VTX-2337 (USAN: motolimod) is a selective toll-like receptor 8 (TLR8) agonist, 
which is in clinical development as an immunotherapy for multiple oncology 
indications, including squamous cell carcinoma of the head and neck (SCCHN). 
Activation of TLR8 enhances natural killer cell activation, increases 
antibody-dependent cell-mediated cytotoxicity, and induces Th1 polarizing 
cytokines. Here, we show that VTX-2337 stimulates the release of mature IL-1β 
and IL-18 from monocytic cells through coordinated actions on both TLR8 and the 
NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome complex. In 
vitro, VTX-2337 primed monocytic cells to produce pro-IL-1β, pro-IL-18, and 
caspase-1, and also activated the NLRP3 inflammasome, thereby mediating the 
release of mature IL-1β family cytokines. Inhibition of caspase-1 blocked 
VTX-2337-mediated NLRP3 inflammasome activation, but had little impact on 
production of other TLR8-induced mediators such as TNFα. IL-18 activated natural 
killer cells and complemented other stimulatory pathways, including FcγRIII and 
NKG2D, resulting in IFNγ production and expression of CD107a. NLRP3 activation 
in vivo was confirmed by a dose-related increase in plasma IL-1β and IL-18 
levels in cynomolgus monkeys administered VTX-2337. These results are highly 
relevant to clinical studies of combination VTX-2337/cetuximab treatment. 
Cetuximab, a clinically approved, epidermal growth factor receptor-specific 
monoclonal antibody, activates NK cells through interactions with FcγRIII and 
facilitates ADCC of tumor cells. Our preliminary findings from a Phase I 
open-label, dose-escalation, trial that enrolled 13 patients with recurrent or 
metastatic SCCHN show that patient NK cells become more responsive to 
stimulation by NKG2D or FcγRIII following VTX-2337 treatment. Together, these 
results indicate that TLR8 stimulation and inflammasome activation by VTX-2337 
can complement FcγRIII engagement and may augment clinical responses in SCCHN 
patients treated with cetuximab.
TRIAL REGISTRATION: ClinicalTrials.gov NCT01334177.