CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：A phase 1 clinical trial of the repurposable acetyllysine mimetic, n-methyl-2-pyrrolidone (NMP), in relapsed or refractory multiple myeloma.
A phase 1 clinical trial of the repurposable acetyllysine mimetic, n-methyl-2-pyrrolidone (NMP), in relapsed or refractory multiple myeloma.
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NMP 在低于 BET 抑制的血浆浓度下显示出潜在的疾病稳定和免疫调节活性，在 RR-MM 中耐受性良好；在每日最大剂量 1 g 时仍未确定最大耐受剂量。
N-甲基-2-吡咯烷酮（NMP）是一种具有表观遗传活性的化学片段和有机溶剂，用途广泛，包括作为药物递送载体。NMP此前被认为具有生物惰性，但现已显示免疫调节和抗骨髓瘤作用，部分可由其模拟乙酰赖氨酸的性质和非特异性抑制溴结构域解释。因此，我们开展口服NMP的I期剂量递增试验，以确定复发/难治性多发性骨髓瘤（RR-MM）患者的最大耐受剂量（MTD）。次要终点包括安全性、药代动力学（PK）、总缓解率和免疫学活性生物标志物。
13名患者接受每日50–400 mg起始剂量的NMP。5名患者进行了患者内剂量递增，其中1名达到方案规定的最高剂量1 g/日。开始治疗的月疗程中位数为3（范围1–20）。7名患者（54%；95%置信区间25%–81%）报告了3–4级不良事件（AE）。最常见的任何级别AE（发生于>30%患者）为恶心和肌肉骨骼疼痛。唯一剂量限制性毒性（DLT）是1名接受200 mg NMP患者出现腹泻（总体DLT率8%；95%置信区间0%–36%），因此未能确定MTD。中位无进展生存期和总生存期分别为57天（范围29–539天）和33个月（95%置信区间9.7至>44个月）。9名患者（69%；95%置信区间39%–91%）最佳疗效为疾病稳定（SD）。PK分析显示，每日剂量至400 mg时剂量与浓度成比例；高于500 mg时二者关系更接近线性。800 mg剂量时血浆最大浓度（Cmax）为16.7 mg/L，低于预计抑制BET溴结构域所需的浓度。外周血免疫分析显示NK细胞得以维持，并出现提示T、B和NK细胞功能增强的基因表达特征；一名长期暴露患者在12个月时B细胞和NK细胞持续恢复。
在低于BET抑制阈值的血浆浓度下，NMP显示出潜在的疾病稳定和免疫调节活性，在RR-MM患者中耐受性良好；每日最高剂量1 g时仍未确定MTD。还需开展进一步剂量探索研究，以优化NMP治疗剂量方案。
N-methyl-2-pyrrolidone (NMP) is an epigenetically active chemical fragment and organic solvent with numerous applications including use as a drug-delivery vehicle. Previously considered biologically inert, NMP demonstrates immunomodulatory and anti-myeloma properties that are partly explained by acetyllysine mimetic properties and non-specific bromodomain inhibition. We therefore evaluated orally administered NMP in a phase 1 dose-escalation trial to establish its maximum tolerated dose (MTD) in patients with relapsed/refractory multiple myeloma (RR-MM). Secondary endpoints were safety, pharmacokinetics (PK), overall response rate and immunological biomarkers of activity.
Thirteen patients received NMP at starting doses between 50 and 400 mg daily. Intra-patient dose escalation occurred in five patients, with one attaining the ceiling protocolised dose of 1 g daily. Median number of monthly cycles commenced was three (range 1-20). Grade 3-4 adverse events (AEs) were reported in seven (54%; 95% CI 25-81%) patients. Most common AEs (> 30% of patients) of any grade were nausea and musculoskeletal pain. The only dose limiting toxicity (DLT) was diarrhoea in a patient receiving 200 mg NMP (overall DLT rate 8%; 95% CI 0-36%). Hence, the MTD was not defined. Median progression-free and overall survival were 57 (range 29-539) days and 33 (95% CI 9.7- > 44) months, respectively. The best response of stable disease (SD) was achieved in nine patients (69%; 95% CI 39-91%). PK analysis demonstrated proportional dose-concentrations up to 400 mg daily, with a more linear relationship above 500 mg. Maximum plasma concentrations (Cmax) of 16.7 mg/L at the 800 mg dose were below those predicted to inhibit BET-bromodomains. Peripheral blood immune-profiling demonstrated maintenance of natural killer (NK) cells, and a gene expression signature suggestive of enhanced T, B and NK cell functions; a subject with prolonged exposure manifested sustained recovery of B and NK cells at 12 months.
NMP demonstrated potential disease stabilising and immunomodulatory activity at sub-BET inhibitory plasma concentrations and was well tolerated in RR-MM; an MTD was not determined up to a maximum dose of 1 g daily. Further dose-finding studies are required to optimise NMP dosing strategies for therapeutic intervention.
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