Chocarro L, Blanco E, Arasanz H, Fernández-Rubio L, Bocanegra A, Echaide M, Garnica M, Ramos P, Fernández-Hinojal G, Vera R, Kochan G, Escors D
Oncoimmunology Research Unit, Navarrabiomed-Fundación Miguel Servet, Universidad Pública de Navarra (UPNA), Hospital Universitario de Navarra (HUN), Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
Division of Gene Therapy and Regulation of Gene Expression, Cima Universidad de Navarra, Instituto de Investigación Sanitaria de Navarra (IdISNA), Pamplona, Spain.
Immunooncol Technol. 2022 Mar 17;14:100079. doi: 10.1016/j.iotech.2022.100079. eCollection 2022 Jun.
Lymphocyte-activated gene 3 (LAG-3) is a cell surface inhibitory receptor and a key regulator of immune homeostasis with multiple biological activities related to T-cell functions. LAG-3 is considered a next-generation immune checkpoint of clinical importance, right next to programmed cell death protein 1 (PD-1) and cytotoxic T-cell lymphocyte antigen-4 (CTLA-4). Indeed, it is the third inhibitory receptor to be exploited in human anticancer immunotherapies. Several LAG-3-antagonistic immunotherapies are being evaluated at various stages of preclinical and clinical development. In addition, combination therapies blocking LAG-3 together with other immune checkpoints are also being evaluated at preclinical and clinical levels. Indeed, the co-blockade of LAG-3 with PD-1 is demonstrating encouraging results. A new generation of bispecific PD-1/LAG-3-blocking agents have also shown strong capacities to specifically target PD-1+ LAG-3+ highly dysfunctional T cells and enhance their proliferation and effector activities. Here we identify and classify preclinical and clinical trials conducted involving LAG-3 as a target through an extensive bibliographic research. The current understanding of LAG-3 clinical applications is summarized, and most of the publically available data up to date regarding LAG-3-targeted therapy preclinical and clinical research and development are reviewed and discussed.
淋巴细胞激活基因3（LAG-3）是一种细胞表面抑制性受体，是免疫稳态的关键调节因子，具有多种与T细胞功能相关的生物学活性。LAG-3被认为是具有临床重要性的下一代免疫检查点，仅次于程序性细胞死亡蛋白1（PD-1）和细胞毒性T淋巴细胞相关抗原4（CTLA-4）。事实上，它是人类抗癌免疫疗法中第三个被开发利用的抑制性受体。几种LAG-3拮抗免疫疗法正处于临床前和临床开发的各个阶段进行评估。此外，将LAG-3与其他免疫检查点联合阻断的联合疗法也在临床前和临床水平进行评估。事实上，LAG-3与PD-1的联合阻断已显示出令人鼓舞的结果。新一代双特异性PD-1/LAG-3阻断剂也显示出强大的能力，能够特异性靶向PD-1+LAG-3+高度功能失调的T细胞，并增强其增殖和效应活性。在这里，我们通过广泛的文献研究确定并分类了以LAG-3为靶点的临床前和临床试验。总结了目前对LAG-3临床应用的理解，并对截至目前有关LAG-3靶向治疗临床前和临床研发的大部分公开数据进行了回顾和讨论。
