title: Late-Stage Cancer Patients Remain Highly Responsive to Immune Activation by the Selective TLR8 Agonist Motolimod (VTX-2337).
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: VentiRx Pharmaceuticals Inc., Seattle, Washington. gdietsch@ventirx.com.
authors.forename: Gregory N
authors.initials: GN
authors.lastname: Dietsch
authors.affiliation: VentiRx Pharmaceuticals Inc., Seattle, Washington.
authors.forename: Tressa D
authors.initials: TD
authors.lastname: Randall
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Raphael
authors.initials: R
authors.lastname: Gottardo
authors.affiliation: Mayo Clinic, Scottsdale, Arizona.
authors.forename: Donald W
authors.initials: DW
authors.lastname: Northfelt
authors.affiliation: Virginia G. Piper Cancer Center, Scottsdale, Arizona. Translational Genomics Research Institution (TGen), Scottsdale, Arizona.
authors.forename: Ramesh K
authors.initials: RK
authors.lastname: Ramanathan
authors.affiliation: Mayo Clinic, Scottsdale, Arizona.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Cohen
authors.affiliation: VentiRx Pharmaceuticals Inc., Seattle, Washington.
authors.forename: Kristi L
authors.initials: KL
authors.lastname: Manjarrez
authors.affiliation: VentiRx Pharmaceuticals Inc., Seattle, Washington.
authors.forename: Mona
authors.initials: M
authors.lastname: Newkirk
authors.affiliation: VentiRx Pharmaceuticals Inc., Seattle, Washington.
authors.forename: James Kyle
authors.initials: JK
authors.lastname: Bryan
authors.affiliation: VentiRx Pharmaceuticals Inc., Seattle, Washington.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Hershberg
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001552:Benzazepines / Q000494:pharmacology / Q000627:therapeutic use*; D016022:Case-Control Studies; D003131:Combined Modality Therapy; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D056747:Immunomodulation / Q000187:drug effects*; D007167:Immunotherapy; D007958:Leukocyte Count; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D051200:Toll-Like Receptor 8 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D001552:Benzazepines; D016207:Cytokines; D051200:Toll-Like Receptor 8; C573973:VTX-2337