肿瘤细胞治疗研究
英文原题：Assessing the safety, tolerability and efficacy of PLGA-based immunomodulatory nanoparticles in patients with advanced NY-ESO-1-positive cancers: a first-in-human phase I open-label dose-escalation study protocol.
对更有效癌症治疗的持续需求推动了新型癌症免疫治疗候选药物的开发。理想的癌症免疫治疗应能诱导强效、靶向且持久的免疫应答，同时规避肿瘤微环境中的免疫抑制。为此，我们开发了一种新型免疫调节纳米药物：PRECIOUS-01。作为一种基于PLGA的纳米载体，PRECIOUS-01包封了一种肿瘤抗原（NY-ESO-1）和一种恒定自然杀伤T细胞激活剂，以靶向并增强NY-ESO-1表达晚期癌症患者中的特异性抗肿瘤免疫应答。方法与分析：这项开放标签、首次人体、I期剂量递增试验旨在研究递增剂量的PRECIOUS-01静脉给药在NY-ESO-1表达晚期实体瘤受试者中的安全性、耐受性和免疫调节活性。
对更有效癌症治疗的持续需求推动了新型癌症免疫治疗候选药物的开发。理想的癌症免疫治疗应能诱导强效、靶向且持久的免疫应答，同时规避肿瘤微环境中的免疫抑制。为此，我们开发了一种新型免疫调节纳米药物：PRECIOUS-01。作为一种基于PLGA的纳米载体，PRECIOUS-01包封了一种肿瘤抗原（NY-ESO-1）和一种恒定自然杀伤T细胞激活剂，以靶向并增强NY-ESO-1表达晚期癌症患者中的特异性抗肿瘤免疫应答。方法与分析：这项开放标签、首次人体、I期剂量递增试验旨在研究递增剂量的PRECIOUS-01静脉给药在NY-ESO-1表达晚期实体瘤受试者中的安全性、耐受性和免疫调节活性。共15名受试者将在三个剂量探索队列中接受三次PRECIOUS-01静脉输注，间隔3周。该试验采用3+3设计进行剂量递增步骤，以确定最大耐受剂量（MTD）和/或推荐的II期剂量（RP2D）。根据毒性情况，两个最高剂量队列将进行扩展，以描述免疫相关参数作为药效学读数。受试者将接受安全性和剂量限制性毒性发生的监测。如果在计划的剂量递增队列中未达到MTD，RP2D将基于观察到的安全性和免疫调节活性作为支持RP2D的药效学参数。初步疗效将作为探索性终点，根据实体瘤疗效评价标准V.1.1，采用最佳总缓解率进行评估。伦理与传播：荷兰主管当局（CCMO）审查了试验申请，医学研究伦理委员会（CMO Arnhem-Nijmegen）以注册号NL72876.000.20批准了该试验。结果将通过（国际）国内会议传播，并提交至同行评审期刊发表。
INTRODUCTION: The undiminished need for more effective cancer treatments stimulates the development of novel cancer immunotherapy candidates. The archetypical cancer immunotherapy would induce robust, targeted and long-lasting immune responses while simultaneously circumventing immunosuppression in the tumour microenvironment. For this purpose, we developed a novel immunomodulatory nanomedicine: PRECIOUS-01. As a PLGA-based nanocarrier, PRECIOUS-01 encapsulates a tumour antigen (NY-ESO-1) and an invariant natural killer T cell activator to target and augment specific antitumour immune responses in patients with NY-ESO-1-expressing advanced cancers. METHODS AND ANALYSIS: This open-label, first-in-human, phase I dose-escalation trial investigates the safety, tolerability and immune-modulatory activity of increasing doses of PRECIOUS-01 administered intravenously in subjects with advanced NY-ESO-1-expressing solid tumours. A total of 15 subjects will receive three intravenous infusions of PRECIOUS-01 at a 3-weekly interval in three dose-finding cohorts. The trial follows a 3+3 design for the dose-escalation steps to establish a maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D). Depending on the toxicity, the two highest dosing cohorts will be extended to delineate the immune-related parameters as a readout for pharmacodynamics. Subjects will be monitored for safety and the occurrence of dose-limiting toxicities. If the MTD is not reached in the planned dose-escalation cohorts, the RP2D will be based on the observed safety and immune-modulatory activity as a pharmacodynamic parameter supporting the RP2D. The preliminary efficacy will be evaluated as an exploratory endpoint using the best overall response rate, according to Response Evaluation Criteria in Solid Tumors V.1.1. ETHICS AND DISSEMINATION: The Dutch competent authority (CCMO) reviewed the trial application and the medical research ethics committee (CMO Arnhem-Nijmegen) approved the trial under registration number NL72876.000.20. The results will be disseminated via (inter)national conferences and submitted for publication to a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT04751786.
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