A New Era for Immune Research

This is indeed an exciting time for research in immunology. Recent salient discoveries on several fronts are ushering in a new age of immune-therapeutics that hold great promise with the potential to provide options for patients who have little to none. These fronts include the discoveries of the programmed cell death protein-1 (PD1) immune checkpoint pathway, the ROR γt-Th 17-IL-17 axis and its role in autoimmune disease, and the role of cannabinoids and their receptors in inflammation. The discovery of PD-1 and its ligand, PD-L1 and PD-L2, quickly led to the realization that tumor cells utilize PD-1 ligand to down regulate T-cell responses and escape from detection and immune attack. This realization came from the finding that PD-L1 expression was detected in numerous cancers but not in normal tissues [1]. Furthermore, PD-L1 or PD-L2 expression by tumor cells was found to be associated with a worse prognosis and decreased survival. In both non small cell lung cancer and melanoma patients, higher levels of PD-1were observed on Tumor-Infiltrating Lymphocytes (TILs) than on circulating lymphocytes [2]. Finally, there was a negative correlation between tumor PD-L2 expression and the presence of CD8+ TILs in esophageal cancer [3]. All of these findings led to the rush of pharmaceutical companies to develop antibodies to PD-1 or its ligands for the blockade of the PD-1 checkpoint pathway. Of these antibodies, nivolumab (Bristol-Myers Squibb), a fully human IgG4 monoclonal antibody against PD-1, is the most advanced in the clinic. In the phase I study, the objective response rate was 31% for a median duration of two years in patients with advanced melanoma [4]. The median overall survival in nivolumab-treated patients was 16.8 months, and 1- and 2-year survival rates were 62% and 43%, respectively. In another study with nivolumab administered concurrently with Yervoy (anti CTLA-4 antibody) in melanoma patients, an overall response rate of 53% was observed [5]. This indicates that even greater efficacy may be observed when multiple checkpoints are targeted while adverse effects remain manageable. The PD-1 checkpoint is also being targeted in combination with vaccines and other immunotherapies to optimize clinical response. There are however, still questions remaining on targeting the PD-1 checkpoint. One important question is in regards to the mechanism responsible for anti-tumor responses in patients who have PDL-1 negative tumors.