title: Immune regulatory antibodies: are they the next advance?
abstract: During the past decade, new insights into the mechanisms by which T-cell activation and proliferation are regulated have led to the identification of checkpoint proteins that either up- or down-modulate T-cell reactivity. In the presence of active malignancy, pathophysiologic inhibition of T-cell activity may predominate over stimulation. A number of antibodies have been generated that can block inhibitory checkpoint proteins or promote the activity of activating molecules. In murine models, their use alone or with a vaccine strategy has resulted in regression of poorly immunogenic tumors and cures of established tumors. The prototypical immune regulatory antibodies are those directed against cytotoxic T-lymphocyte antigen-4, a molecule present on activated T cells. In this review, the preclinical rationale and clinical experience with 2 anticytotoxic T-lymphocyte antigen-4 antibodies are extensively discussed, demonstrating that abrogation of an immune inhibitory molecule can result in significant regression of tumors and long-lasting responses. The unique kinetics of antitumor response and the characteristic immune-related side effects of ipilimumab are also discussed. This clinical efficacy of this promising antitumor agent has been evaluated in 2 randomized phase III trials, whose results are eagerly awaited. Programmed death (PD)-1 is another immune inhibitory molecule against which an abrogating human antibody has been prepared. Initial preclinical testing with anti-PD-1 and anti-PD-L1 has shown encouraging results. Stimulatory molecules such as CD40, 41-BB, and OX-40 are also targets for antibody binding and activation, not blockade, and early dose ranging trials with antibodies against all 3 have shown that they can mediate regression of tumors, albeit with their own spectrum of side effects that are different from those that occur with abrogation of immune inhibition.
authors.affiliation: Ludwig Center for Cancer Immunotherapy, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Jedd D
authors.initials: JD
authors.lastname: Wolchok
authors.forename: Arvin S
authors.initials: AS
authors.lastname: Yang
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Weber
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000627:therapeutic use*; D015703:Antigens, CD / Q000276:immunology*; D060908:CTLA-4 Antigen; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D000074324:Ipilimumab; D008213:Lymphocyte Activation / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D000074324:Ipilimumab