A Phase 1b Study of Neoadjuvant Immune Biomarker Modulation With Cetuximab and Motolimod in Head and Neck Cancer (HNC)

Abstract

Inflamed tumors are known to generate a better response to immunotherapy. HNC has many immunosuppressive features, including impaired natural killer cell (NK) activity. The monoclonal antibody cetuximab (CTX) is effective in a subset of HNC patients, with clinical activity linked to NK-mediated antibody-dependent cellular cytotoxicity (ADCC). Recent data show 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. It is possible that the clinical efficacy of CTX may be improved by enhancing tumor inflammation, activating the immune system, and/or inhibiting the Treg suppressive effects. Motolimod (VTX-2337), a novel Toll-like receptor 8 (TLR8) agonist. Preclinical data show 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 1b study, with enhanced NK cell activity. 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 (TM). In this prospective phase 1b clinical trial (NCT02124850) of preoperative treatment with CTX and motolimod, the primary objective is to evaluate how neoadjuvant CTX plus motolimod modulates innate and adaptive immune biomarkers. An exploratory objective of the study is to assess whether this modulation of biomarkers can predict antitumor response. Subjects (n=12) with stage II–IVA HNC received weekly doses of CTX and motolimod followed by definitive surgical resection. Biomarker modulation in tumor and blood are correlated with clinical response by CT or MRI. Tumor apoptosis/proliferation is assessed by biopsy pre- and posttreatment. Phenotypic markers of suppression in Treg were reduced when motolimod was combined with CTX, including lower levels of CTLA-4 (P=.01), CD73 (P=.04), and membrane-bound TGF-β (P=.05). These mediators were induced in nonresponders in our single-agent cetuximab therapy study (P=.005). Myeloid antigen–presenting cells achieved strong maturation and expression of stimulatory markers in the peripheral blood. CTX plus motolimod induces inflammatory changes in the TM and peripheral blood. Treg-suppressive mediators are reduced with CTX/motolimod, overcoming a negative prognostic biomarker (Treg induction) of CTX therapy alone. A pending amendment will assess the impact of adding checkpoint inhibition to the CTX/motolimod combination.