Targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4) - A novel strategy for the treatment of melanoma and other malignancies
Targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4) - A novel strategy for the treatment of melanoma and other malignancies
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DOI：
10.1002/cncr.23086
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发表时间：
2007-12-15
期刊：
影响因子：
6.2
通讯作者：
Urba, Walter J.
中科院分区：
文献类型：
--
作者：
O'Day, Steven J.;Hamid, Omid;Urba, Walter J.
癌症免疫疗法的中心是调节宿主的肿瘤导向免疫应答。一种有希望的方法涉及通过中断负责免疫下调或耐受的T细胞途径来增强细胞介导的免疫。细胞毒性T淋巴细胞抗原-4（CTLA-4）的发现及其作为T细胞关键负调节因子的作用促使人们努力靶向这种信号分子以改善癌症治疗。应答肿瘤细胞侵袭的初始T细胞的活化或“引发”包括双重信号传导机制。信号I需要T细胞受体识别肿瘤相关抗原，而信号2通过抗原呈递细胞（APC）上的CD 80或CD 86（B7.1/2）与T细胞上的CD 28结合而发生。重要的是，有一个负责天然发生的免疫调节的最后一步;这发生在T细胞上的CTLA-4对APC上的CD 80/CD 86的竞争性结合的响应中。这种“免疫检查点”中断信号2并抑制活化的T细胞。靶向CTLA-4作为抗癌策略：在动物中进行概念验证研究后，开发了全人抗CTLA-4抗体，其中2种正在进行临床评价。伊匹单抗和曲美木单抗已经显示出有希望的抗肿瘤活性，最初在晚期黑色素瘤患者中。类别特异性免疫相关不良事件（irAE）很常见，大多数是一过性和/或可管理的。认为这些事件与作用机制相关，表明免疫耐受性被破坏;这种关系也可以解释在几项试验中观察到的irAE与应答之间的相关性。通过阻断CTLA-4阻断免疫抑制途径似乎是癌症免疫治疗的一种有前途的策略。
Cancer immunotherapy centers on modulating the host's tumor-directed immune response. One promising approach involves augmentation of cell-mediated immunity by interrupting T-cell pathways responsible for immune down-regulation or tolerance. The discovery of cytotoxic T-lymphocyte antigen-4 (CTLA-4) and its role as a key negative regulator for T cells has prompted efforts to target this signaling molecule to improve cancer therapy. Activation, or 'priming', of naive T cells in response to tumor-cell invasion comprises a dual-signaling mechanism. Signal I requires tumor-associated antigen recognition by the T-cell receptor, while signal 2 occurs through binding of CD80 or CD86 (B7.1 of 2) on the antigen presenting cell (APC) with CD28 on the T cell. Importantly, there is a final step responsible for naturally occurring immune regulation; this occurs in response to competitive binding of CD80/CD86 on the APC by CTLA-4 on the T cell. This 'immune checkpoint' interrupts signal 2 and inhibits the activated T cell. Targeting CTLA-4 as an anticancer strategy: Following proof-of-concept studies in animals, fully human anti-CTLA-4 antibodies were developed and 2 are undergoing clinical evaluation. Ipilimumab and tremelimumab have shown promising antitumor activity, initially in patients with advanced melanoma. Class-specific immune-related adverse events (irAEs) were common and mostly transient and/or manageable. These events are thought to be mechanism-of-action-related, indicating immune tolerance is broken; this relation may also explain the association between irAEs and response seen in several trials. Interruption of immune inhibitory pathways via CTLA-4 blockade appears to be a promising strategy for cancer immunotherapy.