A Phase III, Multicentre, Randomised, Double-Blind Study to Assess the Safety and Efficacy of Emactuzumab vs. Placebo in Subjects With Tenosynovial Giant Cell Tumour

This is a multicenter, Phase 3, randomised, double-blind, placebo-controlled study, which aims to evaluate the efficacy and safety of the investigational drug emactuzumab for the treatment of patients with localized or diffuse TGCT where surgical removal of the tumor is not viewed as an option.
The study consists of two parts. In Part 1, eligible subjects will be assigned in a 2:1 ratio to receive either emactuzumab or matching placebo in a double-blind fashion, that will be administered in total 5 times as an intravenous (i.v.) infusion once every 2 weeks. This will be followed by an observation period of 3 months leading to a total duration of 24 weeks in Part 1. A number of assessments will be carried out during the course of the study, including physical examinations, blood tests, imaging studies, electrocardiograms, and questionnaires. Part 2 is a long-term double-blind follow-up phase of the subjects on emactuzumab or placebo. Subjects assigned to placebo in Part 1 have the option, subject to eligibility, to crossover to receive open-label emactuzumab in Part 2. Subjects assigned to active drug in Part 1 have the option to receive open-label retreatment under certain circumstances.

开始日期2024-04-30

申办/合作机构

Synox Therapeutics Ltd.

NCT03768063

/ Active, not recruiting临床3期

An Open Label, Multicenter Extension Study in Patients Previously Enrolled in a Genentech and/or F. Hoffmann-La Roche Ltd Sponsored Atezolizumab Study (IMbrella B)

This is an open-label, multicenter, extension study. Patients who are receiving clinical benefit from atezolizumab monotherapy or atezolizumab in combination with other agent(s) or combination/comparator agent(s) during participation in a Genentech or Roche-sponsored study (the parent study), who are eligible to continue treatment and who do not have access to the study treatment locally, may continue to receive study treatment in this extension study following roll-over from the parent study.

开始日期2019-02-28

申办/合作机构

Hoffmann-La Roche, Inc.

NCT03369964

/ Withdrawn临床1期

A Phase Ib Study of The Safety and Pharmacology of Atezolizumab in Combination With an Immunotherapy Agent Investigated With or Without Anti-Cd20 Therapy in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma

This study will investigate the safety, pharmacology, and activity of atezolizumab in combination with immunotherapy agents with or without an anti-CD20 agent (i.e., obinutuzumab) in patients with relapsed or refractory (R/R) follicular lymphoma (FL). The first immunotherapy molecule investigated will be emactuzumab (Arm A) in two combinations.

开始日期2018-03-14

申办/合作机构

Hoffmann-La Roche, Inc.

100 项与 Emactuzumab 相关的临床结果

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100 项与 Emactuzumab 相关的转化医学

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100 项与 Emactuzumab 相关的专利（医药）

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项与 Emactuzumab 相关的文献（医药）

2023-10-01·Hematology/oncology and stem cell therapy

Updates on the Treatment of Tenosynovial Giant Cell Tumor

Review

作者: Chan, Abigail S. ; Singh, Vikas ; Katiyar, Vatsala ; Dy, Paul

Tenosynovial giant cell tumor (TGCT) is a rare inflammatory disorder affecting the joint synovium, bursae, and tendon sheaths that causes non-specific and often insidious joint discomfort. The application of systemic chemotherapy has been limited due to poor and unsustained disease responses. Surgery with or without adjuvant radiation is the primary treatment modality for TGCT. With its locally destructive nature and increased recurrence, multiple surgical interventions become necessary throughout the course of the disease, leading to disfigurement, decreased quality of life, and increased mortality. However, owing to recent evidence demonstrating the overexpression of colony-stimulating factor 1 (CSF-1) in TGCT, selective tyrosine kinase inhibitors targeting CSF-1 receptors are being developed. Pex- idartinib is the first CSF-1 receptor inhibitor approved for the treatment of TGCT. Here, we discuss various available treatment strategies and ongoing investigations and trials targeting diffuse TGCT, which include nilotinib, lacnotuzu- mab, cabiralizumab, vimseltinib, and emactuzumab.

2022-05-01·Journal for immunotherapy of cancer2区 · 医学

Anti-CSF-1R emactuzumab in combination with anti-PD-L1 atezolizumab in advanced solid tumor patients naïve or experienced for immune checkpoint blockade

2区 · 医学

ArticleOA

作者: Taus, Alvaro ; Machiels, Jean-Pascal ; Zamarin, Dmitriy ; Mcdermott, David ; Korski, Konstanty ; Jegg, Anna-Maria ; Jacob, Wolfgang ; Terret, Catherine ; Gomez-Roca, Carlos ; Martinez Garcia, Maria ; Eder, Joseph P ; Cannarile, Michael A ; Babitzki, Galina ; Delord, Jean-Pierre ; Christen, Randolph ; Boni, Valentina ; Stephen Hodi, F ; Hafez, Navid ; Sullivan, Ryan ; Meneses-Lorente, Georgina ; Aspeslagh, Sandrine ; Watson, Carl ; Weisser, Martin ; Ries, Carola ; Michielin, Francesca ; Rüttinger, Dominik ; Marabelle, Aurelien ; Cassier, Philippe ; Champiat, Stephane ; Perez Gracia, Jose Luis

Background:

This phase 1b study (NCT02323191) evaluated the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of colony-stimulating factor-1 receptor-blocking monoclonal antibody (mAb) emactuzumab in combination with the programmed cell death-1 ligand (PD-L1)-blocking mAb atezolizumab in patients with advanced solid tumors naïve or experienced for immune checkpoint blockers (ICBs).

Methods:

Emactuzumab (500–1350 mg flat) and atezolizumab (1200 mg flat) were administered intravenously every 3 weeks. Dose escalation of emactuzumab was conducted using the 3+3 design up to the maximum tolerated dose (MTD) or optimal biological dose (OBD). Extension cohorts to evaluate pharmacodynamics and clinical activity were conducted in metastatic ICB-naive urothelial bladder cancer (UBC) and ICB-pretreated melanoma (MEL), non-small cell lung cancer (NSCLC) and UBC patients.

Results:

Overall, 221 patients were treated. No MTD was reached and the OBD was determined at 1000 mg of emactuzumab in combination with 1200 mg of atezolizumab. Grade ≥3 treatment-related adverse events occurred in 25 (11.3%) patients of which fatigue and rash were the most common (14 patients (6.3%) each). The confirmed objective response rate (ORR) was 9.8% for ICB-naïve UBC, 12.5% for ICB-experienced NSCLC, 8.3% for ICB-experienced UBC and 5.6% for ICB-experienced MEL patients, respectively. Tumor biopsy analyses demonstrated increased activated CD8 +tumor infiltrating T lymphocytes (TILs) associated with clinical benefit in ICB-naïve UBC patients and less tumor-associated macrophage (TAM) reduction in ICB-experienced compared with ICB-naïve patients.

Conclusion:

Emactuzumab in combination with atezolizumab demonstrated a manageable safety profile with increased fatigue and skin rash over usual atezolizumab monotherapy. A considerable ORR was particularly seen in ICB-experienced NSCLC patients. Increase ofCD8 +TILs under therapy appeared to be associated with persistence of a TAM subpopulation.

2020-12-01·European journal of cancer (Oxford, England : 1990)1区 · 医学

Long-term clinical activity, safety and patient-reported quality of life for emactuzumab-treated patients with diffuse-type tenosynovial giant-cell tumour

1区 · 医学

Article

作者: Jegg, Anna-Maria ; Klaman, Irina ; Gomez-Roca, Carlos ; Blay, Jean-Yves ; Toulmonde, Maud ; Cassier, Philippe A ; Watson, Carl ; Jacob, Wolfgang ; D'Angelo, Sandra P ; Weisser, Martin ; Weber, Kristy ; Michielin, Francesca ; Le Tourneau, Christophe ; Ries, Carola H ; Delord, Jean-Pierre ; Abiraj, Keelara ; Loirat, Delphine ; Italiano, Antoine ; Cannarile, Michael ; Christen, Randolph ; Rüttinger, Dominik

OBJECTIVES:

This study investigated the safety, clinical activity and patient-reported outcomes of patients with diffuse-type tenosynovial giant-cell tumour (dTGCT) of the soft tissue who were treated with emactuzumab, a humanised anti-colony stimulating factor 1 receptor (CSF1R) monoclonal antibody and were followed up for up to 2 years after the start of treatment.

METHODS:

In this open-label phase 1 study (ClinicalTrials.govNCT01494688), patients received intravenous (IV) emactuzumab from 900 to 2000 mg every two weeks in the dose-escalation phase and at the optimal biological dose of 1000 mg with different schedules in the dose-expansion phase. Adverse event (AE) rates and biomarker assessments from tumour biopsies were analysed. Quality of life was assessed using a standard questionnaire (EuroQol-5D-3L) and the WOMAC® 3.1 Osteoarthritis Index. Tumour responses were determined with magnetic resonance imaging.

RESULTS:

Altogether, 63 patients were enrolled into the study. The most frequently reported AEs were pruritus, asthenia and oedema. In 36 patients for whom biopsy tissue was available a substantial decrease of CSF1R-positive and CD68/CD163-positive macrophages was detected. The independently reviewed best overall objective response rate (ORR) (Response Evaluation Criteria in Solid Tumors version 1.1) was 71%. Responses were durable, and an ORR of 70% and 64% was determined after one or two years after enrolment into the study. Clinical activity was accompanied by an improvement in EuroQol-5D-3L and particularly the joint disorder-specific WOMAC score.

CONCLUSIONS:

Systemic therapy of dTGCT patients with emactuzumab resulted in pronounced and durable responses associated with symptomatic improvement and a manageable safety profile.

项与 Emactuzumab 相关的新闻（医药）

2025-06-09

·医脉通

2025 ASCO大咖谈 | 徐海荣教授：破茧新生，MANEUVER研究突破治疗困境，TGCT治疗或将迎来高效低毒新选择

2025 ASCO<<< 美国临床肿瘤学会年会 >>>Driving Knowledge to Action: Building a Better Future医脉通：2024年CSCO骨与软组织肿瘤诊疗指南新增了TGCT章节内容，这也是国内首次有权威临床指南系统性阐述这一疾病。请您结合指南内容与临床经验，简要介绍TGCT并分享其诊疗难点与治疗现状。徐海荣教授TGCT既往被称为色素沉着绒毛结节性滑膜炎，从名称的演变就可以看出，医学界对其认识已从最初的炎症性病变转变为肿瘤性病变。然而，在肿瘤治疗领域，TGCT具有其特殊性，它被归类为中间性肿瘤而非恶性肿瘤。在临床实践中，大多数患者常因关节或其他部位的疼痛、肿胀等症状，就诊于骨科、外科或运动医学科等。该病的诊疗难点在于患者就诊机构的不同而存在差异：如果患者在基层医疗机构就诊，由于医生对该疾病认识不足，往往不会将其明确判断为肿瘤性病变并采取相应的处理措施，加之TGCT术后复发率较高，这使得基层医生在制定治疗决策时感到非常棘手。如果患者就诊于大型医疗中心，临床医生具备丰富的诊疗经验和成熟的手术技术，虽能及时、全面地处理病灶，但手术本身仍可能会给患者带来长期功能损害。究其原因，TGCT发病隐匿，术前症状常呈间歇性（休息后可缓解，活动后加重），尽管手术能成功切除肿瘤，但术后功能受限等长期不良反应往往成为患者新的困扰，这种“两难”局面构成了TGCT诊疗的核心挑战。医脉通：本次ASCO大会，您所在团队主导的III期MANEUVER研究迎来重磅数据更新，请您为我们解读MANEUVER研究的设计、研究数据以及该研究结果对临床实践的意义。徐海荣教授MANEUVER研究是一项国际多中心、随机、双盲、安慰剂对照的Ⅲ期临床试验，主要研究终点是BIRC基于RECIST v1.1标准评估的第25周时肿瘤的客观缓解率（ORR）。研究的创新性之一在于纳入了相当比例的亚洲人群，弥补了既往国际研究中亚洲人群代表性不足的缺陷。其次，研究结果证实，新型CSF-1R抑制剂Pimicotinib在TGCT治疗中实现疗效的突破：与安慰剂组相比，Pimicotinib组的ORR显著提高，第25周时经BIRC评估的ORR高达54%（vs 3.2%，p＜0.0001），在预先设定的所有亚组人群中均观察到一致的ORR获益。最后，TGCT作为中间性肿瘤，患者通常不会因这一疾病而直接面临生命威胁，主要困扰在于功能障碍。鉴于此，药物治疗期间的安全性尤为重要。MANEUVER研究整体安全性显示，Pimicotinib大多数治疗期间发生的不良事件（TEAE）为1-2级，且未观察到发色/皮肤改变、胆汁淤积性肝毒性或药物性肝损伤的证据。基于MANEUVER研究中Pimicotinib展现出高应答率及安全性可控的特性，或将为全球TGCT患者提供非常振奋人心的治疗新选择。医脉通：医学技术的进步和临床研究的开展推动着TGCT诊疗的规范化和精准化发展。您认为TGCT领域还有哪些值得深入研究与探索的方向？徐海荣教授随着新型CSF-1R抑制剂的临床突破，TGCT正式迈入靶向治疗时代。在期待药物上市改变患者预后的同时，我们仍需关注两大关键研究方向。第一，鉴于TGCT的良性/中间性肿瘤本质，终身持续给药并非理想方案，需要优化长期用药策略，比如探索延长给药间隔（如间歇疗法）及个体化停药标准。第二，单纯用药物替代传统手术并非可行的方案，手术治疗依然是重要的治疗选择，因此新辅助治疗的探索更具临床价值，通过药物新辅助治疗实现术前缩瘤从而帮助降低手术难度及功能损伤风险。通过给药方案优化与多学科协作模式创新，有望在保障功能完整性的同时实现疾病根治，这将成为未来TGCT领域的核心攻关方向。此外，在本次ASCO大会的poster session还有多个关于TGCT领域的研究新进展值得关注。小编汇总如下，供大家参考。摘要号: 11544全球大规模TGCT登记注册研究揭示122例儿童患者疾病特征：儿童TGCT存在诊断延迟率高、手术过度依赖、全身治疗匮乏三大问题，亟需加强儿童特异性系统疗法的研发，以降低复发率并改善生活质量。摘要号: 11558在针对不可手术的TGCT患者的III期MOTION试验中，口服CSF1R变构抑制剂Vimseltinib治疗1年（49周）持续展现出显著临床获益，结果显示与第1部分结果一致，1年时COAs持续显示出相比于基线的改善。对于无法手术的症状性TGCT患者，在25周后持续治疗可继续为患者带来有临床意义的获益。摘要号: TPS11584Emactuzumab为高选择性CSF-1R单抗，本次ASCO披露了Emactuzumab针对TGCT患者的III期随机、双盲、安慰剂对照研究（TANGENT）设计方案，目前处于全球患者招募阶段。专家简介徐海荣教授北京积水潭医院，主任医师，副教授，硕士生导师北京积水潭医院聊城医院执行院长中国抗癌协会（CACA）肉瘤专业委员会副主任委员中国临床肿瘤学会（CSCO）肉瘤专家委员会常务委员兼秘书长中国抗癌协会骨与软组织肿瘤整合康复专委会副主任委员中国医药教育协会转化医学专委会常务委员国家卫健委能力建设和继续教育肿瘤学专家委员会委员中国临床肿瘤学会（CSCO）理事国际保肢学会（ISOLS）Education Committee委员《中国骨与关节杂志》编委《中国药物警戒》青年编委往期内容回顾RECOMMENDASCO大会TGCT热点前瞻，MANEUVER研究结果即将发布2025 ASCO速递 | 新进展，新希望，TGCT领域重磅研究发布，靶向CSF-1R助力精准诊疗2025 ASCO速递 | 牛晓辉教授：让罕见被看见，MANEUVER等研究为TGCT患者带来精准治疗新希望2025 ASCO大咖谈 | 牛晓辉教授：道阻且长，行则将至，MANEUVER研究实现TGCT全面获益2025 ASCO大咖谈 | 沈靖南教授：TGCT精准诊疗升级，靶向CSF-1R实现疗效与生活质量双重获益感谢默克雪兰诺公司对本项目的支持。公司未参与内容创作，本页内容仅代表基金会/学协会疾病观念，不代表公司立场。撰写：Ariel审校：Kristen排版：Atai执行：Atai本平台旨在为医疗卫生专业人士传递更多医学信息。本平台发布的内容，不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议。如该等信息被用于了解医学信息以外的目的，本平台不承担相关责任。本平台对发布的内容，并不代表同意其描述和观点。若涉及版权问题，烦请权利人与我们联系，我们将尽快处理。

ASCO会议CSCO会议临床3期临床结果

2025-05-27

·小药说药

巨噬细胞肿瘤免疫治疗的研究进展

-01-引言肿瘤相关巨噬细胞（TAM）是免疫抑制细胞和细胞因子网络的核心，在肿瘤免疫逃避中起着至关重要的作用。因此，了解巨噬细胞和其他免疫细胞之间的相互作用以及增强现有抗癌治疗的因素至关重要。TAM在功能上是异质性的，分为两个主要亚群，M1和M2巨噬细胞。M1巨噬细胞是抵抗微生物感染的第一道防线，M1巨噬细胞还保持强大的抗原呈递能力，诱导强烈的Th1反应。相反，M2巨噬细胞在限制免疫反应、诱导血管生成和组织修复方面起着关键作用。因此，M2型TAM的存在与促肿瘤活性相关，而M1型TAM的存在与抗肿瘤活性相关。总之，TAM是产生免疫抑制性TME的关键，并且巨噬细胞与TME中的各种免疫细胞和细胞因子之间的串扰起着不可替代的作用。了解巨噬细胞参与肿瘤免疫逃逸的主要机制和相关靶向治疗，有助于我们改善临床方案，制定克服巨噬细胞相关免疫耐受的潜在新策略。-02-一、调节巨噬细胞吞噬的信号途径CD47/SIRPαCD47是一种广泛分布于正常细胞表面的免疫球蛋白，可通过抑制吞噬作用负调节抗肿瘤免疫，并参与介导细胞增殖、迁移、凋亡和免疫稳态。其主要配体信号调节蛋白α（SIRPα）是一种在髓细胞膜上高表达的跨膜蛋白，其胞外区的N末端可与CD47结合，导致免疫受体酪氨酸抑制基序（ITIM）上的酪氨酸磷酸化，释放“不要吃我”信号，从而抑制巨噬细胞介导的吞噬作用，保护正常细胞免受免疫系统的破坏。研究表明CD47在多种肿瘤中高表达，如恶性血液肿瘤和肝细胞癌（HCC），这也与不良预后相关。给予CD47阻断抗体或靶向灭活CD47基因可显著抑制肿瘤生长。此外，抗CD47治疗还可以改变TME中巨噬细胞的极化状态，诱导TAM转化为抗肿瘤状态。LILRB1/MHCI白细胞免疫球蛋白样受体B（LILRB）在大多数免疫细胞上表达，由细胞外Ig样区、跨膜区和含有ITIM的细胞内区组成。它与主要配体主要组织相容性复合体I（MHCI）结合后可介导免疫细胞激活的负调控。MHCI是由HLAα链和β2-微球蛋白（β2M）形成的复合体，某些肿瘤细胞高表达β2M，其可与巨噬细胞上的LILRB1结合以抑制吞噬作用，导致免疫监视丧失。因此，在肿瘤细胞上MHCI正常或高表达的患者中，靶向MHCI/LILRB1轴的药物可能促进抗肿瘤免疫反应，并与靶向CD47/SIRPα轴的药物发挥协同作用。CD24/Siglec-10CD24，也称为热稳定抗原，是一种高度糖基化的表面蛋白，由糖基磷脂酰肌醇锚定，可与唾液酸结合免疫球蛋白样凝集素-10（Siglec-10）相互作用，以减少感染或肝损伤引起的先天免疫介导的有害炎症。肿瘤细胞高表达CD24，而TAM高表达Siglec-10。与CD24结合后，Siglec-10的ITIM可招募并激活含有SH2结构域的酪氨酸磷酸酶SHP-1或SHP-2，从而阻断巨噬细胞吞噬所需的细胞骨架重排，触发抑制性信号转导级联。“不要吃我”发出CD47、β2M和CD24信号，所有这些信号都涉及基于ITIM的巨噬细胞信号，导致巨噬细胞耐药癌细胞亚群的免疫选择，使肿瘤细胞逃避巨噬细胞的监视和清除。因此，掌握肿瘤细胞表达抗吞噬信号的机制可以更好地预测治疗效果以及靶向治疗。-03- 二、巨噬细胞参与免疫逃避的机制巨噬细胞参与形成抑制性髓系微环境TME中的各种介质参与调节MDSC和单核细胞的募集，并通过不同的信号通路极化巨噬细胞，从而促进免疫抑制髓系微环境的形成。此外，巨噬细胞、MDSC和树突状细胞之间的串扰进一步形成免疫抑制髓系微环境。卵巢癌细胞高表达CD39和CD73，有助于催化细胞外ATP转化为腺苷，腺苷可以招募单核细胞并诱导它们分化为分泌IL-10的TAM。TAM表达CD39和CD73，进一步增加MDSC和TAM的浸润，从而形成一种自我放大机制，促进局部免疫逃逸。肿瘤相关中性粒细胞（TAN）也是免疫抑制髓系微环境的重要组成部分。与巨噬细胞一样，中性粒细胞可以被描述为两个亚群，N1和N2，N1表现出抗肿瘤活性，N2被认为能促进肿瘤转移。在乳腺癌模型中，TAMs分泌的IL-1β诱导γδT细胞释放IL-17以调节G-CSF的释放并促进中性粒细胞的募集以刺激转移，表明TANs在肿瘤进展中与TAMs密切相关。然而，TAN和TAM在肿瘤发生和免疫逃逸中的特异性相互作用机制尚不清楚。巨噬细胞影响Th细胞巨噬细胞和辅助性T细胞之间存在相互调节作用。巨噬细胞依赖TGF-β和IL-10将Th1细胞转化为Th2细胞，以逆转CD8+细胞毒性T细胞和CD4+Th1细胞的抗肿瘤作用，这被认为是一种肿瘤免疫逃逸机制。而Th细胞通过改变巨噬细胞的极化方向影响肿瘤TME。Th1细胞分泌IFN-γ以诱导M1极化，而Th2细胞可分泌IL-4、IL-5和IL-10以促进M2巨噬细胞的生成。此外，Treg表型和功能对免疫抑制性TME发挥重要作用。最近的研究表明，巨噬细胞可以通过各种途径影响Treg的增殖、迁移和功能。首先，TAMs可分泌IL-23，促进Treg的增殖以及IL-10和TGF-β的表达，抑制CTL杀伤肿瘤细胞；其次，巨噬细胞过度表达CCL1，即Treg上表达的CCR8的配体，以吸引Treg进入肿瘤区域；类似地，巨噬细胞分泌CCL22以诱导Treg迁移到卵巢癌的肿瘤区域，抑制T细胞免疫并促进肿瘤生长。巨噬细胞与CAF 的相互作用CAF是TME中最丰富的基质细胞，可释放大量细胞因子，合成和重塑细胞外基质，形成促瘤纤维微环境。CAF可分泌IL-6、M-CSF、MCP-1和基质细胞衍生因子-1，以促进巨噬细胞的浸润和分化。而M2可分泌TGF-β，以促进内皮细胞向间质细胞的转化，并增加CAF的反应性，从而增强癌细胞的侵袭性。巨噬细胞通过PD-1/PD-L1轴介导免疫逃逸TAMs调节肿瘤细胞上PD-L1和CD8+T细胞上PD-1的表达。PD-L1在多种肿瘤组织中高表达，可被TAM衍生的TNF-α上调，并与肿瘤基质中的巨噬细胞浸润呈正相关。在TME中，PD-L1在TAMs上的表达也受到许多因素的影响。IL-27/STAT3轴在淋巴瘤浸润巨噬细胞中诱导PD-L1/2过表达。Progranulin可以通过STAT3途径上调TAMs上的PD-L1，从而促进乳腺癌的免疫逃避。同时，PD-1/PD-L1轴对巨噬细胞功能有着深刻的影响。TAMs上PD-1表达的增加可抑制其吞噬作用，并在结构上作用于mTOR途径，对巨噬细胞的增殖和活化起负调节作用。因此，PD-1/PD-L1阻断也可直接影响巨噬细胞。PD-1/PD-L1阻断剂可促进巨噬细胞的促炎极化，增强效应T细胞的活性，并与其他免疫检查点抑制剂合作限制肿瘤扩散。除了PD-1/PD-L1轴外，一些实验结果表明TAM还可以与其他免疫检查点（如CTLA/CD86轴和TIM3/galectin-9轴）一起诱导免疫逃逸，但仍缺乏确切的证据。巨噬细胞与这些免疫检查点在免疫逃逸中的相互作用值得进一步研究。巨噬细胞有助于形成免疫无反应部位免疫无应答是肿瘤组织逃避免疫监视的重要原因，巨噬细胞可能通过以下机制参与肿瘤组织的免疫豁免。首先，巨噬细胞可以通过聚集CAF到肿瘤区域，CAF沉积纤维胶原、透明质酸、纤维连接蛋白和其他物质，并分泌赖氨酰氧化酶刺激I型胶原交联，从而形成物理屏障。其次，与肿瘤细胞类似，诱导的TAM可表达Fas-L并释放活性可溶性Fas-L，诱导Fas+淋巴细胞凋亡，而CAF可通过MHC-1抗原交叉呈递上调Fas-L和PD-L2，抑制CD8+T细胞的活性，从而形成缺乏淋巴细胞浸润的TME。此外，肿瘤细胞分泌的透明质酸可与巨噬细胞表面的TLR4结合，诱导TAM迁移至肿瘤相关区域，并通过miR935抑制C/EBPβ的表达，促进巨噬细胞向M2表型的分化，从而促进恶性肿瘤细胞逃避免疫监视并“冷却”免疫反应。-04-三、巨噬细胞免疫治疗的临床进展靶向TAM越来越多的证据表明TAM有助于化疗耐药性,以TAM为靶点的单一疗法或联合化疗的治疗方法正在临床前和临床中进行试验。TAM被CSF-1招募到TME中，促进乳腺癌的发展和转移。因此，用单克隆抗体或小分子化合物靶向CSF-1/CSF-1R轴的治疗方法正在试验中。RG7155是一种靶向CSF-1R的单克隆抗体，在一项1期临床试验（NCT01494688）中对7名诊断为弥漫型巨细胞瘤的患者进行治疗，所有患者均出现PR，2名患者出现CR。此外，在RG7155治疗的患者肿瘤活检中，CD68+CD163+巨噬细胞的数量减少，表明TAM向TME的募集减少。靶向CSF-1R、c-Kit和Flt3的酪氨酸激酶抑制剂PLX3397通过使TAM的M2表型去极化来阻断肿瘤进展。PLX3397正在包括黑色素瘤（NCT02071940、NCT02975700）、前列腺癌（NCT0149043）和胶质母细胞瘤（NCT01349036）患者中进行临床试验。其他CSF-1R抑制剂，如ARRY-382（NCT01316822）、BLZ945（NCT02829723）、AMG820（NCT01444404）和IMC-CS4（NCT01346358）也正在各种实体瘤患者中进行测试。除了单药治疗外，针对CSF-1或CSF-1R的抑制剂还与化疗联合进行测试。例如，PLX3397与紫杉醇联合用于晚期实体瘤患者（NCT01525602）；PLX3397与eribulin联合用于乳腺癌患者的试验（NCT01596751）；PLX3397与vemurafenib用于BRAF突变黑色素瘤患者（NCT01826448）；PLX3397联合sirolimus用于晚期肉瘤患者（ NCT02584647）等。此外，TAM的靶向剂和免疫检查点抑制剂的联合应用也在开发中。IMC-CS4与durvalumab或tremelimumab联合用于实体瘤患者的临床试验（NCT02718911）正在进行中。还有PLX3397与pembrolizumab联合用于各种肿瘤患者的1期临床试验（NCT02452424），ARRY-382与pembrolizumab的联合试验（NCT02880371），BLZ945与PDR001（一种针对PD-1的单克隆抗体）的联合试验（NCT02829723），RG7155与atezolizumab的联合试验（NCT02323191），以及AMG820与使用pembrolizumab的联合试验（NCT02713529）。CAR-巨噬细胞直到2020年11月，两个基于CAR-M策略的临床试验已经获得FDA的批准。第一个是来自CARISMA Therapeutics的候选药物CT-0508，它用抗HER2的CAR-M治疗复发/难治性HER2过度表达的肿瘤患者（I期临床试验）。另一个是Maxyte的MCY-M11，它利用mRNA转染PBMC表达靶向间皮素的CAR（包括CAR-M），治疗复发/难治性卵巢癌和腹膜间皮瘤患者，目前正在招募志愿者进行I期临床试验。-05-结语越来越多的研究表明巨噬细胞在肿瘤发展、转移、免疫调节、肿瘤血管形成、TME重塑和癌症治疗反应中起着关键作用。巨噬细胞靶向治疗有望成为肿瘤免疫治疗的下一个前沿，阐明其相互作用模式将有助于对免疫抑制性TME形成更全面的认识，避免免疫反弹，减少肿瘤免疫逃避，促进相关研究的发展。参考资料：1.Next frontier in tumor immunotherapy:macrophage-mediated immune evasion. Biomark Res. 2021; 9: 72.公众号内回复“ADC”或扫描下方图片中的二维码免费下载《抗体偶联药物：从基础到临床》的PDF格式电子书！公众号已建立“小药说药专业交流群”微信行业交流群以及读者交流群，扫描下方小编二维码加入，入行业群请主动告知姓名、工作单位和职务。

免疫疗法

2025-04-14

·GlobeNewswire-Health Care

SynOx Therapeutics Receives Fast Track Designation from U.S. Food and Drug Administration for Emactuzumab for Tenosynovial Giant Cell Tumours (TGCT)

DUBLIN, Ireland and OXFORD, United Kingdom, April 14, 2025 (GLOBE NEWSWIRE) -- SynOx Therapeutics Limited (“SynOx”), a late-stage clinical biopharmaceutical company developing of emactuzumab for Tenosynovial Giant Cell Tumours (TGCT), today announced that the United States Food and Drug Administration (FDA) has granted Fast Track Designation (FTD) to emactuzumab for the treatment of TGCT patients that are not amenable to or who would not benefit from surgery. Emactuzumab, a potentially best-in-class CSF-1 receptor (CSF-1R) inhibiting monoclonal antibody, is currently being evaluated in the TANGENT study, a global, multi-centre, randomized, double-blind, placebo-controlled registrational Phase 3 trial. TGCT is a rare, non-malignant but aggressively growing tumour of the synovium, tendon sheaths and bursa membranes primarily located in knee, hip, and ankle joints and caused by excessive production of CSF-1. It is a chronically debilitating disease for patients causing loss of function of the affected joints, as well as pain, stiffness and limited range of motion. Receipt of FTD for TGCT was supported by data from Phase 1/2 clinical studies demonstrating rapid, robust tumour reduction and durable response combined with a manageable safety profile. Emactuzumab has also previously received Orphan Medicinal Project designation from the European Medicines Agency. “The granting of FTD for emactuzumab in TGCT highlights the devastating toll that this disease has on patients, as well as the critical need that remains for new treatment options,” said Elyse Seltzer, M.D., Chief Medical Officer of SynOx Therapeutics. “Based on our clinical work to date, we believe that emactuzumab has significant potential to address key patient needs by offering an effective, short-course treatment with rapid onset and a durable response that allows individuals suffering from TGCT to better manage their disease and move forward with their lives. We look forward to completing the ongoing TANGENT study and progressing emactuzumab toward potential commercialization.” About Fast Track DesignationThe FDA grants Fast Track designation to facilitate the development and expedite the review of medicines to treat serious conditions and fill an unmet medical need. Fast Track status allows for enhanced communication and collaboration between the FDA and drug developers, potentially speeding up the delivery of life-saving treatments to patients. About Tenosynovial Giant Cell Tumour (TGCT)Tenosynovial Giant Cell Tumour (TGCT), previously termed pigmented villonodular synovitis (PVNS), is a type of tumour that affects the soft tissue lining of joints and tendons. TGCTs are categorised as fibrohistiocytic tumours by the WHO classification and are subclassified based on growth patterns (localised and diffuse types) and location (tendon sheath, intra- and extra-articular forms). TGCTs are locally destructive and can be aggressive. The disease causes significant joint pain, stiffness, loss of function and reduced quality of life. While most patients undergo surgery, more than 50% of those with diffuse TGCT experience tumour recurrence within three years. If left untreated, TGCT can cause joint deformity, degenerative changes, and even lead to arthrodesis or amputation in severe cases. About CSF-1 and EmactuzumabCSF-1 (or macrophage colony-stimulating factor) is a cytokine that binds to the CSF-1 receptor (CSF-1R), expressed on macrophages and other immune cells. Emactuzumab is a humanised IgG1 monoclonal antibody targeting CSF-1R, designed to inhibit and deplete macrophages in tumour tissue. Originally developed by Roche, emactuzumab has shown substantial efficacy in clinical studies in TGCT, including an objective response rate of ~71%, rapid tumour reduction, functional improvement, and good tolerability with a manageable safety profile. Emactuzumab may also have utility in other macrophage-driven diseases, and SynOx is actively exploring further development opportunities in these areas. Additional details regarding the ongoing registrational Phase 3 TANGENT study can be found on ClinicalTrials.gov (Identifier: NCT05417789). About SynOx TherapeuticsSynOx Therapeutics Limited is a Dublin and Oxford-based, late-stage clinical biopharmaceutical company developing emactuzumab, a best-in-class monoclonal antibody against CSF-1R, for the treatment of Tenosynovial Giant Cell Tumour (TGCT) and other CSF-1-related and macrophage-driven disorders. SynOx is led by an experienced team of industry professionals with a successful track record of developing and bringing products to commercialization. The company is backed by a strong syndicate of premier life science investors including Forbion, Gilde Healthcare, HealthCap, Bioqube Ventures and Medicxi. Contacts: SynOx Therapeutics Ray Barlow Chief Executive Officer Tel: +44 (0) 208 058 5619 Email: enquiries@synoxtherapeutics.com Vida Strategic Partners (on behalf of SynOx) Tim Brons (Media) 415-675-7402 tbrons@vidasp.com

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100 项与 Emactuzumab 相关的药物交易

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KEGG	Wiki	ATC	Drug Bank
D11234	Emactuzumab	-	DB14905

研发状态

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适应症	最高研发状态	国家/地区	公司	日期
腱鞘巨细胞瘤	临床3期	美国	Synox Therapeutics Ltd.	2024-04-30
腱鞘巨细胞瘤	临床3期	奥地利	Synox Therapeutics Ltd.	2024-04-30
腱鞘巨细胞瘤	临床3期	比利时	Synox Therapeutics Ltd.	2024-04-30
腱鞘巨细胞瘤	临床3期	加拿大	Synox Therapeutics Ltd.	2024-04-30
腱鞘巨细胞瘤	临床3期	法国	Synox Therapeutics Ltd.	2024-04-30
腱鞘巨细胞瘤	临床3期	意大利	Synox Therapeutics Ltd.	2024-04-30
腱鞘巨细胞瘤	临床3期	荷兰	Synox Therapeutics Ltd.	2024-04-30
腱鞘巨细胞瘤	临床3期	韩国	Synox Therapeutics Ltd.	2024-04-30
腱鞘巨细胞瘤	临床3期	西班牙	Synox Therapeutics Ltd.	2024-04-30
腱鞘巨细胞瘤	临床3期	瑞典	Synox Therapeutics Ltd.	2024-04-30

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT02323191 (Pubmed \| J Immunother Cancer)	临床1期	晚期恶性实体瘤	221	Emactuzumab + Atezolizumab	鏇齋觸鹹壓淵繭糧淵廠(網鹹憲遞齋遞顧積顧醖) = Grade ≥3 treatment-related adverse events occurred in 25 (11.3%) patients of which fatigue and rash were the most common (14 patients (6.3%) each) 願窪選鑰艱遞膚夢觸範 (築糧艱齋製夢衊衊淵糧 )	积极	2022-05-01
NCT01494688 (Pubmed \| Eur J Cancer Care (Engl) \| Eur J Cancer) 人工标引	临床1期	色素沉着的绒毛结节性滑膜炎	63	Emactuzumab	醖築淵醖壓窪膚鹹築夢(範餘鑰繭夢鬱糧繭夢鏇) = pruritus, asthenia and oedema 膚夢膚艱選選製鬱選遞 (夢獵範願蓋醖鏇糧鏇壓 )	积极	2020-12-01
NCT01494688 (Pubmed \| Ann Oncol) 人工标引	临床1期	实体瘤	99	paclitaxel+emactuzumab	簾襯襯鹽製窪夢築淵醖(夢餘醖選鹹觸襯餘艱夢) = No maximum tolerated dose was reached in either study arm 獵襯鹹壓壓鬱選構獵夢 (窪築壓選壓衊鹹鹹願簾 )	不佳	2019-08-01
NCT01494688 (Pubmed \| Ann Oncol) 人工标引	临床1期	实体瘤	99	emactuzumab		不佳	2019-08-01
NCT01494688 (Pubmed \| Lancet Oncol) 人工标引	临床1期	巨细胞瘤	25	emactuzumab	積餘築膚積積襯艱遞襯(鹽積鹹網鹽壓鹹壓襯鹽) = 5 events in 5 pts [lupus erythematosus（2 pts）, periorbital oedema（1 pt）, erythema（1 pt）, dermohypodermitis（1 pt）] 築鬱鹹鏇艱壓鬱壓蓋鑰 (蓋獵窪艱願鹹蓋餘遞淵 ) 更多	积极	2015-08-01