TY - JOUR
T1 - Phase Ib study of immune biomarker modulation with neoadjuvant cetuximab and TLR8 stimulation in head and neck cancer to overcome suppressive myeloid signals
AU - Shayan, Gulidanna
AU - Kansy, Benjamin A.
AU - Gibson, Sandra P.
AU - Srivastava, Raghvendra M.
AU - Bryan, James Kyle
AU - Bauman, Julie E.
AU - Ohr, James
AU - Kim, Seungwon
AU - Duvvuri, Umamaheswar
AU - Clump, David A.
AU - Heron, Dwight E.
AU - Johnson, Jonas T.
AU - Hershberg, Robert M.
AU - Ferris, Robert L.
N1 - Funding Information: This study was supported by NIH grants R01 CA206517, DE019727, P50 CA097190, and T32 CA060397, and the University of Pittsburgh Cancer Institute award P30 CA047904. This project used the UPCI Flow Cytometry Facility that is supported in part by award P30 CA047904. G. Shayan was supported by the China Scholarship Council. Publisher Copyright: © 2017 AACR.
PY - 2018/1/1
Y1 - 2018/1/1
N2 - Purpose: The response rate of patients with head and neck squamous cell carcinoma (HNSCC) to cetuximab therapy is only 15% to 20%, despite frequent EGFR overexpression. Because immunosuppression is common in HNSCC, we hypothesized that adding a proinflammatory 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 to 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 myeloid-derived suppressor cell (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 tumor-infiltrating lymphocytes. Motolimod plus cetuximab also decreased induction of Treg and reduced markers of suppression, including CTLA-4, CD73, and membrane-bound TGFβ. Significantly increased circulating EGFRspecific T cells were observed, concomitant with enhanced CD8+ T-cell infiltration into tumors. These T cells manifested increased T-cell receptor (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.
AB - Purpose: The response rate of patients with head and neck squamous cell carcinoma (HNSCC) to cetuximab therapy is only 15% to 20%, despite frequent EGFR overexpression. Because immunosuppression is common in HNSCC, we hypothesized that adding a proinflammatory 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 to 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 myeloid-derived suppressor cell (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 tumor-infiltrating lymphocytes. Motolimod plus cetuximab also decreased induction of Treg and reduced markers of suppression, including CTLA-4, CD73, and membrane-bound TGFβ. Significantly increased circulating EGFRspecific T cells were observed, concomitant with enhanced CD8+ T-cell infiltration into tumors. These T cells manifested increased T-cell receptor (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.
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U2 - 10.1158/1078-0432.CCR-17-0357
DO - 10.1158/1078-0432.CCR-17-0357
M3 - Article
C2 - 29061643
SN - 1078-0432
VL - 24
SP - 62
EP - 72
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 1
ER -