A Phase Ib Study of Immune Biomarker Modulation with Neoadjuvant Cetuximab and TLR8 stimulation in Head and Neck Cancer to Overcome Suppressive Myeloid Signals

Purpose: The response rate of head and neck squamous cell carcinoma (HNSCC) patients to cetuximab therapy is only 15-20%, despite frequent EGFR overexpression. Since immunosuppression is common in HNSCC, we hypothesized that adding a pro-inflammatory TLR8 agonist to cetuximab therapy might result in enhanced T lymphocyte stimulation and anti-EGFR specific priming. Experimental Design: Fourteen patients with previously untreated HNSCC were enrolled in this neoadjuvant trial and treated preoperatively with 3-4 weekly doses of motolimod (2.5 mg/m²) and cetuximab. Correlative tumor and peripheral blood specimens were obtained at baseline and at the time of surgical resection and analyzed for immune biomarker changes. Preclinical in vitro studies were also performed to assess the effect of cetuximab plus motolimod on myeloid cells. Results: TLR8 stimulation skewed monocytes toward an M1 phenotype and reversed MDSC suppression of T cell proliferation in vitro. These data were validated in a prospective phase Ib neoadjuvant trial, in which fewer MDSC and increased M1 monocyte infiltration were found in TIL. Motolimod plus cetuximab also decreased induction of Treg, and reduced markers of suppression, including CTLA-4, CD73 and membrane bound TGF-β. Significantly increased circulating EGFR-specific T cells were observed, concomitant with enhanced CD8+ T cell infiltration into tumors. These T cells manifested increased TCR clonality, upregulation of the costimulatory receptor CD27, and downregulation of inhibitory receptor TIGIT. Conclusions:Enhanced inflammatory stimulation in the tumor microenvironment using a TLR agonist overcomes suppressive myeloid and regulatory cells, enhancing the cellular antitumor immune response by therapeutic mAb in HNSCC.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2y1yQxL