美国休斯顿卫理公会癌症中心/威尔康奈尔医学中心鲁勇研究小组在研究中取得进展。他们报道临床药物筛选显示氯法齐明增强了抗PD-1和CTLA-4免疫治疗的疗效，同时降低了毒性。这一研究成果于2024年3月21日发表在国际顶尖学术期刊《癌细胞》上。

课题组研究人员筛选了约3000种FDA批准的药物，并确定氯法齐明是优化抗PD-1+CTLA-4 ICB的潜在第三种药物。值得注意的是，在逆转免疫相关不良事件的致死性方面，氯法齐明优于ICB剂量减少或类固醇治疗，但与类固醇对抗肿瘤疗效的不利影响不同，氯法齐明增强了抗PD-1+CTLA-4 ICB的治疗反应。

在机制上，氯法齐明促进CD8+ T细胞中的E2F1激活，克服耐药性并中和致病性Th17细胞以消除免疫相关不良事件。总的来说，氯法齐明增强了抗PD-1+CTLA-4 ICB的抗肿瘤疗效，抑制了难治的免疫相关不良事件，可能填补了提高患者生存率的迫切临床需求。

据了解，作为最有效和持久的联合免疫治疗，双重抗PD-1和CTLA-4免疫检查点阻断(ICB)治疗众所周知会增加患者的3-5级免疫相关不良事件(irAEs)。因此，由于担心会进一步增加致死性毒性，通过加入额外的治疗来提高抗PD-1+CTLA-4 ICB的抗肿瘤效力的尝试在很大程度上被放弃了。

附：英文原文

Title: Clinical drug screening reveals clofazimine potentiates the efficacy while reducing the toxicity of anti-PD-1 and CTLA-4 immunotherapy

Author: Gang Xue, Xin Li, Muhammad Kalim, Jing Fang, Zhiwu Jiang, Ningbo Zheng, Ziyu Wang, Xiaoyin Li, Maen Abdelrahim, Zhiheng He, Mikhail Nikiforov, Guangxu Jin, Yong Lu

Issue&Volume: 2024-03-21

Abstract: Emerging as the most potent and durable combinational immunotherapy, dual anti-PD-1and CTLA-4 immune checkpoint blockade (ICB) therapy notoriously increases grade 3–5immune-related adverse events (irAEs) in patients. Accordingly, attempts to improvethe antitumor potency of anti-PD-1+CTLA-4 ICB by including additional therapeuticshave been largely discouraged due to concerns of further increasing fatal toxicity.Here, we screened ～3,000 Food and Drug Administration (FDA)-approved drugs and identifiedclofazimine as a potential third agent to optimize anti-PD-1+CTLA-4 ICB. Remarkably,clofazimine outperforms ICB dose reduction or steroid treatment in reversing lethalityof irAEs, but unlike the detrimental effect of steroids on antitumor efficacy, clofaziminepotentiates curative responses in anti-PD-1+CTLA-4 ICB. Mechanistically, clofaziminepromotes E2F1 activation in CD8+ T cells to overcome resistance and counteracts pathogenic Th17 cells to abolish irAEs.Collectively, clofazimine potentiates the antitumor efficacy of anti-PD-1+CTLA-4 ICB,curbs intractable irAEs, and may fill a desperate clinical need to improve patient survival.

DOI: 10.1016/j.ccell.2024.03.001

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(24)00080-1