CTLA-4 antibodies: new directions, new combinations.

Checkpoint blockade is a transformative therapeutic approach to a broad spectrum of malignancies because it increases the power of antitumor immunity to obtain durable responses. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) is the prototypical inhibitory checkpoint receptor. Since US Food and Drug Administration approval of the anti-CTLA-4 antibody ipilimumab for use in patients with melanoma, there has been ever-increasing excitement among oncologists about new ways to use this method of releasing the "brakes" on patients' endogenous immune systems. This review will summarize the preclinical and clinical development of CTLA-4-blocking antibodies, discuss recent insights into the biology of CTLA-4 blockade, review the use of these antibodies in combination with established and novel therapeutic modalities, and comment on ongoing questions regarding their administration.