Cytotoxic T-Lymphocyte - Associated antigen-4
Cytotoxic T-Lymphocyte - Associated antigen-4
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DOI：
10.1158/1078-0432.ccr-07-0813
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发表时间：
2007-09-15
影响因子：
11.5
通讯作者：
Hodi, F. Stephen
中科院分区：
文献类型：
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作者：
Hodi, F. Stephen
以前，基于免疫的疗法的发展主要集中在疫苗和细胞因子上，在一小部分患者中产生了好处。最近我们对共刺激分子功能的了解的进展重新激发了人们对癌症免疫疗法开发的热情。这个蛋白质家族具有与淋巴细胞激活和免疫抑制功能相关的特性。到目前为止，临床上翻译最多的共刺激分子是CTL相关抗原-4(CTLA-4)。CTLA-4的参与通过两种主要机制导致T细胞抑制。第一个涉及与CD28竞争结合抗原提呈细胞上的B7。第二种是CTLA-4胞浆尾巴介导的直接细胞内抑制信号。许多临床试验用完全人类的单抗阻断CTLA-4信号，已经治疗了各种癌症，在治疗转移性黑色素瘤方面经验最丰富。已经观察到显著的抗肿瘤活性以及潜在的自身免疫相关毒性。CTLA-4阻断的进一步临床研究，测试其他共刺激分子操作的计划中的临床试验，以及对共刺激通路的理解的持续改进，为癌症患者的免疫治疗开辟了一个新时代。
Previously, the development of immune-based therapies has primarily focused on vaccines and cytokines, yielding benefit in a small percentage of patients. Recent advances in our understanding of the function of costimulatory molecules have revitalized enthusiasm in the development of immune therapies for cancer. This family of proteins possesses properties involved in both lymphocyte activation and immune- inhibitory functions. The costimulatory molecule with the greatest translation into the clinic thus far is CTL-associated antigen-4 (CTLA-4). CTLA-4 engagement leads to T-cell inhibition by two principle mechanisms. The first involves competitive binding with CD28 for B7 on the antigen -presenting cell. The second is direct intracellular inhibitory signals mediated by the CTLA-4 cytoplasmic tail. Numerous clinical trials testing the blockade of CTLA-4 signaling with fully human monoclonal antibodies have treated a variety of cancers, with the most experience in the treatment of metastatic melanoma. Significant antitumor activity as well as potential autoimmune-related toxicities have been observed. Further clinical investigation with CTLA-4 blockade, planned clinical trials testing manipulation of other costimulatory molecules, and continued improvement in understanding of costimulatory pathways present a new era of immune therapies for cancer patients.