Abstract 3000: Intra-tumoral accumulation of NK1.1CD3 cells and anti-metastasis effects of dose-intensified ONC201 in tumor-bearing mice

• Published in: Cancer research (Chicago, Ill.) Ill.), 2016-07, Vol.76 (14_Supplement), p.3000-3000
• Main Authors: Wagner, Jessica, Kline, Christina LB, Baumeister, Marie, El-Deiry, Wafik S
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2016-3000

ONC201, a novel first-in-class, orally active anti-tumor agent that upregulates the cytotoxic ligand TRAIL (Allen et al., Sci. Trans. Med., 2013; Wagner et al., Oncotarget, 2014), activates the integrated stress response leading to tumor cell upregulation of TRAIL death receptor 5 (Kline et al., Sci. Sig., in press). ONC201 is active against bulk tumor and cancer stem cells (Prabhu et al., Can. Res., 2015). ONC201 is under clinical development by Oncoceutics, and is being evaluated in multiple phase III clinical trials. Results of the first-in-human ONC201 study presented at the 2015 AACR-NCI-EORTC meeting (Stein et al., Abstract C138) demonstrated ONC201 to be safe in humans, to exhibit predicted PK and sustained PD characteristics, and revealed a preliminary efficacy signal. As patients were dosed on an every 3-week schedule, based on supportive preclinical data, we investigated dose-intensification of ONC201 to determine whether a higher dosefrequency schedule might impact efficacy with limited toxicity. We hypothesized that ONC201 may be effective in dose-intensified schedule and may inhibit metastases. We tested a range of ONC201 doses including 25, 50, and 100 mgkg and frequencies including every 4, 3, 2, 1 week as well as twice a week dosing. In colon and triple-negative breast cancer we observed that ONC201 exerts a dose- and schedule-dependent effect on tumor progression in vivo. Frequency effects were more pronounced at lower doses and dose-dependency was more impactful with less frequent schedules. We noted a potent anti-metastasis effect of ONC201 in vivo, not previously reported, as a function of both increased ONC201 dose and frequency of administration. ONC201 inhibits cancer cell migration and invasion in vitro in a TRAIL-dependent manner. We found ONC201 more potently suppresses Akt and ERK in tumors in vivo in a dose- and frequency-dependent manner, whereas its effect on TRAIL serum levels appeared to be impacted by frequency. We observed accumulation of CD3NK1.1 cells within ONC201-treated tumors in athymic nude mice that lack T-cells. Accumulation of CD3NK1.1 cells within ONC201-treated tumors was more pronounced with dose intensification that correlated with superior efficacy. In summary, we have uncovered a potent anti-metastasis effect of ONC201 coupled with the appearance of CD3NK1.1 cells within ONC201-treated tumors. We are further evaluating the biomarker characteristics and immune function of the CD3NK1.1 cells and the relations