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癌症是人类健康的最大挑战之一,因癌症失去生命的人数与日俱增。为了与癌症进行抗争,人类走上了漫漫求索之路,研究[1]发现免疫疗法治疗肿瘤有显著成效。免疫防御是免疫系统的一大功能,能使机体免受癌症等各种疾病的侵袭。癌细胞能通过免疫逃避在体内大量增殖,例如癌细胞表面主要组织相容性复合体Ⅰ(MHCⅠ)类分子作用受抑制,合成免疫抑制因子,抑制免疫防御功能在体内增殖分化。因此,恢复免疫防御作用是抗癌研究的一个重要手段。与传统治疗手段相比,肿瘤免疫疗法通过靶向免疫系统而不是肿瘤本身对肿瘤进行杀伤清除[2]。近年来,免疫检查点阻断剂[3]、嵌合抗原受体T淋巴细胞治疗[4]和肿瘤浸润淋巴细胞治疗[5]等肿瘤免疫疗法在临床上取得了巨大成功。肿瘤免疫治疗的目的是通过拮抗肿瘤微环境(TME)中各种造成免疫抑制的因素进行靶向治疗,其中“免疫检查点”是研究最多最成熟的免疫治疗方法。1996年美国德州大学安德森癌症中心发现细胞毒性T淋巴细胞相关抗原4(CTLA-4)抗体可在小鼠身上增强抗肿瘤效应,并提出“阻断免疫检查点”治疗肿瘤的思路,从此一种新的研究方向——免疫检查点被用于研发临床药物。但抗CTLA-4治疗存在癌症治疗和药物开发问题。程序性死亡受体-1(PD-1)/程序性死亡配体-s(PD-Ls)介导的免疫信号通路可诱导肿瘤细胞发生免疫逃逸,PD-1与PD-Ls结合能抑制T淋巴细胞效应活性。以PD-1/PD-Ls为靶点的药物能增强T淋巴细胞对肿瘤的杀伤作用,抗PD-1/PD-Ls抗体在多种肿瘤治疗中均取得较好的疗效,成为最有前景的免疫疗法[6-8]。本文就肿瘤免疫疗法中抗PD-1/PD-Ls抗体的相关研究进展作一综述。
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免疫相关不良反应:肿瘤治疗药物按正常用法和合理剂量治疗肿瘤,调节T细胞活性介导免疫激活,可诱发免疫相关的不良反应,继而造成相应脏器不同程度的损伤[40-41]。免疫治疗效果在临床上已较好的体现,但仍存在一些无法避免的不良反应,造成神经系统、呼吸系统、内分泌系统、消化系统等多系统损伤[42](见表 1)。在肿瘤药物治疗肿瘤时,不良反应也应得到与治疗效果同样的重视,了解不良反应对于临床指导用药至关重要。同时也可利用其他途径对药物治疗带来的不良反应进行抑制,从而更好地治疗[43]。
肿瘤类型 治疗药物 主要不良反应 黑素瘤 Nivolumab 疲乏、皮肤瘙痒、腹泻、皮疹、恶心、白癜风、关节痛、无力、便秘、甲状腺功能减退(甲减)、食欲减退 Pembrolizumab 疲乏、皮肤瘙痒、腹泻、皮疹、关节痛、恶心、甲减 尿路上皮癌 Nivolumab 疲乏、皮肤瘙痒、食欲减退、甲减、腹泻、恶心、发热、皮疹、无力 Pembrolizumab 皮肤瘙痒、疲乏、恶心、腹泻、食欲减退、甲减、无力、肺炎、甲状腺功能亢进(甲亢) Atezolizumab 疲乏、恶心、食欲减退、皮肤瘙痒、发热、腹泻、皮疹、关节痛、呕吐 Avelumab 注射相关不良反应、疲乏、皮疹、腹泻、无力、食欲减退、甲减、肺炎 Durvalumab 疲乏、食欲减退、腹泻、皮疹、恶心、关节痛、发热、皮肤瘙痒、ALT升高、AST升高、GGT升高 非小细胞肺癌 Nivolumab 疲乏、食欲减退、无力、恶心、腹泻、关节痛、发热、肺炎、皮疹 Pembrolizumab 腹泻、疲乏、发热、恶心、食欲减退、甲减、甲亢、肺炎、贫血、皮肤毒性 Atezolizumab 疲乏、食欲减退、咳嗽、呼吸困难、无力、恶心、发热、便秘、腹泻、呕吐、关节痛、贫血、背痛 肝癌 Nivolumab 皮疹、AST升高、脂肪酶升高、淀粉酶升高、皮肤瘙痒、ALT升高、腹泻、食欲减退、贫血、疲乏、无力 胃癌 Pembrolizumab 疲乏、皮肤瘙痒、皮疹、甲减、食欲减退、贫血、恶心、腹泻、关节痛 结直肠癌 Nivolumab 疲乏、腹泻、皮肤瘙痒、脂肪酶升高、皮疹、恶心、甲减、无力、淀粉酶升高、AST升高、ALT升高、关节痛 头颈鳞癌 Nivolumab 疲乏、恶心、皮疹、食欲减退、皮肤瘙痒、腹泻、贫血、无力 Pembrolizumab 疲乏、皮肤瘙痒、皮疹、骨骼肌酸痛、腹泻、ALT升高、AST升高、低血钠 肾细胞癌 Nivolumab 疲乏、恶心、皮肤瘙痒、腹泻、食欲减退、皮疹、咳嗽、贫血、呼吸困难、外周水肿、肺炎 霍奇金淋巴瘤 Nivolumab 疲乏、输注相关不良反应、皮疹、关节痛、发热、恶心、腹泻、皮肤瘙痒 Pembrolizumab 发热、咳嗽、疲乏、腹泻、呕吐、恶心、甲减、中性粒细胞减少、上呼吸道感染、皮疹、皮肤瘙痒、头疼、关节痛 Merkel细胞瘤 Avelumab 疲乏、输注相关不良反应、皮疹、恶心、腹泻、皮肤瘙痒、无力、食欲减退、斑丘疹 表 1 抗PD-1/PD-Ls抗体临床治疗不良反应
抗PD-1/PD-Ls抗体在肿瘤治疗中的应用研究进展
抗PD-1/PD-Ls抗体在肿瘤治疗中的应用研究进展
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表 1 抗PD-1/PD-Ls抗体临床治疗不良反应
肿瘤类型 治疗药物 主要不良反应 黑素瘤 Nivolumab 疲乏、皮肤瘙痒、腹泻、皮疹、恶心、白癜风、关节痛、无力、便秘、甲状腺功能减退(甲减)、食欲减退 Pembrolizumab 疲乏、皮肤瘙痒、腹泻、皮疹、关节痛、恶心、甲减 尿路上皮癌 Nivolumab 疲乏、皮肤瘙痒、食欲减退、甲减、腹泻、恶心、发热、皮疹、无力 Pembrolizumab 皮肤瘙痒、疲乏、恶心、腹泻、食欲减退、甲减、无力、肺炎、甲状腺功能亢进(甲亢) Atezolizumab 疲乏、恶心、食欲减退、皮肤瘙痒、发热、腹泻、皮疹、关节痛、呕吐 Avelumab 注射相关不良反应、疲乏、皮疹、腹泻、无力、食欲减退、甲减、肺炎 Durvalumab 疲乏、食欲减退、腹泻、皮疹、恶心、关节痛、发热、皮肤瘙痒、ALT升高、AST升高、GGT升高 非小细胞肺癌 Nivolumab 疲乏、食欲减退、无力、恶心、腹泻、关节痛、发热、肺炎、皮疹 Pembrolizumab 腹泻、疲乏、发热、恶心、食欲减退、甲减、甲亢、肺炎、贫血、皮肤毒性 Atezolizumab 疲乏、食欲减退、咳嗽、呼吸困难、无力、恶心、发热、便秘、腹泻、呕吐、关节痛、贫血、背痛 肝癌 Nivolumab 皮疹、AST升高、脂肪酶升高、淀粉酶升高、皮肤瘙痒、ALT升高、腹泻、食欲减退、贫血、疲乏、无力 胃癌 Pembrolizumab 疲乏、皮肤瘙痒、皮疹、甲减、食欲减退、贫血、恶心、腹泻、关节痛 结直肠癌 Nivolumab 疲乏、腹泻、皮肤瘙痒、脂肪酶升高、皮疹、恶心、甲减、无力、淀粉酶升高、AST升高、ALT升高、关节痛 头颈鳞癌 Nivolumab 疲乏、恶心、皮疹、食欲减退、皮肤瘙痒、腹泻、贫血、无力 Pembrolizumab 疲乏、皮肤瘙痒、皮疹、骨骼肌酸痛、腹泻、ALT升高、AST升高、低血钠 肾细胞癌 Nivolumab 疲乏、恶心、皮肤瘙痒、腹泻、食欲减退、皮疹、咳嗽、贫血、呼吸困难、外周水肿、肺炎 霍奇金淋巴瘤 Nivolumab 疲乏、输注相关不良反应、皮疹、关节痛、发热、恶心、腹泻、皮肤瘙痒 Pembrolizumab 发热、咳嗽、疲乏、腹泻、呕吐、恶心、甲减、中性粒细胞减少、上呼吸道感染、皮疹、皮肤瘙痒、头疼、关节痛 Merkel细胞瘤 Avelumab 疲乏、输注相关不良反应、皮疹、恶心、腹泻、皮肤瘙痒、无力、食欲减退、斑丘疹 -
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