CD137 Stimulation Enhances Cetuximab-Induced Natural Killer: Dendritic Cell Priming of Antitumor T-Cell Immunity in Patients with Head and Neck Cancer

Abstract

Purpose Cetuximab, an EGFR-specific antibody (mAb), modestly improves clinical outcome in head and neck cancer (HNC) patients. Cetuximab mediates natural killer (NK) cell:dendritic cell (DC) cross-talk by cross-linking FcγRIIIa, which is important for inducing anti-tumor cellular immunity. Cetuximab activated NK cells upregulate the costimulatory receptor CD137 (4-1BB) which, when triggered by agonistic mAb urelumab, might enhance NK cell functions, to promote T cell based immunity. Experimental design CD137 expression on tumor infiltrating lymphocytes was evaluated in a prospective cetuximab neoadjuvant trial, and CD137 stimulation was evaluated in a phase Ib trial, in combining agonistic urelumab with cetuximab. Flow cytometry and cytokine release assays using NK cells and DC were employed in vitro, testing the addition of urelumab to cetuximab-activated NK, DC, and cross presentation to T cells. Results CD137 agonist mAb urelumab enhanced cetuximab-activated NK cell survival, DC maturation and tumor antigen cross-presentation. Urelumab boosted DC maturation markers, CD86 and HLA DR, and antigen processing machinery (APM) components TAP1/2, leading to increased tumor antigen cross-presentation. In neoadjuvant cetuximab treated HNC patients, upregulation of CD137 by intratumoral, cetuximab-activated NK cells correlated with FcγRIIIa V/F polymorphism and predicted clinical response. Moreover, immune biomarker modulation was observed in an open label, phase Ib clinical trial, of HNC patients treated with cetuximab plus urelumab. Conclusion These results suggest a beneficial effect of combination immunotherapy using cetuximab and CD137 agonist in HNC.

T cell receptor richness in peripheral blood increases after cetuximab therapy and correlates with therapeutic response

“…26 Our group has demonstrated substantial cross-presentation through enhanced NK:DC cross talk, 27 Cetuximab associated NK-cell induced DC maturation therefore influences TA cross-presentation. 13,27,28 This effect on adaptive immunity was also observed by Lou and colleagues, who reported effects on T cell diversity after a combination of cetuximab treatment with chemotherapy in a subgroup of patients. 29 …”

Stimulating T Cells Against Cancer With Agonist Immunostimulatory Monoclonal Antibodies

“…These new trials with the lower dose of urelumab that have minimal liver toxicity are promising as we wait for the final results. The bioactivity of urelumab has been examined in many of these trials and found that urelumab in combination with cetuximab (anti-epidermal growth factor receptor) increases dendritic cell (DC) maturation and NK cell cytotoxicity (Kohrt, Colevas et al, 2014, Srivastava, Trivedi et al, 2017). …”

Biological mechanisms of immune escape and implications for immunotherapy in head and neck squamous cell carcinoma

“…Thirty percent of activated Tregs isolated from HNSCC patients demonstrate OX40 expression in both tumours and tumour draining lymph node samples, compared to none of the peripheral blood mononuclear cells [140]. However, OX40-L expression is low in the tumour, and therefore fails to activateantitumour immune proliferation and cytokine production [141]. If this costimulatory pathway can be expanded and activated, it may enhance tumour-specific immunity and improve patient outcome.…”