Marcq Elly, Van Audenaerde Jonas R M, De Waele Jorrit, Merlin Céline, Pauwels Patrick, van Meerbeeck Jan P, Fisher Scott A, Smits Evelien L J
Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, 2610 Wilrijk, Belgium.
Department of Pathology, Antwerp University Hospital, 2650 Edegem, Belgium.
Cancers (Basel). 2021 Jan 14;13(2):282. doi: 10.3390/cancers13020282.
Malignant pleural mesothelioma (MPM) is an aggressive cancer that is causally associated with previous asbestos exposure in most afflicted patients. The prognosis of patients remains dismal, with a median overall survival of only 9-12 months, due to the limited effectiveness of any conventional anti-cancer treatment. New therapeutic strategies are needed to complement the limited armamentarium against MPM. We decided to focus on the combination of different immune checkpoint (IC) blocking antibodies (Abs). Programmed death-1 (PD-1), programmed death ligand-1 (PD-L1), T-cell immunoglobulin mucin-3 (TIM-3), and lymphocyte activation gene-3 (LAG-3) blocking Abs were tested as monotherapies, and as part of a combination strategy with a second IC inhibitor. We investigated their effect in vitro by examining the changes in the immune-related cytokine secretion profile of supernatant collected from treated allogeneic MPM-peripheral blood mononuclear cell (PBMC) co-cultures. Based on our in vitro results of cytokine secretion, and flow cytometry data that showed a significant upregulation of PD-L1 on PBMC after co-culture, we chose to further investigate the combinations of anti PD-L1 + anti TIM-3 versus anti PD-L1 + anti LAG-3 therapies in vivo in the AB1-HA BALB/cJ mesothelioma mouse model. PD-L1 monotherapy, as well as its combination with LAG-3 blockade, resulted in in-vivo delayed tumor growth and significant survival benefit.
恶性胸膜间皮瘤（MPM）是一种侵袭性癌症，在大多数患病患者中与既往石棉暴露存在因果关系。由于任何传统抗癌治疗的效果有限，患者的预后仍然很差，中位总生存期仅为9至12个月。需要新的治疗策略来补充针对MPM的有限治疗手段。我们决定专注于不同免疫检查点（IC）阻断抗体（Abs）的联合使用。对程序性死亡1（PD-1）、程序性死亡配体1（PD-L1）、T细胞免疫球蛋白粘蛋白3（TIM-3）和淋巴细胞激活基因3（LAG-3）阻断抗体进行了单药治疗测试，并作为与第二种IC抑制剂联合策略的一部分进行了测试。我们通过检测从处理过的同种异体MPM-外周血单核细胞（PBMC）共培养物中收集的上清液中免疫相关细胞因子分泌谱的变化，在体外研究了它们的作用。基于我们关于细胞因子分泌的体外结果以及流式细胞术数据显示共培养后PBMC上PD-L1显著上调，我们选择在AB1-HA BALB/cJ间皮瘤小鼠模型中进一步在体内研究抗PD-L1 + 抗TIM-3与抗PD-L1 + 抗LAG-3疗法的联合使用。PD-L1单药治疗及其与LAG-3阻断的联合使用均导致体内肿瘤生长延迟和显著的生存获益。
