Late-Stage Cancer Patients Remain Highly Responsive to Immune Activation by the Selective TLR8 Agonist Motolimod (VTX-2337)

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, 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.

A phase 2, randomized, double-blind, placebo- controlled study of chemo-immunotherapy combination using motolimod with pegylated liposomal doxorubicin in recurrent or persistent ovarian cancer: a Gynecologic Oncology Group partners study

“…In vivo analytes were quantified in plasma samples collected from patients before and 8 h following motolimod dosing. Post-dose levels of responsive mediators in patients treated with motolimod plus PLD showed statistically significant increases consistent with previous findings in human volunteers and cancer patients who received motolimod monotherapy [18, 19] and ovarian cancer patients treated with motolimod plus PLD [20] (Figure 2A and B; supplementary Table S3, available at Annals of Oncology online). In vivo responses were not significantly associated with longer OS or irPFS (data not shown).…”

“…TLR8 is localized in endosomal compartments of monocytes and mDC and its activation stimulates the release of inflammatory mediators, including T cell helper 1 (Th1)-polarizing cytokines [18, 19]. Motolimod (previously identified as VTX-2337) is a synthetic, small molecule, selective agonist of TLR8 comprising a 2-aminobenzazepine core [20, 21].…”

Integrative Development of a TLR8 Agonist for Ovarian Cancer Chemoimmunotherapy

“…Doses that were proven to be safe and biologically active for each species were used (10, 17). A dose-dependent increase in cytokines and chemokines indicative of TLR8-induced monocyte activation— including IL-6, MCP-1, and MIP-1β—were observed in all species (Figure 2).…”

“…Five men and 5 women healthy volunteers enrolled in a randomized, open-label, phase 1 study of motolimod (Study VRXP-A105) received two doses of motolimod 2.5 mg/m 2 SC separated by one week (17). Plasma samples were collected pre-dose and 6 hours after dosing, and analyzed for mediator levels as described above.…”

Targeting tumor tolerance: A new hope for pancreatic cancer therapy?

“…VTX-2337 is a synthetic TLR8 agonist that demonstrated effectiveness in preclinical models of head and neck cancer through innate immune modulation (Stephenson, et al, 2013). Subsequent phase I dose escalation studies demonstrated safety in patients with advanced cancer (Dietsch, et al, 2015;Northfelt, et al, 2014). However, clinical benefit of this strategy is currently unproven and concerns regarding off-target effects persist.…”