PURPOSE: Immunotherapy as a treatment for cancer holds the promise of complete 
and durable tumor remission, yet the immunosuppressive environment created by 
many tumors, advanced patient age, and previous treatments with cytotoxic agents 
may limit the approach. The activity of motolimod (VTX-2337), a potent and 
selective Toll-like receptor 8 (TLR8) agonist, was therefore assessed in the 
context of advanced, late-stage cancer patients.
EXPERIMENTAL DESIGN: The repertoire of mediators induced from human peripheral 
blood mononuclear cells in response to motolimod was characterized. 
Translational studies in cynomolgus monkeys elucidated the activity of motolimod 
on an intact immune system, identified biomarkers of TLR8 activation, and 
defined the relationship between the pharmacokinetic and pharmacodynamic (PK/PD) 
response. The PK/PD relationship for motolimod in cancer patients was assessed, 
compared with preclinical findings, and contrasted with activity in healthy 
volunteers.
RESULTS: In late-stage cancer patients, plasma levels of multiple biomarkers, 
including IL6, G-CSF, MCP-1, and MIP1-β, increased with increasing motolimod 
dose. The magnitude and breadth of the biomarker response closely aligned with 
the response seen in preclinical studies, demonstrating that advanced cancer 
patients remained responsive to TLR8 activation. In addition, the PK/PD response 
in cancer patients closely aligned with the activity of motolimod seen in 
healthy volunteers.
CONCLUSIONS: Late-stage cancer patients are highly sensitive to TLR8 activation 
by motolimod. Tumor burden, advanced age, and prior treatment history with 
cytotoxic agents did not moderate or modify the response predicted by 
nonclinical studies and confirmed in healthy volunteers. Clin Cancer Res; 
21(24); 5445-52. ©2015 AACR.