Anti-CTLA-4 immunotherapy: uncoupling toxicity and efficacy

• 来源期刊: 细胞研究（英文版）
• 年，卷（期）: 2018,（5）
• 页码范围: 501-502
• 页数: 2页
• 语种: 英文
• DOI: 10.1038/s41422-018-0031-9

摘要

A CTLA-4-specific antibody, ipilimumab, is clinically used in anticancer immunotherapy, yet induces severe autoimmune side effects. Two papers by Du et al. published recently in Cell Research now suggest strategies for potentially uncoupling toxicity and efficacy of CTLA-4-targeting antibodies. Although modern pharmacological agents are designed to target specific molecules and processes, it appears that they often (always?) mediate clinical efficacy by other or additional mechanisms than those they have been initially designed for. Ipilimumab, a clinically-used so-called immune checkpoint inhibitor (ICI) is probably not an exception to this rule. Ipilimumab has been FDA approved for the treatment of metastatic melanoma and might get clinical approval for additional oncological indications, most likely in combination with other ICls targeting PD-1 or its ligand PD-L1.1 Ipilimumab is thought to bind to CTLA-4 expressed by T lymphocytes and to block its interaction with CTLA-4 ligands, in particular B7-1 (CD80) and B7-2 (CD86), expressed by antigen presenting cells (APCs), such as dendritic cells (DCs), within the tumor microenvironment or lymphoid organs.2 By blocking the interaction between CTLA-4 and B7-1 or B7-2, ipilimumab then would inhibit the transmission of inhibitory signals to CTLA-4-expressing T lymphocytes (Fig.1a), thereby favoring desirable anticancer immune responses1 and also undesirable autoimmune side effects.3 Two papers published in Cell Research by Du et al. challenge this mode of action of ipilimumab and indeed suggest a strategy for uncoupling antitumor efficacy and pro-autoimmune toxicity.