Abstract
Abstract VTX-2337 (motolimod) is a selective toll-like receptor 8 (TLR8) agonist in clinical development as an immunotherapy for multiple oncology indications, including squamous cell carcinomas of the head and neck (SCCHN). Activation of TLR8 has been found to enhance natural killer (NK) cell activation, increase antibody-dependent cell-mediated cytotoxicity (ADCC), and induce Th1 polarizing cytokines. Further characterization of VTX-2337 reveals the release of mature IL-1β and IL-18 from monocyte cell populations through coordinated actions on both TLR8 and NLRP3. In vitro, VTX-2337 primes monocytes to produce pro-IL-1β, pro-IL-18 and caspase 1, while activating the NLRP3 inflammasome, leading to the release of mature IL-1 family cytokines. Inflammasome activation by VTX-2337 is blocked by inhibiting caspase 1, with little impact on the production of other TLR8 induced mediators such as TNFα. The release of IL-18 stimulates NK cells, and augments other activation pathways including: FcγRIII and NKG2D receptors, resulting in IFNγ production and induction of CD107α. NLRP3 activation in vivo was confirmed by a dose-related increase in plasma levels of IL-1β and IL-18 in cynomolgus monkeys administered VTX-2337. This pathway for NK activation was subsequently assessed in SCCHN patients treated with VTX-2337 in combination with cetuximab, a clinically approved epidermal growth factor receptor (EGFR) specific monoclonal antibody (mAb). Cetuximab can activate NK cells through an interaction with FcγRIII, and facilitate ADCC of tumor cells. Preliminary data from a Phase I clinical trial found that prior to treatment, patient NK cells did not effectively activate in response to ex vivo stimulation by NKG2D or FcγRIII. However, following VTX-2337 treatment, patient NK cells become more responsive to these activating signals. These results show that TLR8 stimulation and inflammasome activation by VTX-2337, can complement FcγRIII engagement, and may augment clinical responses in SCCHN patients treated with cetuximab. Citation Format: Greg Dietsch, Haling Lu, Yi Yang, Chihiro Morishima, Laura Q. Chow, Mary L. Disis, Robert Hershberg. Coordinated activation of TLR8 and NLRP3 by VTX-2337 (motolimod) ignites tumoricidal NK cell activity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 286. doi:10.1158/1538-7445.AM2015-286
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