Abstract A07: Plinabulin: Evidence for an immune-mediated mechanism of action

Abstract

Abstract The purpose of this study was to investigate the evidence for an immune-mediated mechanism of action for plinabulin. Plinabulin, a novel compound for use in oncology, is an inhibitor of tubulin polymerization, induces direct tumor cell apoptosis (Nicholson et al, 2006), inhibits angiogenesis and activates the JNK pathway (Singh et al, 2011) and is in Phase 3 trials for NSCLC (Bazhenova, 2015). The methods for the in vitro and in vivo studies performed are described by Martin et al (2014) and Müller et al (2014). Recent data from in vitro studies demonstrate that plinabulin enhances immune responses as (1) it increases dendritic cell maturation as evidenced by elevated levels of CD40, MHCII, CD80 and CD86 and (2) the release of pro-inflammatory cytokines such as IL-1beta, IL-6 and IL12p40. These increases were similar to those observed with LPS. Paclitaxel and etoposide were inactive in these assays. In the MC-38 syngeneic colon tumor model in the C57BL/6 immunocompetent mouse, plinabulin (7.5 mg/kg, IP, BIW) significantly enhanced the therapeutic effect of combined PD-1/CTLA-4 inhibition on tumor volume, with a maximal effect occurring between days 13-20 after initiation of treatment. When tumor weight was measured at necropsy, plinabulin significantly enhanced the effect of both PD-1 inhibition and combined PD-1 + CTLA-4 inhibition. In this regard, evidence has been provided that agents which interfere with tubulin polymerization (e.g. ansamytocin-P3, dolastatin-10), but not microtubule stabilizing agents (e.g. docetaxel, paclitaxel) promote anti-tumor immunity as demonstrated by dendritic cell maturation and enhanced T-cell activation both in vitro and in vivo. In addition, the microtubule depolymerizing agents act synergistically with immune checkpoint inhibitors (Martin et al, 2014, Müller et al, 2014). These data indicate an immune mediated mechanism of action of plinabulin and provide the basis for initiating a clinical trial of plinabulin with the PD-1 mAb Nivolumab in metastatic NSCLC (Yeh et al, 2015). Citation Format: George Kenneth Lloyd, Philipp Mueller, ALfred Zippelius, Lan Huang. Plinabulin: Evidence for an immune-mediated mechanism of action. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr A07.