Immue checkpoint inhibitors. Clinical point of views from JSMO

Abstract

Recent progress in cancer immunotherapy has been remarkable. Most striking is the clinical development and approval of immunomodulators, also known as immune checkpoint inhibitors. While mAbs targeting tumor associated antigens, such as anti-CD20 mAb and anti-Her2 mAb, directly recognize tumor cells and induce cell death using such as ADCC activity, immune checkpoint inhibitors restore and augment the anti-tumor immune activities of cytotoxic T cells by mainly blocking immune checkpoint molecules on T cells or their ligands on antigen presenting and tumor cells. Based on preclinical data, many clinical trials have demonstrated the acceptable safety profiles and efficacies of immune checkpoint inhibitors in a variety of cancers. The first in class approved immune checkpoint inhibitor is ipilimumab, a fully humanized mAb that blocks the immune suppressive signal by cytotoxic Tlymphocyte antigen 4 (CTLA-4). Two pivotal phase III randomized controlled trials demonstrated a survival benefit for it in patients with metastatic melanoma. In 2011, the US Food and Drug Administration (FDA) approved ipilimumab for advanced metastatic melanoma, marking a milestone in the field of immunotherapy. In 2014, nivolumab and pembrolizumab, humanized mAbs which block programmed death-1 (PD-1) molecule (an immune check point molecule on T cells), was approved for advanced melanoma. In March 2015, FDA also approved nivolumab for squamous cell lung cancer. And, blocking antibodies against PD-L1 (the ligand of PD-1) also showed clinical responses against several solid tumors in early-phase clinical trials. Phase III trials of various kinds of anti-PD-1/PD-L1 mAbs in non-small lung cancer, renal cell cancer, head and neck cancer, and bladder cancer etc. are ongoing. Many clinical trials have since investigated new agents, alone and in combination, in various cancers. The current development status of and future challenges in utilizing immune checkpoint inhibitors will be discussed.