近年来，基于单克隆抗体（mAb）诱导共刺激受体信号传导以抗击癌症的方法引起了极大的兴趣。然而，有前景的非临床数据尚未转化为有意义的临床益处。可诱导T细胞共刺激分子（ICOS）是一种重要的免疫应答的共刺激受体。我们使用一种新型临床阶段的抗ICOS免疫球蛋白G4 mAb（feladilimab），它能诱导而不微量耗损ICOS阳性T细胞及其啮齿动物模型，对通过抗体介导的ICOS共刺激在抗肿瘤潜力方面进行了全面评估，包括单独使用和与细胞凋亡程序相关蛋白质1（PD-1）阻断剂联合使用。我们一致地表明，ICOS 在多种癌症中表达，其诱导能够刺激抗肿瘤反应性T细胞的增长。此外，feladilimab 在小鼠和人源化肿瘤模型中单独使用和与PD-1抑制剂联合使用均能诱导抗肿瘤活性。除了非临床评估之外，我们还提供了来自人体初次临床试验（INDUCE-1；ClinicalTrials.gov：NCT02723955）的三个患者病例研究，评估了feladilimab单独使用和与pembrolizumab联合使用对晚期实体瘤患者的疗效。之前曾报道使用feladilimab单独或与pembrolizumab联合治疗的癌症患者的临床益处的初步数据；这里描述了一些示例病例。还需要进一步开展工作来进一步验证跨越到临床的可行性，包括确定将从这种治疗方法中获益的特定患者群体，并使用生存终点的随机数据以阐明其潜力，类似于CTLA-4和PD-1阻断抗体所显示的结果。刺激T细胞活化标志物ICOS与抗-ICOS激动剂mAb feladilimab的单独使用和与PD-1抑制剂联合使用，在非临床模型和特定的晚期实体瘤患者中诱导抗肿瘤活性。© 2023年作者；由美国癌症研究协会出版。

In recent years, there has been considerable interest in mAb-based induction of costimulatory receptor signaling as an approach to combat cancer. However, promising nonclinical data have yet to translate to a meaningful clinical benefit. Inducible T-cell costimulator (ICOS) is a costimulatory receptor important for immune responses. Using a novel clinical-stage anti-ICOS immunoglobulin G4 mAb (feladilimab), which induces but does not deplete ICOS+ T cells and their rodent analogs, we provide an end-to-end evaluation of the antitumor potential of antibody-mediated ICOS costimulation alone and in combination with programmed cell death protein 1 (PD-1) blockade. We demonstrate, consistently, that ICOS is expressed in a range of cancers, and its induction can stimulate growth of antitumor reactive T cells. Furthermore, feladilimab, alone and with a PD-1 inhibitor, induced antitumor activity in mouse and humanized tumor models. In addition to nonclinical evaluation, we present three patient case studies from a first-time-in-human, phase I, open-label, dose-escalation and dose-expansion clinical trial (INDUCE-1; ClinicalTrials.gov: NCT02723955), evaluating feladilimab alone and in combination with pembrolizumab in patients with advanced solid tumors. Preliminary data showing clinical benefit in patients with cancer treated with feladilimab alone or in combination with pembrolizumab was reported previously; with example cases described here. Additional work is needed to further validate the translation to the clinic, which includes identifying select patient populations that will benefit from this therapeutic approach, and randomized data with survival endpoints to illustrate its potential, similar to that shown with CTLA-4 and PD-1 blocking antibodies.Stimulation of the T-cell activation marker ICOS with the anti-ICOS agonist mAb feladilimab, alone and in combination with PD-1 inhibition, induces antitumor activity across nonclinical models as well as select patients with advanced solid tumors.© 2023 The Authors; Published by the American Association for Cancer Research.