Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain.
Navarra Institute for Health Research (IdiSNA), Pamplona, Spain.
Cancer Discov. 2023 Mar 1;13(3):552-569. doi: 10.1158/2159-8290.CD-22-1029.
Twenty-five years ago, we reported that agonist anti-CD137 monoclonal antibodies eradicated transplanted mouse tumors because of enhanced CD8+ T-cell antitumor immunity. Mouse models indicated that anti-CD137 agonist antibodies synergized with various other therapies. In the clinic, the agonist antibody urelumab showed evidence for single-agent activity against melanoma and non-Hodgkin lymphoma but caused severe liver inflammation in a fraction of the patients. CD137's signaling domain is included in approved chimeric antigen receptors conferring persistence and efficacy. A new wave of CD137 agonists targeting tumors, mainly based on bispecific constructs, are in early-phase trials and are showing promising safety and clinical activity.
CD137 (4-1BB) is a costimulatory receptor of T and natural killer lymphocytes whose activity can be exploited in cancer immunotherapy strategies as discovered 25 years ago. Following initial attempts that met unacceptable toxicity, new waves of constructs acting agonistically on CD137 are being developed in patients, offering signs of clinical and pharmacodynamic activity with tolerable safety profiles.
目的： 25 年前，我们报道了激动型抗 CD137 单克隆抗体通过增强 CD8+T 细胞抗肿瘤免疫作用消除移植的小鼠肿瘤。小鼠模型表明，抗 CD137 激动型抗体与各种其他疗法具有协同作用。在临床上，激动型抗体 urelumab 对黑色素瘤和非霍奇金淋巴瘤显示出单药活性的证据，但在一部分患者中引起严重的肝脏炎症。CD137 的信号域包含在批准的嵌合抗原受体中，赋予其持久性和疗效。针对肿瘤的新一代 CD137 激动剂主要基于双特异性构建体，正在进行早期临床试验，并显示出有希望的安全性和临床活性。
意义：CD137（4-1BB）是 T 细胞和自然杀伤细胞的共刺激受体，其活性可以在 25 年前发现的癌症免疫治疗策略中得到利用。在最初的尝试遇到不可接受的毒性后，新一波作用于 CD137 的构建体正在患者中开发，具有可耐受安全性的临床和药效学活性的迹象。
