New Drugs and Early Drug Development for Innovative Therapies Division, IEO, European Institute of Oncology IRCCS, Milan, Italy.
New Drugs and Early Drug Development for Innovative Therapies Division, IEO, European Institute of Oncology IRCCS, Milan, Italy; University of Milano, Department of Hematology and Hemato-Oncology, Italy.
Eur J Cancer. 2019 Aug;117:14-31. doi: 10.1016/j.ejca.2019.04.035. Epub 2019 Jun 21.
'First-generation' immune checkpoint inhibitors targeting Cytotoxic T-Lymphocyte Antigen 4 (CTLA4) and Programmed death-ligand 1 (PD(L)1) have undoubtedly revolutionised the treatment of multiple cancers in the advanced setting. Targeting signalling pathways other than core inhibitory modules may strongly impact the outcome of the antitumour immune response. Drugs targeting these pathways ('next-generation' immune modulators, NGIMs) constitute a major frontier in translational research and have generated unprecedented scientific and financial investment. Here, we systematically reviewed published literature, abstracts from major cancer conferences and pharma pipelines to identify NGIMs that have reached clinical development. We identified 107 molecules targeting 16 pathways, which we classified into 6 groups according to function (inhibitory vs stimulatory) and cell of predominant expression (lymphoid, non-lymphoid and natural killer). We identified all registered past and ongoing clinical trials (n = 428). We summarise the preclinical rationale for these targets, extracting translationally relevant information, and review published and preliminary clinical results. Some targets like indoleamine-2,3-dioxygenase 1, lymphocyte activation gene-3 and IL15 have experienced exceptional growth of interest, measured in terms of activated studies and expected patient enrolment over time. We conclude that in this vast and rapidly changing drug development landscape, novel trial designs and better biomarker identification are necessary to optimise resource allocation.
“第一代”免疫检查点抑制剂靶向细胞毒性 T 淋巴细胞相关抗原 4（CTLA4）和程序性死亡配体 1（PD(L)1），无疑彻底改变了晚期多种癌症的治疗方法。靶向核心抑制模块以外的信号通路可能会强烈影响抗肿瘤免疫反应的结果。针对这些通路的药物（“下一代”免疫调节剂，NGIMs）是转化研究的一个主要前沿领域，已经产生了前所未有的科学和财务投资。在这里，我们系统地回顾了已发表的文献、主要癌症会议的摘要和药物研发管道，以确定已进入临床开发的 NGIMs。我们确定了 107 种靶向 16 条通路的分子，根据功能（抑制性与刺激性）和主要表达细胞（淋巴样、非淋巴样和自然杀伤细胞）将它们分为 6 组。我们确定了所有已注册的过去和正在进行的临床试验（n=428）。我们总结了这些靶点的临床前原理，提取了具有转化意义的信息，并回顾了已发表和初步的临床结果。一些靶点，如吲哚胺 2,3-双加氧酶 1、淋巴细胞激活基因 3 和 IL15，其研究活跃度和预期患者入组人数都在随着时间的推移而显著增加。我们得出的结论是，在这个广阔而快速变化的药物开发领域，需要新的试验设计和更好的生物标志物识别，以优化资源分配。
