The monoclonal antibody (mAb) cetuximab is an important component of cancer therapy for the treatment of squamous cell carcinoma (SCC). Cetuximab targets the epidermal growth factor receptor (EGFR) but patient responses are unpredictable and the biological determinants of antibody therapy sensitivity remain unknown. We hypothesised that the trafficking status of the EGFR may impact the efficacy of the monoclonal antibody treatments directed at this receptor. Analysis of pre-treatment patient SCC tumours showed EGFR trafficking defects which correlated to positive patient outcome after anti-EGFR mAb therapy. By modulating EGFR trafficking in vitro using dynamin inhibitors which blocked the EGFR on the plasma membrane we were able to enhance anti-EGFR mAb (cetuximab)-induced SCC tumour cell death by antibody dependent cellular cytotoxicity (ADCC) in both cetuximab-sensitive and insensitive SCC cells.  In contrast, blocking endocytosis with clathrin inhibitors did not promote ADCC. While both classes of endocytosis inhibitor increased cell surface levels of EGFR, only the dynamin inhibitors induced their cell surface clustering, which may directly influence immune cell activation. Therefore induction of EGFR clustering may promote improved ADCC response in patients, suggesting a new model for targeted combination therapy of cetuximab with dynamin inhibitors. Significantly, we showed in vitro and in mouse models that the commonly used anti-nausea drug, prochlorperazine, inhibited dynamin, and in combination with cetuximab increased ADCC and cleared tumour burden, respectively.  This data supported a phase 1 proof of mechanism trial where we showed in patient tumour biopsies that after prochlorperazine infusion, EGF ligand uptake was blocked at the cell plasma membrane.  Together this data has informed the CESTEM study - Open-label Phase I study investigating the safety and efficacy of Cetuximab and prochlorperazine (STEMetil) combination therapy in patients with metastatic Head and Neck Squamous Cell Carcinoma, Triple Negative Breast Cancer and Adenoid Cystic Carcinoma.  This work is a translation of our laboratory findings to the clinic and is being performed in collaboration with PA Hospital. This trial has the potential to change clinical practice for numerous mAbs used for cancer treatment and improve patient outcomes.