Lotem Michal, Merims Sharon, Frank Steven, Ospovat Inna, Peretz Tamar
Sharett Institute of Oncology, Hadassah Hebrew University Hospital, Jerusalem.
Harefuah. 2012 Oct;151(10):585-8, 604.
Ipilimumab (Yervoy) is a monocLonal antibody designed to block cytotoxic T cell antigen 4 (CTLA-4), an inhibitory receptor of T lymphocytes. This drug is the first to receive US FDAs approval for advanced stage malignant melanoma in the last 13 years. So far, no survival benefit was achieved for this patient group with single drug or combination chemo- and chemo-immunotherapy. In phase II and III trials, up to 15% of patients had melanoma regressions, with a decreased hazard ratio of death of 0.72 compared to the standard chemotherapy with Dacarbazine. The development of Ipilimumab marks a success in deciphering the check-point control on the immune response. Activated T cells over-express CTLA-4 molecule on their surface and become susceptible to its inhibitory effect. CTLA-4 decreases the signaling network derived by antigen recognition of T cells. Alongside of its therapeutic effect, the CTLA-4 blockade enhances autoimmune responses. Severe diarrhea results from toxicity to the colonic mucosa which may eventuate in perforation and, in rare cases, death. Other adverse events of varying severity occur in many patients and include skin eruption, uveitis, endocrinopathies such as thyroiditis and hypophysitis and autoimmune hepatitis. Ipilimumab toxicity is reversible with systemic use of corticosteroids, but the use of TNF inhibitors is sometimes indicated in the absence of resolution. The clinical success of the CTLA-4 blockade motivated intense searches for additional check-point modifiers, such as PD-1 molecule, with encouraging preliminary results. Ipilimumab's entry into the clinic is the opening of a new chapter in the immunotherapy of melanoma in particular, and of cancer, in general.
伊匹单抗（Yervoy）是一种单克隆抗体，旨在阻断细胞毒性T细胞抗原4（CTLA-4），这是一种T淋巴细胞的抑制性受体。该药是过去13年来首个获得美国食品药品监督管理局（FDA）批准用于晚期恶性黑色素瘤的药物。到目前为止，对于该患者群体，单药治疗或化疗与化疗免疫联合治疗均未取得生存获益。在II期和III期试验中，高达15%的患者黑色素瘤出现消退，与达卡巴嗪标准化疗相比，死亡风险比降低了0.72。伊匹单抗的研发标志着在破解免疫反应的检查点控制方面取得了成功。活化的T细胞在其表面过度表达CTLA-4分子，并变得容易受到其抑制作用的影响。CTLA-4会减少T细胞抗原识别所衍生的信号网络。除了其治疗效果外，CTLA-4阻断还会增强自身免疫反应。严重腹泻是由于对结肠黏膜有毒性作用，这可能导致穿孔，在极少数情况下会导致死亡。许多患者还会出现其他不同严重程度的不良事件，包括皮疹、葡萄膜炎、内分泌病，如甲状腺炎和垂体炎以及自身免疫性肝炎。伊匹单抗毒性可通过全身使用皮质类固醇逆转，但在症状未缓解时有时需要使用TNF抑制剂。CTLA-4阻断的临床成功促使人们积极寻找其他检查点调节剂，如PD-1分子，并取得了令人鼓舞的初步结果。伊匹单抗进入临床尤其为黑色素瘤免疫治疗，以及总体上的癌症免疫治疗开启了新的篇章。
