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Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and incombination
Celine Boutros1, Ahmad Tarhini2, Emilie Routier1, Olivier Lambotte35,
Francois Leroy Ladurie6, Franck Carbonnel4,7, Hassane Izzeddine8, Aurelien Marabelle9, Stephane Champiat10, Armandine Berdelou11, Emilie Lanoy12, Matthieu Texier12, Cristina Libenciuc1, Alexander M.M. Eggermont1,4, Jean-Charles Soria4,9,10, ChristineMateus1 and Caroline Robert1,4,10
Abstract | Inhibition of immune checkpoints using anti-programmed cell death-1 (PD-1) or anti cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibodies has revolutionized the management of patients with advanced-stage melanoma and is among the most promising treatment approaches for many other cancers. Use of CTLA-4 and PD-1 inhibitors, either as single agents, or in combination, has been approved by the US FDA for the treatment of metastatic melanoma. Treatment with these novel immunotherapies results in a unique and distinct spectrum of adverse events, which are mostly related to activation of the immune system and are, therefore, an unwanted consequence of their mechanisms of action. Adverse effects of CTLA-4 and/or PD-1 inhibition are most commonly observed in the skin, gastrointestinal tract, liver and endocrine systems and include pruritus, rash, nausea, diarrhoea and thyroid disorders. In this Review, the authors describe the adverse event profile of checkpoint inhibitors targeting CTLA-4 and PD-1, used both as monotherapies and in combination and aim to provide some general guidelines, based upon the mechanisms of action of these therapies and on the management of these immune-related adverse events.
Under normal physiological conditions, the relative activation of signalling pathways that stimulate, and those that inhibit activation of the immune system provides the optimal balance between the ability to generate an immune response to antigens and the maintenance of self-tolerance1,2. Cancer cells harbour genetic and epi genetic alterations that render them different to the hosts healthy cells, and can generate antigens and stimu late T-cell-mediated immunity3,4. However, cancer cells are able to evade recognition and destruction by the host immune system through activation of spec ific inhibitory signalling pathways, known as immune checkpoints57. Thus, inhibition of these immune checkpoints has drawn increasing research interest as a new approach to the treatment of patients with advanced-stage mela noma, and, likewise, patients with various other solidtumours8,9.
Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) was the first immune checkpoint receptor to be clinically targeted1012. In the past decade, ipilimumab
and tremelimumab, two...