Monoclonal antibody therapy of pancreatic cancer with cetuximab: potential for immune modulation

Pancreatic cancer is a devastating disease, with a median survival of around 6 months for patients with stage IV disease. The epidermal growth factor receptor (EGFR, or HER1) belongs to the erbB receptor tyrosine kinase family. HER1-mediated cell signaling has been shown to play a major role in promoting tumor proliferation, angiogenesis, metastasis, and evasion of apoptosis. Over-expression of HER1 is observed in multiple human malignancies, including colorectal, lung, breast and pancreatic cancers. In pancreatic carcinoma, over-expression of HER1 is observed in greater than 70% of patients and is associated with a poor prognosis and a significant decrease in survival. Cetuximab (Erbitux) is a chimeric monoclonal antibody (mAb) that binds to the extracellular domain of the HER1 molecule preventing ligand binding and promoting internalization and subsequent degradation of the HER1 receptor. Cetuximab has shown anti-tumor activity either alone or in combination with other agents and is currently FDA approved for use in both squamous cell carcinoma of the head and neck (SCCHN) and colorectal carcinoma. Research efforts continue to elucidate a possible role for cetuximab in the treatment of pancreatic cancer. Despite promising preclinical work, phase II and phase III clinical trials have failed to consistently show efficacy of cetuximab treatment in advanced pancreatic cancer either alone or in combination with cytotoxic agents. Alternative approaches to HER1 blockade and mAbs including immune modulation with cytokines might be necessary in order to improve the efficacy of mAbs in pancreatic cancer therapy.