Motolimod (VTX-2337)

Target: TLR8

IC50: 100 nM (EC50)

Motolimod (VTX-2337) is a small molecule, selective Toll-like receptor (TLR) 8 agonist with EC50 value of 100 nM [1]. VTX-2337 is currently in clinical development as an immunotherapy for multiple oncology indications, including ovarian cancer and squamous cell carcinoma of the head and neck [2]. TLR8 is located in the endosome where it functions in the recognition of foreign nucleic acids from intracellular pathogens. TLR8 has emerged as a potential target for anticancer immunotherapies [1].

In vitro: VTX-2337 (800 nmol/L) activated NK cells, leading to increased TNFα and IL-12, IFNγ production and VTX-2337 (167 or 500 nmol/L) augmented rituximab- and trastuzumab-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) [1]. Moreover, VTX-2337 (3 or 10 μM) induced mature IL-1β and IL-18 production through NLRP3 inflammasome activation in THP-1 cells [2].

In vivo: VTX-2337 (1 or 10 mg/kg, subcutaneous injection) induced IL-1β and IL-18 production in male cynomolgus monkeys [2].

Clinical trial: In a phase I dose-finding study, VTX-2337 (0.1–3.9 mg/m2, subcutaneous administration) was well tolerated and active with a predictable pharmacologic profile in adult subjects with advanced solid tumors or lymphoma [3].

References:
1.  Lu H, Dietsch GN, Matthews MA, Yang Y, Ghanekar S, Inokuma M, et al. VTX-2337 is a novel TLR8 agonist that activates NK cells and augments ADCC. Clin Cancer Res. 2012;18(2):499-509.
2.  Dietsch GN, Lu H, Yang Y, Morishima C, Chow LQ, Disis ML, et al. Coordinated Activation of Toll-Like Receptor8 (TLR8) and NLRP3 by the TLR8 Agonist, VTX-2337, Ignites Tumoricidal Natural Killer Cell Activity. PLoS One. 2016;11(2):e0148764.
3.  Northfelt DW, Ramanathan RK, Cohen PA, Von Hoff DD, Weiss GJ, Dietsch GN, et al. A phase I dose-finding study of the novel Toll-like receptor 8 agonist VTX-2337 in adult subjects with advanced solid tumors or lymphoma. Clin Cancer Res. 2014;20(14):3683-91.

Phase Ib Trial of the Toll-like Receptor 8 Agonist, Motolimod (VTX-2337), Combined with Cetuximab in Patients with Recurrent or Metastatic SCCHN.[Pubmed:27810904]

Clin Cancer Res. 2017 May 15;23(10):2442-2450.

Purpose: As Toll-like receptors (TLR) are key mediators of immune responses, TLR agonists may be important for augmenting the efficacy of therapies for squamous cell carcinoma of the head and neck (SCCHN). Motolimod (VTX-2337), a selective small-molecule agonist of TLR8, stimulates natural killer (NK) cells, dendritic cells, and monocytes. A phase Ib clinical trial assessed the safety and antitumor activity of motolimod in combination with cetuximab in patients with SCCHN. Correlative biomarkers of immune activity were explored.Experimental Design: Thirteen patients with recurrent or metastatic SCCHN were enrolled in this open-label, dose-escalation study using a standard 3 + 3 design. Doses of motolimod (2.5, 3.0, or 3.5 mg/m(2)) were given on days 1, 8, and 15, in combination with fixed weekly doses of cetuximab in 28-day cycles.Results: There were no protocol-defined dose-limiting toxicities, drug-related deaths, or evidence of synergistic toxicities between motolimod and cetuximab. Clinical tolerability at the 3.5 mg/m(2) dose level was not optimal for repeated dosing and 3.0 mg/m(2) was identified as the MTD. Two patients achieved partial responses for an overall response rate of 15%. Five patients had disease stabilization equating to a disease control rate of 54%. Statistically significant increases in plasma cytokines and in the frequency and activation of circulating NK cells were observed.Conclusions: Motolimod can be safely administered in combination with cetuximab with an acceptable toxicity profile. Encouraging antitumor activity and robust pharmacodynamic responses were observed. Motolimod is being further investigated in a phase II trial in patients with SCCHN (ClinicalTrials.gov ID: NCT01836029). Clin Cancer Res; 23(10); 2442-50. (c)2016 AACR.

Late-Stage Cancer Patients Remain Highly Responsive to Immune Activation by the Selective TLR8 Agonist Motolimod (VTX-2337).[Pubmed:26152744]

Clin Cancer Res. 2015 Dec 15;21(24):5445-52.

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-beta, 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. (c)2015 AACR.