Late-stage cancer patients remain highly responsive to immune activation by the selective TLR8 agonist motolimod (VTX-2337)

Gregory N. Dietsch, Tressa D. Randall, Raphael Gottardo, Donald W. Northfelt, Ramesh K. Ramanathan, Peter A. Cohen, Kristi L. Manjarrez, Mona Newkirk, James Kyle Bryan, Robert M. Hershberg

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

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, latestage 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.

Original languageEnglish (US)
Pages (from-to)5445-5452
Number of pages8
JournalClinical Cancer Research
Volume21
Issue number24
DOIs
StatePublished - Dec 15 2015

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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