Background

HNC is immunosuppressive, with low absolute lymphocyte counts, impaired activity of effectors such as natural killer cells (NK), and poor antigen-presenting function. The anti-EGFR monoclonal antibody cetuximab (CTX) prolongs survival in HNC, but only in a subset of patients. The clinical activity of CTX has been mechanistically linked to NK-mediated antibody-dependent cellular cytotoxicity (ADCC). However, recent data has shown that CTX increases the frequency of intratumoral CTLA-4⁺FoxP3⁺ regulatory T cells (Treg), which suppress ADCC and are associated with poor clinical outcome. In ex vivo experiments, this effect could be attenuated by targeting CTLA-4 on Tregs. Therefore it is possible that the clinical efficacy of CTX may be improved by strategies to enhance the activation of the immune system or inhibit the Treg suppressive effects.

Motolimod (formerly VTX-2337) is a novel Toll-like receptor 8 (TLR8) agonist which stimulates myeloid dendritic cells (mDC), monocytes, and NK. Preclinical data have demonstrated enhanced CTX and NK-mediated lysis of HNC cells and dendritic cross-priming of EGFR-specific CD8+ T cells. CTX and motolimod in HNC patients was tolerable and active in a Phase Ib study, with enhanced mobilization and activation of NK cells. The central hypothesis in this study is that NK and monocyte/mDC activation by CTX is enhanced by concomitant administration of motolimod, thereby amplifying the innate and adaptive immune response in the circulation and in the tumor microenvironment.