Overcoming Immune Suppression: Therapeutic Strategies Targeting T-Cell Function in Cancer

The first clinical success in overcoming immune suppression in cancer was shown by the development of human antibodies with antitumor activity against the checkpoint proteins cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death-1 (PD-1). In 2011, the Food and Drug Administration (FDA) approved the anti-CTLA-4 antibody ipilimumab for metastatic melanoma. Patients with objective responses to ipilimumab can have remissions lasting more than 5 years, although significant immune-related toxicity can occur in 5–15 % of patients. More recently, PD-1 and PD-L1 antibodies have been tested in the clinic, with PD-1 antibodies nivolumab and MK-3475 showing impressive response rates of 20–40 % in previously treated patients. These antibodies are being tested in randomized phase II and III registration studies in metastatic melanoma and non-small cell lung cancer.