Review: Anti–CTLA‐4 Antibody Ipilimumab: Case Studies of Clinical Response and Immune‐Related Adverse Events

SECTION EDITOR'S NOTE: In this issue of The Oncologist , two articles describe the recent clinical experience with two novel antibodies that abrogate the function of CTLA‐4, a molecule expressed on T cells that acts to exert a dampening effect on the immune system. These antibodies were produced using different types of mice with engineered immune systems, and are thus fully human, with long half‐lives of 2–4 weeks. Both antibodies, one produced by Pfizer and the other from Bristol‐Myers Squibb/Medarex, have been shown to have clinical activity against metastatic melanoma and other histologies. Their use is accompanied by a unique spectrum of autoimmune side effects that in some cases are associated with clinical response and long‐term freedom from progression. The kinetics of response in patients receiving either of these antibodies can be unusually prolonged, and in some cases patients with mixed responses or even progressive disease may subsequently achieve an objective response. Their clinical testing has ushered in a new era in immunotherapy, with a new set of side effects to be managed, and encouraging clinical activity that has driven the two companies to conduct four registration trials. If the trials are successful, and if one or both CTLA‐4‐antibodies are approved by the U.S. Food and Drug Administration, that would mark the first new agents approved for melanoma in over a decade. The initial success with these antibodies has encouraged the rapid development of new agonistic and antagonistic antibodies that alter immune regulation, such as anti‐PD‐1, anti‐4‐1BB, anti‐CD40, and anti‐OX‐40. As new members of the co‐stimulatory interactions between effector cells and antigen presenting cells are described, exciting new targets for immunotherapeutic intervention in oncology will be defined. Jeffrey Weber, M.D., Ph.D.