V Deligiorgi Maria, Panayiotidis Mihalis I, Trafalis Dimitrios T
Department of Pharmacology - Clinical Pharmacology Unit, National and Kapodistrian University of Athens, Faculty of Medicine, Building 16, 1st Floor, 75 Mikras Asias, 11527-Goudi, Athens, Greece.
J BUON. 2020 Jan-Feb;25(1):1-14.
The designation of immune checkpoint inhibitors (ICPi) as scientific breakthrough of the year 2013 marked a turning point in cancer therapeutics, unleashing the host immune system against tumors. ICPi block the cytotoxic T lymphocyte antigen 4 (CTLA-4), the programmed cell death protein (PD) 1 (PD-1), and the ligand of the latter (PD-L1) ‒the landmark immune checkpoints‒abrogating the escape of cancer cells from immunosurveillance. Despite the durable antitumor response elicited by ICPi in an expanding list of cancer types and a substantial fraction of patients, the resistance to this modality ‒primary and acquired‒ has inspired research on combinational regimens to reinvigorate immunosurveillance in immune-refractory tumors. Besides various combinations of ICPi with other ICPi, targeted therapies, chemotherapy, and radiation, emphasis is placed on identification of novel partners of ICPi. Scientists capitalize on repurposing already-approved drugs to overcome τhe diminishing efficiency of commercial drug research and development. Denosumab, a human monoclonal immunoglobulin antibody inhibiting receptor activator of nuclear factor kappa-B ligand (RANKL), is excellent candidate for repurposing in oncology, given its anticancer potential and accepted safety profile. Originally approved as anti-osteoporotic agent inhibiting the osteoclast driven bone resorption, denosumab has demonstrated multifaceted anticancer efficacy, beyond abolishing the osteoclast-dependent RANKL signaling. The present review provides a comprehensive overview of the preclinical and clinical evidence indicating denosumab as effective partner of ICPi, emphasizing the mechanisms underlying the enhanced anticancer efficacy of this combination as compared to monotherapies. Current challenges and future perspectives in incorporating the combination of ICPi with denosumab in clinical practice are discussed.
免疫检查点抑制剂（ICPi）被评为2013年的科学突破，这标志着癌症治疗领域的一个转折点，它激活了宿主免疫系统来对抗肿瘤。ICPi阻断细胞毒性T淋巴细胞相关抗原4（CTLA-4）、程序性细胞死亡蛋白1（PD-1）及其配体（PD-L1）——具有里程碑意义的免疫检查点——从而消除癌细胞的免疫逃逸。尽管ICPi在越来越多的癌症类型和相当一部分患者中引发了持久的抗肿瘤反应，但对这种治疗方式的耐药性——原发性和获得性的——激发了人们对联合治疗方案的研究，以恢复免疫难治性肿瘤中的免疫监视。除了ICPi与其他ICPi、靶向治疗、化疗和放疗的各种联合，重点还在于确定ICPi的新搭档。科学家们利用已获批药物的重新利用来克服商业药物研发效率的下降。地诺单抗是一种抑制核因子κB受体活化因子配体（RANKL）的人源化单克隆免疫球蛋白抗体，鉴于其抗癌潜力和已被认可的安全性，它是肿瘤学领域重新利用的优秀候选药物。地诺单抗最初被批准作为抑制破骨细胞驱动的骨吸收的抗骨质疏松药物，除了消除破骨细胞依赖性RANKL信号外，它还显示出多方面的抗癌功效。本综述全面概述了临床前和临床证据，表明地诺单抗是ICPi的有效搭档，强调了与单一疗法相比这种联合疗法增强抗癌功效的潜在机制。还讨论了将ICPi与地诺单抗联合应用于临床实践中的当前挑战和未来前景。
