Department of Internal Medicine, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA; Holden Comprehensive Cancer Center, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA.
Department of Internal Medicine, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA; Holden Comprehensive Cancer Center, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA.
Redox Biol. 2022 Jul;53:102318. doi: 10.1016/j.redox.2022.102318. Epub 2022 Apr 20.
Platinum-based chemotherapy with or without immunotherapy is the mainstay of treatment for advanced stage non-small cell lung cancer (NSCLC) lacking a molecular driver alteration. Pre-clinical studies have reported that pharmacological ascorbate (P-AscH-) enhances NSCLC response to platinum-based therapy. We conducted a phase II clinical trial combining P-AscH- with carboplatin-paclitaxel chemotherapy.
Chemotherapy naïve advanced stage NSCLC patients received 75 g ascorbate twice per week intravenously with carboplatin and paclitaxel every three weeks for four cycles. The primary endpoint was to improve tumor response per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 compared to the historical control of 20%. The trial was conducted as an optimal Simon's two-stage design. Blood samples were collected for exploratory analyses.
The study enrolled 38 patients and met its primary endpoint with an objective response rate of 34.2% (p = 0.03). All were confirmed partial responses (cPR). The disease control rate was 84.2% (stable disease + cPR). Median progression-free and overall survival were 5.7 months and 12.8 months, respectively. Treatment-related adverse events (TRAE) included one grade 5 (neutropenic fever) and five grade 4 events (cytopenias). Cytokine and chemokine data suggest that the combination elicits an immune response. Immunophenotyping of peripheral blood mononuclear cells demonstrated an increase in effector CD8 T-cells in patients with a progression-free survival (PFS) ≥ 6 months.
The addition of P-AscH- to platinum-based chemotherapy improved tumor response in advanced stage NSCLC. P-AscH- appears to alter the host immune response and needs further investigation as a potential adjuvant to immunotherapy.
对于缺乏分子驱动改变的晚期非小细胞肺癌（NSCLC）患者，铂类化疗联合或不联合免疫治疗是治疗的基础。临床前研究报告称，药理学抗坏血酸（P-AscH-）可增强 NSCLC 对铂类治疗的反应。我们进行了一项 II 期临床试验，将 P-AscH-与卡铂-紫杉醇化疗联合使用。
化疗初治的晚期 NSCLC 患者每周两次静脉注射 75g 抗坏血酸，每 3 周用卡铂和紫杉醇治疗 4 个周期。主要终点是根据实体瘤反应评估标准（RECIST）v1.1 提高肿瘤反应率，与 20%的历史对照相比。该试验采用最佳西蒙两阶段设计进行。采集血样进行探索性分析。
该研究共纳入 38 例患者，达到了主要终点，客观缓解率为 34.2%（p=0.03）。所有患者均确认为部分缓解（cPR）。疾病控制率为 84.2%（稳定疾病+ cPR）。中位无进展生存期和总生存期分别为 5.7 个月和 12.8 个月。与治疗相关的不良事件（TRAE）包括 1 例 5 级（中性粒细胞发热）和 5 例 4 级事件（血细胞减少症）。细胞因子和趋化因子数据表明，该联合治疗引发了免疫反应。外周血单核细胞免疫表型分析显示，无进展生存期（PFS）≥6 个月的患者中效应 CD8 T 细胞增加。
在铂类化疗基础上加用 P-AscH-可提高晚期 NSCLC 的肿瘤反应率。P-AscH-似乎改变了宿主的免疫反应，需要进一步研究作为免疫治疗的潜在辅助药物。
