A phase 1/2 clinical trial of the nitric oxide synthase inhibitor L-NMMA and taxane for treating chemoresistant triple-negative breast cancer
A phase 1/2 clinical trial of the nitric oxide synthase inhibitor L-NMMA and taxane for treating chemoresistant triple-negative breast cancer
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DOI：
10.1126/scitranslmed.abj5070
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发表时间：
2021-12-15
影响因子：
17.1
通讯作者：
Chang, Jenny C.
中科院分区：
文献类型：
--
作者：
Chung, Andrew W.;Anand, Kartik;Chang, Jenny C.
诱导型一氧化氮信号传导（iNOS）通路与三阴性乳腺癌（TNBC）的不良预后相关。先前使用体内模型的研究表明，使用泛NOS抑制剂NG-单甲基-L-精氨酸（L-NMMA）抑制iNOS信号传导途径可减少TNBC患者的肿瘤生长并提高生存率。在这里，我们报告了一项L-NMMA联合紫杉烷治疗化疗难治性局部晚期乳腺癌（LABC）或转移性TNBC患者的1/2期临床试验。我们还检查了化疗反应的免疫细胞相关性。招募了35例转移性TNBC患者：15例在I期试验中，24例在II期试验中（包括来自I期试验的4例推荐II期剂量患者）。总体缓解率为45.8%（11/24）：LABC患者为81.8%（9/11），转移性TNBC患者为15.4%（2/13）。在LABC患者中，3例患者在手术时病理学完全缓解（27.3%）。在21%的患者中观察到≥ 3级毒性;然而，没有不良事件归因于L-NMMA。通过CyTOF分析的免疫细胞表明，化疗无应答者表现出与M2巨噬细胞极化相关的标记物的更高表达以及循环IL-6和IL-10细胞因子浓度的增加。相比之下，化疗反应者血液中CD 15（+）中性粒细胞增加，治疗结束时肿瘤活检中的CD 15（+）中性粒细胞减少（一种促肿瘤N2中性粒细胞的标志物）。L-NMMA联合紫杉烷值得在乳腺癌患者的大型临床研究中进一步研究。
The inducible nitric oxide signaling (iNOS) pathway is associated with poor prognosis in triple-negative breast cancer (TNBC). Prior studies using in vivo models showed that inhibition of the iNOS signaling pathway using the pan-NOS inhibitor NG-monomethyl-L-arginine (L-NMMA) reduced tumor growth and enhanced survival in patients with TNBC. Here, we report a first-in-class phase 1/2 trial of L-NMMA combined with taxane for treating patients with chemorefractory, locally advanced breast cancer (LABC) or metastatic TNBC. We also examined immune cell correlates of chemotherapy response. 35 patients with metastatic TNBC were recruited: 15 in the phase 1 trial and 24 in the phase 2 trial (including 4 recommended phase 2 dose patients from the phase 1 trial). The overall response rate was 45.8% (11 of 24): 81.8% (9 of 11) for patients with LABC and 15.4% (2 of 13) for patients with metastatic TNBC. Among the patients with LABC, three patients had a pathological complete response at surgery (27.3%). Grade >= 3 toxicity was noted in 21% of patients; however, no adverse events were attributed to L-NMMA. Immune cells analyzed by CyTOF indicated that chemotherapy nonresponders showed greater expression of markers associated with M2 macrophage polarization and increased concentrations of circulating IL-6 and IL-10 cytokines. In contrast, chemotherapy responders showed an increase in CD15(+) neutrophils in blood, as well as a decrease in arginase ( a marker of protumor N2 neutrophils) in tumor biopsies obtained at the end of treatment. L-NMMA combined with taxane warrants further investigation in larger clinical studies of patients with breast cancer.