Progress in gastrointestinal cancer immunotherapy

The dramatic success of immune checkpoint inhibitors (ICIs) in metastatic melanoma and nonsmall cell lung cancer (NSCLC) has made them a cornerstone in the therapeutic armamentarium of these malignancies. However, the role of these immunomodulating agents in the spectrum of gastrointestinal (GI) tumors has only recently come into focus. Pre-clinical studies have demonstrated up-regulation of checkpoint molecules [i.e., programmed death-ligand 1 (PD-L1)] and increased somatic mutations in select GI tumors, making checkpoint blockade potentially effective. In the clinical setting, patients with microsatellite instability high (MSI-high) and PD-L1 positive gastric and esophageal cancer have shown pronounced responses to single-agent administration of checkpoint antibodies. More recently, responses have also been seen in subsets of patients with biliary and anal cancer. Furthermore, novel immunotherapeutic strategies have been employed in patients with pancreatic cancer and microsatellite stable colorectal cancer (CRC) with preliminary success. Despite current limitations of small sample sizes, highly anticipated prospective data are expected to accrue in the coming years. Finding new combination strategies and predictive biomarkers of response will be critical in optimizing efficacy of these agents and ensuring the highest likelihood of benefit. In this review, we will explore key clinical trials that investigate ICIs alone or in combination with additional chemotherapy, radiotherapy or immunotherapy in patients with gastric, esophageal, colorectal, pancreas, biliary and anal cancer.