Wolchok Jedd D, Saenger Yvonne
Melanoma/Sarcoma Oncology Service and Ludwig Center for Cancer Immunotherapy, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box #340, New York, New York 10065, USA.
Oncologist. 2008;13 Suppl 4:2-9. doi: 10.1634/theoncologist.13-S4-2.
The survival rate of patients diagnosed with late-stage melanoma is poor--only 5%-10%. Enlisting the immune system in the fight against cancers such as melanoma could help improve the prognosis of these patients. Data have shown that melanocyte proteins make good targets for immune system-based therapy in this disease. However, self-tolerance, which develops to inhibit autoimmune attack, makes this strategy difficult. Two proteins on the surface of T cells--CD28 and cytotoxic T-lymphocyte antigen 4 (CTLA-4)--play important roles in the regulation of immune activation and tolerance. CD28 provides positive modulatory signals in the early stages of an immune response, while CTLA-4 signaling inhibits T-cell activation, particularly during strong T-cell responses. CTLA-4 blockade using anti-CTLA-4 monoclonal antibody therapy has great appeal because suppression of inhibitory signals results in the generation of an antitumor T-cell response. Both clinical and preclinical data indicate that CTLA-4 blockade results in direct activation of CD4+ and CD8+ effector cells, and anti-CTLA-4 monoclonal antibody therapy has shown promise in a number of cancers, particularly melanoma. Interestingly, the occurrence of adverse events among patients treated with CTLA-4 blockade helps shed light on the mechanism of action of anti-CTLA-4 monoclonal antibodies. Most adverse events involve immune-related toxicity to the skin and gastrointestinal tract. Major gastrointestinal toxicity develops in up to 21% of treated patients, and while an objective response occurs in approximately 36% of melanoma patients who develop enterocolitis with treatment, an objective response is found in only 11% of patients who do not experience this adverse reaction.
被诊断为晚期黑色素瘤的患者生存率很低，仅为5%-10%。借助免疫系统对抗黑色素瘤等癌症有助于改善这些患者的预后。数据表明，黑色素细胞蛋白是这种疾病基于免疫系统治疗的良好靶点。然而，为抑制自身免疫攻击而形成的自身耐受性使这一策略难以实施。T细胞表面的两种蛋白——CD28和细胞毒性T淋巴细胞抗原4（CTLA-4）——在免疫激活和耐受性调节中发挥着重要作用。CD28在免疫反应早期提供正向调节信号，而CTLA-4信号传导抑制T细胞激活，尤其是在强烈的T细胞反应期间。使用抗CTLA-4单克隆抗体疗法阻断CTLA-4具有很大吸引力，因为抑制抑制性信号会产生抗肿瘤T细胞反应。临床和临床前数据均表明，CTLA-4阻断可直接激活CD4+和CD8+效应细胞，抗CTLA-4单克隆抗体疗法在多种癌症，尤其是黑色素瘤中显示出前景。有趣的是，接受CTLA-4阻断治疗的患者中不良事件的发生有助于阐明抗CTLA-4单克隆抗体的作用机制。大多数不良事件涉及皮肤和胃肠道的免疫相关毒性。高达21%的接受治疗的患者会出现严重的胃肠道毒性，在接受治疗时发生小肠结肠炎的黑色素瘤患者中，约36%会出现客观反应，而在未经历这种不良反应的患者中，只有11%会出现客观反应。
