n = 7. **P < 0.01, ***P < 0.001, relative to vehicle using 2-sided Wilcoxon’s rank-sum test. For immunofluorescence: green, GFP; blue, DAPI. Merge performed by ImageJ. Analysis was performed on 4 sections per tumor; quantitation is shown in Supplemental Figure 9B. Data represent the mean ± SD.