Immunological Effect of Anti-Epidermal Growth Factor Receptor (EGFR) Antibodies in Squamous Cell Carcinoma of the Head and Neck (HNSCC): the Present and the Future Denaro Nerina 1* , Elvio Grazioso Russi 2 , Lo Nigro Cristiana 3 and Marco Carlo Merlano 1 1Oncology Department Santa Croce e Carle, General Hospital, Via Michele Coppino 21 12100 Cuneo, Italy 2Radiotherapy Department Santa Croce e Carle, General Hospital, Via Michele Coppino 21 12100 Cuneo, Italy 3 Oncology Translational Laboratory, Oncology Department, Santa Croce e Carle, General Hospital Via Michele Coppino, 21 12100 Cuneo, Italy * Corresponding author: Denaro Nerina, Oncology Department Santa Croce e Carle, General Hospital, Via Michele Coppino 21 12100 Cuneo, Italy, Tel: +39 0171616350; Fax: +39 0171616360; E-mail: nerinadenaro@gmail.com Rec date: Jan 29, 2016; Acc date: Mar 10, 2016; Pub date: Mar 14, 2016 Copyright: © 2016 Nerina, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abstract Targeted therapy with anti Epidermal growth factor receptor (EGFR) monoclonal Antibodies (mAbs) offers the potential to improve outcomes in HNSCC. EGFR is over-expressed in 80 to 90% of HNSCC and leads to tumor cell proliferation and invasion. HNSCC is an immunogenic disease, it has a multiplicity of non-mutually exclusive mechanisms of immune suppression (e.g. reduction CD8+ cell influx and altered function of intra-tumoral CD4+ cells). Monoclonal Abs possess the potential advantage of recruiting immune effector mechanisms, such as complement-dependent cytotoxicity (CDC) and Ab-dependent cellular cytotoxicity (ADCC), as additional mechanisms of tumor cell killing. However immunotherapy with the EGFR-specific mAb Cetuximab is clinically effective in 10-20% of patients. There is a need to further understand the immunological mechanism of the mAbs to optimize the design of a target-based immunotherapy. Keywords: Anti EGFR; ADCC; Cetuximab; Immune efectors Introduction Epidermal growth factor receptor (EGFR) is over-expressed in a wide range of malignancies, including HNSCC, and initiates important signal transduction pathways in HNSCC carcinogenesis. mAbs neutralize EGFR promoting apoptosis or arrest growth of tumor cells merely by binding their target. Monoclonal antibodies (mAbs) anti EGFR are widely used in clinical practice, although their optimal use remain unclear [1]. Ideal patient candidate to mAbs, mechanisms of action and resistance of anti EGFR mAbs, the efect of human papillomavirus status on outcomes, their role when combined with induction chemotherapy or adjuvant radiation, and optimal management of skin toxicity and hypersensitivity reactions. Tese mAbs can exert direct antiproliferative/cytotoxic efects as they inhibit pro-survival signal transduction cascades but probably they also induce a tumor-targeting immune response [2]. Primary and acquired resistances are serious problems and are responsible for low single- agent response rate and tumor recurrence. Terapeutic resistance to anti-EGFR therapy may arise from mechanisms that can compensate for reduced EGFR signaling and/or mechanisms that can modulate EGFR-dependent signaling. New anti- EGFR mAbs Nimotuzumab, MEHD7945A, Necitumumab, and RO5083945) are currently under investigation in phase II and III clinical trials in diferent HNSCC therapeutic settings. Te aim of this review is to provide a comprehensive analysis of immuno-modulatory efect of anti EGFR Antibodies. Antibodies Cetuximab is an anti EGFR monoclonal Antibody, chimeric IgG1, with multiple approved indications. It is indicated worldwide for treatment of RAS wild-type, EGFR- expressing, metastatic colorectal cancer in combination with FOLFIRI (irinotecan, 5-fuorouracil, leucovorin) for frst-line treatment; in combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy, and as a single agent in patients who have failed OR are intolerant oxaliplatin- and irinotecan-based chemotherapy. It is used in initial treatment of locally or regionally advanced HNSCC with radiation therapy (RT) OR in monotherapy for recurrent or metastatic HNSCC progressing afer platinum-based therapy (FDA) OR combined with platinum-based therapy with 5-FU for metastatic HNSCC [3,4]. It binds to an epitope of the domain 3 that is stored in Variant III, so that it is active even in the case of EGFRvIII. It has been shown to improve survival in cancers of the head and neck and colon. Recently Schmitz et al. demonstrated that Cetuximab promotes epithelial to mesenchymal transition and cancer associated fbroblasts (which are implicated in clinical resistance) [5]. Panitumumab is an anti EGFR Antibody, human IgG2 indicated for wild-type KRAS (exon 2 in codons 12 or 13) metastatic colororectal carcinoma (mCRC) as determined by an FDA-approved test for this use (eg, therascreen KRAS RGQ PCR Kit). In HNSCC phase III trial SPECTRUM did not reach the primary endpoint (HR 0.87) [6]. ADCC utilizes the response of innate immune cells to provide antitumor cytotoxicity triggered by the interaction of the Fc portion of the antibody with the Fc receptor on the immune cell. Nerina, et al., J Cancer Res Immunooncol 2016, 2:1 Review Open access J Cancer Res Immunooncol, an open access journal Volume 2 • Issue 1 • 1000103 Journal of Cancer Research and Immuno-Oncology J o u r n a l o f C a n c e r R e s e a r c h a n d I m m u n o - O n c o l o g y