PO.ET09.05 · 实验与分子治疗
同类首创的共价过氧化物还原酶3（PRX3）抑制剂RSO-021调节间皮瘤中的免疫表型
The first-in-class covalent peroxiredoxin 3 (PRX3) inhibitor RSO-021 modulates immune phenotypes in mesothelioma
该海报暂无可下载的资料
AACR 官方页面
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
RSO-021是同类首创的共价过氧化物还原酶3（PRX3）抑制剂thiostrepton（TS）的临床制剂。TS共价灭活PRX3活性位点的半胱氨酸，导致氧化应激增加和肿瘤细胞凋亡性死亡。RSO-021在一项针对间皮瘤或肺转移性疾病所致恶性胸腔积液（MPE）患者的1期试验中安全，并显示出早期抗肿瘤活性（Fennell等，J Clin Oncol 42, 3019-3019(2024)）。2期试验目前正在进行中（NCT05278975）。在本研究中，我们对经TS处理的人间皮瘤细胞系和患者来源移植物，以及经RSO-021治疗患者的恶性胸腔积液的免疫特征进行了分析。人间皮瘤细胞系的处理结果显示，TS下调PD-L1的表达并增加MHC I类分子的表达。对经TS处理的人间皮瘤细胞和患者来源间皮瘤移植物的RNA测序显示，转化生长因子β（TGFbeta）、肿瘤坏死因子（TNFalpha）、干扰素α和干扰素γ基因特征受到调节。我们对经RSO-021（通过胸膜内导管注入胸膜腔）治疗患者的MPE中的细胞因子进行了多重ELISA分析。Resistin（一种与间皮瘤中巨噬细胞信号传导相关的细胞因子）水平在RSO-021治疗后24小时和7天显著升高。IL-6和IL-8水平在RSO-021治疗后24小时升高，并在7天时恢复至基线。最后，在间皮瘤同基因小鼠模型中，评估了经TS、anti-PD1/anti-CTLA4抗体或TS与anti-PD1/anti-CTLA4抗体联合治疗小鼠的终末期肿瘤负荷。TS治疗的小鼠肿瘤缩小30%。anti-PD1/anti-CTLA4抗体治疗的动物表现出部分缓解，6只中有2只肿瘤完全缩小。TS联合anti-PD1/anti-CTLA4抗体的组合在6只中的6只中显示肿瘤完全缩小。总之，这些数据凸显了RSO-021在细胞、小鼠模型和人组织中的免疫调节活性，并支持RSO-021与免疫肿瘤学疗法联用的进一步临床开发。
查看英文原文 English abstract
RSO-021 is the clinical formulation of the first-in-class covalent peroxiredoxin 3 (PRX3) inhibitor thiostrepton (TS). TS covalently inactivates PRX3 active site cysteines leading to increased oxidative stress and apoptotic tumor cell death. RSO-021 was safe and showed early anti-tumor activity in a phase 1 trial in patients with malignant pleural effusion (MPE) arising from mesothelioma or metastatic disease to the lung (Fennell et al. J Clin Oncol 42, 3019-3019(2024)). The phase 2 trial is currently ongoing (NCT05278975). In this study we profiled immune signatures of human mesothelioma cell lines and patient derived explants treated with TS, and malignant pleural effusions from patients treated with RSO-021. Treatment of human mesothelioma cell lines showed TS down-regulated expression of PD-L1 and increased MHC class 1 expression. RNA-sequencing of human mesothelioma cells and patient-derived mesothelioma explants treated with TS showed modulation of transforming growth factor beta (TGFbeta), tumor necrosis factor (TNFalpha), interferon alpha, and interferon gamma gene signatures. We performed multiplex ELISA analysis of cytokines in MPE from patients treated with RSO-021 via an intrapleural catheter to the pleural space. The levels of Resistin, a cytokine related to macrophage signaling in mesothelioma, was significantly increased 24 hours and 7-days post RSO-021 treatment. Levels of IL-6 and IL-8 were increased 24 hours after RSO-021 treatment and returned to baseline at 7 days. Lastly, in a syngeneic mouse model of mesothelioma end stage tumor burden was assessed in mice treated with TS, anti-PD1/anti-CTLA4 antibodies, or a combination of TS and anti-PD1/anti-CTLA4 antibodies. TS treated mice showed 30% tumor reduction. Anti-PD1/anti-CTLA4 antibody treated animals showed partial responses with 2 of 6 mice having complete tumor reduction. The combo of TS plus anti-PD1/anti-CTLA4 antibody showed complete tumor reduction in 6 of 6 mice. Together, these data highlight the immunomodulatory activity in cells, mouse models, and human tissue with RSO-021 and support further clinical development of RSO-021 in combination with immune-oncology therapies.
利益披露 Disclosure
V. Gibson, None..
J. Dzialo, None..
A. Habibovic, None..
C. Landry, None.
D. Fennell,
RS Oncology Independent Contractor, ), Travel.
B. Cunniff,
RS Oncology Independent Contractor, Stock, ), Travel.