Abstract LB-431: Augmented induction of tumor antigen-specific CTL by cetuximab in head and neck cancer patients does not correlate with Fcγ receptor IIIa genotype, but relies on NK:DC cross talk mediated by interferon-γ and NKG2D

Abstract

Abstract Despite over-expression of epidermal growth factor receptor (EGFR) in 80-90% of head and neck cancers (HNC), only ∼20% of HNC patients are clinically responsive to treatment with the EGFR-specific monoclonal antibody (mAb) cetuximab. To date, no reliable biomarker of clinical efficacy has been identified to predict clinical response to cetuximab therapy in HNC. Modest, yet statistically significant correlations of Fcγ receptor (FcγR) IIIa polymorphisms with clinical outcome have been noted in B cell lymphoma, breast, and colorectal cancer patients treated with rituximab, trastuzumab, and cetuximab, respectively. Therefore, we have investigated whether a known FcγRIIIa polymorphism in natural killer (NK) cells at amino acid position 158 (valine [V] vs. phenylalanine [F]) correlates with the anti-tumor activity of cetuximab in immunodeficient mice engrafted with human HNC tumors as well as with the induction of EGFR-specific cytotoxic T lymphocytes (CTL) and clinical course in HNC patients treated with cetuximab. When injected into immunodeficient mice, human NK cells expressing the V allele at this position demonstrated significantly greater ability to control the growth of xenografted HNC tumors. However, we did not find a significant correlation between FcγRIIIa genotype and disease free survival (p=0.683) in a cohort of 107 consecutive HNC patients treated with regimens incorporating cetuximab. Furthermore, we demonstrate for the first time that in the presence of cetuximab-opsonized HNC cells, NK cells trigger maturation of dendritic cells (DC), leading to augmented TA-specific cross-priming of EGFR and MAGE-specific CTL in vitro, and in vivo in cetuximab-treated HNC patients. The significantly higher frequencies of EGFR-specific CTL we found in HLA-A2+ PBMC from cetuximab-treated HNC patients relative to cetuximab-naive HNC patients (p<0.001) also did not correlate with FcγRIIIa genotype, but their induction was dependent on NK:DC cross talk mediated by interferon-γ and NKG2D. Taken together, our data indicate that cetuximab treatment augments the priming of both EGFR and non-EGFR TA-specific cellular immunity in vivo, thereby providing a novel immune mechanism for enhanced anti-tumor activity of TA-specific mAb relevant to clinical response, as well as a potential biomarker for monitoring this response in mAb-treated cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-431. doi:1538-7445.AM2012-LB-431