A Phase 1a/1b, Open-label, Multicenter Trial Investigating the Safety, Tolerability, and Preliminary Anti-neoplastic Activity of S095029 (Anti-NKG2A) as Monotherapy and in Combination With Sym021 (Anti-PD-1) in Patients With Advanced Solid Tumor Malignancies Followed by an Expansion Part With Triplet Combinations of S095029 and Sym021 and an Anti-HER2 mAb or Anti-EGFR mAbs (Futuximab/Modotuximab) in Patients With Metastatic Gastric or Colorectal Cancers

The purpose of the study is to investigate the safety, tolerability, and preliminary anti-neoplastic activity of S095029 alone and in combination with Sym021 in patients with advanced solid tumor malignancies followed by an expansion phase of triple combinations.
*The study sponsor has made the decision not to move forward to the expansion part of the study due to strategic considerations, unrelated to any safety issues or concerns. The study will be stopped after completion of dose escalation parts 1a and 1b of the study.

开始日期2021-10-15

申办/合作机构

Institut de Recherches Intern Servier

[+1]

NCT04195373

/ Withdrawn临床1期

A Phase I Open-label, Safety Study of Intra-tumoral Application of TMV-018 in Combination With 5-FC or Anti-PD-1 Therapy in Patients With Tumors of the Gastrointestinal Tract

This study aims to determine the safety and tolerability of TMV-018 when given alone or in combination with the prodrug 5-Fluorocytosine (5-FC) or an anti-PD-1 checkpoint inhibitor in patients with gastrointestinal tumors. Furthermore, the maximum tolerated dose (MTD) and recommended Phase II dose of TMV-018 shall be determined.

开始日期2020-11-23

申办/合作机构

Themis Bioscience GmbH

[+2]

NCT04672434

/ Completed临床1期

A Phase 1, Open-Label, Multicenter Trial Investigating the Safety, Tolerability, and Preliminary Antineoplastic Activity of Sym024 (Anti-CD73) as Monotherapy and in Combination With Sym021 (Anti-PD-1) in Patients With Advanced Solid Tumor Malignancies

The primary purpose of this study is to see if Sym024 is safe and tolerable as monotherapy and in combination with Sym021 in patients with solid tumor malignancies.

开始日期2020-11-19

申办/合作机构

Servier Symphogen A/S

100 项与 Sym-021 相关的临床结果

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100 项与 Sym-021 相关的转化医学

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100 项与 Sym-021 相关的专利（医药）

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项与 Sym-021 相关的文献（医药）

2026-03-01·Journal for ImmunoTherapy of Cancer

Phase Ib multicenter study of anti-TIM-3 (S095018/Sym023) in combination with anti-PD-1 (Sym021) in patients with advanced/metastatic recurrent biliary tract cancer

Article

作者: Skartved, Niels ; Lakhani, Nehal ; Geronimi, Julia ; Darcel, Pauline ; Rodrigues, Christelle ; Rodon Ahnert, Jordi ; Harouki, Najah ; Kim, Richard ; Askoxylakis, Vasileios ; Raimbourg, Judith ; Hald, Rikke ; Ianopoulos, Xenophon ; Kaplon, Hélène ; Marron, Thomas ; Moreno, Irene ; Liao, Chih-Yi ; Macarulla, Teresa ; He, Peng ; Davis, Sarah Lindsey ; Jakobsen, Janus Schou ; Ghiringhelli, Francois ; Abdul Razak, Albiruni ; Mahipal, Amit ; Lopez-Ravnborg, Daleen

Background:

T-cell immunoglobulin and mucin-domain containing 3 (TIM-3) is an inhibitory receptor linked to decreased antitumor activity of immune cells. S095018 is a human anti-TIM-3 IgG2 antibody that blocks the binding of phosphatidyl serine to TIM-3. Sym021 is a humanized IgG1 antibody that inhibits the binding of programmed cell death protein-1 (PD-1) to its ligands programmed death-ligand 1 (PD-L1) and PD-L2.

Methods:

S095018 in combination with Sym021 was tested in patients with advanced/metastatic biliary tract cancers (BTC) whose disease progressed under treatment with at least 1 line of systemic therapy and who had not received prior treatment with PD-(L)1 inhibitors ( NCT04641871 ). Patients received 3 mg/kg of Sym021 and 10 mg/kg of S095018 once every 2 weeks. Primary endpoints included overall response rate and incidence/severity of adverse events. Key secondary endpoints included pharmacokinetics, immunogenicity assessment, progression-free survival (PFS) and overall survival (OS).

Results:

35 patients with stage IV BTC received S095018 in combination with Sym021. A partial response was achieved in 2 patients (5.7%) and stable disease in 11 patients (31.4%) for a disease control rate of 37%; 4 patients were not evaluable for response. Median PFS and OS were 1.9 months (90% CI 1.8 to 3.7) and 13.4 months (90% CI 8.2 to 27.1), respectively. The most common treatment-emergent adverse events of any grade included fatigue, pruritus, infusion-related reaction, and increases in amylase (8.6% each). Exploratory biomarker analyses in paired tumor biopsies showed an increase in intratumoral CD8 T-cell density and an upregulation of gene signatures related to interferon-γ signaling, antigen presentation, and T-cell activation with treatment without, however, clear association with efficacy endpoints.

Conclusions:

Dual PD-1/TIM-3 inhibition was tolerable but exhibited modest antitumor activity in patients with advanced/metastatic recurrent BTC who had not received prior anti-PD-(L)1 treatment.

2024-09-20·Nan fang yi ke da xue xue bao = Journal of Southern Medical University

[High RNF7 expression enhances PD-1 resistance of non-small cell lung cancer cells by promoting CXCL1 expression and myeloid-derived suppressor cell recruitment via activating NF-κB signaling].

Article

作者: Zhong, N ; Geng, B ; Sun, Z ; Zhao, W ; Wang, H

OBJECTIVE:

To investigate the mechanism of RNF7 for regulating myeloid-derived suppressor cells (MDSCs) in nonsmall cell lung cancer (NSCLC).

METHODS:

TIMER2.0 database and immunohistochemistry were used to analyze RNF7 expression level and its correlation with immune cell infiltration in non-small cell lung cancer. The impact of RNF7 expression levels on prognosis of lung cancer patients was analyzed using Kaplan-Meier survival analysis. CMT-167 cells with RNF7 overexpression or knockdown were inoculated subcutaneously in C57BL/6 mice, and the mice in RNF7 knockdown group were treated with anti-PD-1 or IgG isotype control 7 days after the inoculation. The tumor tissues were harvested after 30 days for tumor volume measurement, detection of S100A8+A9 and Gr-1 expressions with immunohistochemistry, and analysis of MDSC infiltration. Gene set enrichment analysis (GSEA) was performed to identify the potential pathways regulated by RNF7 in NSCLC. Western blotting and luciferase assays were used to assess the impact of RNF7 on the NF-κB signaling pathway. ELISA and RT-qPCR were used to measure chemokine (C-X-C motif) ligand 1 (CXCL1) expression.

RESULTS:

RNF7 expression was significantly upregulated in NSCLC, and high RNF7 expression levels were associated with poor prognosis of the patients (P < 0.001). TIMER2.0 analysis revealed a positive correlation between RNF7 expression and MDSC infiltration (P < 0.001). GSEA suggested that RNF7 was enriched in the NF-κB signaling pathway. In NSCLC cells, RNF7 knockdown significantly inhibited NF-κB activation and reduced CXCL1 expression. In the tumor-bearing mice, RNF7 overexpression significantly increased MDSC infiltration in the tumor tissue, and RNF7 knockdown obviously reduced MDSC infiltration and enhanced the efficacy of anti-PD-1 therapy.

CONCLUSION:

High expression of RNF7 in NSCLC cells promotes CXCL1 expression by activating the NF-κB signaling pathway, thus leading to the chemotactic recruitment of MDSCs, which contributes to tumor resistance to antiPD-1 therapy.

2020-12-01·Journal of hematology & oncology1区 · 医学

CDK7 inhibitor THZ1 enhances antiPD-1 therapy efficacy via the p38α/MYC/PD-L1 signaling in non-small cell lung cancer

1区 · 医学

ArticleOA

作者: Dong, Xiaorong ; Wu, Gang ; Chen, Yaobing ; Zhou, Xiaoshu ; Xu, Shuangbing ; Zhang, Tao ; Meng, Rui ; Liu, Li ; Zhang, Sheng ; Hong, Jiaxin ; Wang, Jian ; Zhang, Ruiguang ; Tang, Jing ; Lin, Zhenyu ; Zong, Yan ; Yang, Kunyu ; Xu, Yingzhuo

Abstract:

Background:

The cyclin-dependent kinase 7 (CDK7) subunit of TFIIH regulates RNA polymerase-II-based transcription and promotes tumor progression. However, the mechanisms involved in CDK7-mediated immune evasion are unclear in non-small cell lung cancer (NSCLC).

Methods:

RNA silencing and pharmacologic inhibitors were used to evaluate the functions of CDK7/p38α/MYC/PD-L1 axis in cancer cell proliferation and antiPD-1 therapy resistance. Flow cytometry was performed to detect the status of the immune microenvironment after CDK7 inhibition and antiPD-1 therapy in vivo. CD8 depletion antibodies were used to assess the role of CD8+ T cells in combined CDK7 and PD-1 blockade. The associations among CDK7, p38α, MYC, PD-L1, infiltrating T cells, and survival outcomes were validated in two tissue microarrays and public transcriptomic data of NSCLC.

Results:

High CDK7 mRNA and protein levels were identified to be associated with poor prognosis in NSCLC. CDK7 silencing and CDK7 inhibitor THZ1 elicited apoptosis and suppressed tumor growth. Moreover, CDK7 ablation specifically suppressed p38α/MYC-associated genes, and THZ1 inhibited MYC transcriptional activity through downregulating p38α. CDK7 inhibition sensitized NSCLC to p38α inhibitor. Further, THZ1 suppressed PD-L1 expression by inhibiting MYC activity. THZ1 boosted antitumor immunity by recruiting infiltrating CD8+ T cells and synergized with antiPD-1 therapy. The CDK7/MYC/PD-L1 signature and infiltrating T cell status collectively stratified NSCLC patients into different risk groups.

Conclusion:

These data suggest that the combined CDK7 inhibitor THZ1 and antiPD-1 therapy can be an effective treatment in NSCLC.

101

项与 Sym-021 相关的新闻（医药）

2026-09-14

·博安生物

Boan Biotech Receives IND Clearance in China for BA1203 (A Masked Anti-PD-1/IL-2 Fusion Protein)

Boan Biotech announced today that the Center for Drug Evaluation (CDE) of China’s National Medical Products Administration (NMPA) has cleared the Investigational New Drug (IND) application for BA1203, a PD-1/IL-2 antibody-cytokine prodrug intended to be developed for the treatment of multiple types of solid tumors. To the company’s knowledge, BA1203 is the world’s only PD-1/IL-2 molecule that combines high activity at the IL-2α receptor with an IL-2 masking design and PD-1-blocking activity. Immuno-oncology (IO) therapies, represented by PD-1/PD-L1 inhibitors, have become a cornerstone treatment for malignancies. However, a significant proportion of patients still experience primary non-response, recurrence, or resistance. Previous meta-analyses have shown that PD-1/PD-L1 inhibitor monotherapy achieves an overall objective response rate (ORR) of approximately 20%1, with response rates varying significantly across tumor types and patient populations with different levels of PD-L1 expressions. These findings underscore the significant unmet clinical need that remain with current immunotherapies. IL-2 is a key cytokine that promotes T-cell proliferation and functional recovery. However, traditional IL-2 therapies are limited by a narrow therapeutic window, non-selective activation of peripheral immune cells, and the risk of systemic toxicity. Achieving targeted delivery and selective activation of L-2 within the tumor microenvironment (TME) has become a key focus of next-generation IO therapies. As a next-generation IO therapy developed by Boan Biotech, BA1203 combines the mechanism of action of a PD-1 antibody and an IL-2 cytokine, aiming to achieve immune checkpoint blockade and localized immune activation within the TME simultaneously. Through its IL-2 masking prodrug design, BA1203 is intended to selectively activate IL-2 within the TME while maintaining lower IL-2 activity in peripheral tissues, thereby enhancing local antitumor immunity and reducing the risk of systemic toxicity. The molecule also incorporates a high-affinity, bivalent PD-1 binding design that strengthens checkpoint blockade and facilitates the precise delivery of IL-2 to PD-1-positive tumor-infiltrating T cells. In addition, BA1203 features a symmetric molecular structure, which helps improve molecular stability and the controllability of manufacturing process. Preclinical studies have shown that BA1203 demonstrates excellent anti-tumor activity, significantly outperforming existing PD-1/PD-L1 antibodies across multiple tumor models in which such checkpoint inhibitors showed low or no response. In tumor-bearing mouse models, BA1203 demonstrated superior efficacy compared to competitors in the same class and exhibited a favorable safety profile characterized by tumor-dependent activation, with low peripheral toxicity alongside enhanced local immune activation within tumors. BA1203 also demonstrated excellent tolerability in cynomolgus monkey studies. Following this IND clearance, Boan Biotech plans to conduct a multicenter, open-label Phase I clinical study to evaluate the preliminary efficacy, safety, tolerability, and pharmacokinetics of BA1203 in patients with advanced solid tumors. The study is designed to further validate BA1203’s advantages in efficacy and safety, explore its development as a monotherapy and in combination regimens, and assess its differentiated therapeutic potential in PD-1 binding, immune pathway blockade, and immune activation within the TME. About Boan Biotech Boan Biotech (6955.HK) is a fully-integrated biopharmaceutical company developing, manufacturing, and marketing biologics, with a focus on oncology, autoimmune diseases, ophthalmology, and metabolic diseases. The company’s drug discovery activities revolve around multiple platforms: Human Antibody Transgenic Mouse Technology Platform, Bispecific/Multi-specific/Probody Technology Platform, ADC Technology Platform and Artificial Intelligence/Big Data Application Platform. Boan Biotech operates across the entire value chain of the industry covering antibody discovery, cell line development, upstream and downstream process development, analytical and bio-analytical method development, technology transfer, non-clinical research, clinical research, regulatory affairs and registration, and commercial production. Boan Biotech currently has five products that have been approved for marketing, along with a robust pipeline of proprietary investigational biologics and biosimilars. In addition to China, the company is also developing biopharmaceutical products in overseas markets, including the U.S., Europe, and Japan. With a differentiated portfolio and well-established commercial capabilities, Boan Biotech operates across the industry’s value chain from research and development to manufacturing and commercialization, laying a solid foundation for long-term, high-quality growth in the future. References： 1. Zhao B, et al. Therapeutic Advances in Medical Oncology, 2020

2026-08-27

·今日头条

别把“水疱”当成普通皮疹！警惕肿瘤免疫治疗背后隐匿的“大疱性类天疱疮”

作者导语随着以 PD-1/PD- L1抑制剂为代表的免疫检查点抑制剂（ICIs）在临床的广泛应用，肿瘤治疗进入了免疫时代。然而，伴随而来的免疫相关不良反应（irAEs）也给临床医生带来了全新的挑战。在众多irAEs中，皮肤毒性是最常见且发生最早的副反应之一。尽管临床医生对常规的斑丘疹、瘙痒或苔藓样皮损等早已不陌生，但在面对免疫治疗引发的“大疱性类天疱疮”（Bullous Pemphigoid, BP）这一罕见却病情严重的自身免疫性皮肤病时，却常因早期诊断意识不足而面临“漏诊”或“误诊”的困局。 BP的典型表现为全身突发张力性水疱和剧烈瘙痒，如不及时识别并有效干预，极易因水疱破溃导致继发感染或低蛋白血症，甚至被迫终止极具临床获益的肿瘤免疫治疗。更具欺骗性的是，这类患者在水疱出现之前的数周乃至数月，往往仅表现为非特异性的皮肤瘙痒或湿疹样红斑，常被临床医生当成“普通皮肤过敏”进行简单处理。本文将结合国际权威循证医学证据，系统梳理免疫治疗相关BP的临床识别要点、发病机制及现代管理策略，旨在提升多学科诊疗背景下对这一不良反应的精准化管理水平。早期症状极具欺骗性非特异性瘙痒往往是BP的“前驱信号” 许多临床医生习惯于将“突发满身水疱”作为大疱性类天疱疮（BP）的唯一诊断线索。然而，由免疫制剂引发的BP在起病过程上具有明显的特殊性与隐匿性。权威研究表明，免疫相关BP在进展为典型水疱之前，往往存在一个漫长且极具迷惑性的“前驱期” ，其主要临床表现仅为持续加重的皮肤瘙痒、湿疹样皮损或荨麻疹样风团。这种非特异性的皮肤改变，在临床表现上与其他低级别的免疫皮肤毒性（如普通的斑丘疹或皮炎）几乎无法区分。如果接诊医生在此阶段缺乏警惕，仅给予常规的抗组胺药物或弱效局部激素治疗，往往难以遏制病情的持续进展。随着体内自身抗体滴度的累积，患者常在数周至数月后，在红斑或原本正常的皮肤上突然爆发大量张力性、壁厚且不易破裂的水疱，此时才被确诊为BP。这意味着，对于接受免疫治疗的肿瘤患者，任何常规对症治疗无效、顽固且持续恶化的皮肤瘙痒和非特异性红斑，都不能仅简单地归为“一过性药物过敏”，而必须将其视为BP的潜在“前驱信号” 。及时的皮肤科联络会诊及必要的皮肤活检，是避免其演变为大面积表皮剥脱性损害的黄金干预窗口。并非简单的药物过敏其本质是抗肿瘤免疫对皮肤半桥粒结构的“交叉攻击” 理解免疫治疗相关BP的发病机制，有助于临床医生深刻认识这一疾病的顽固性。从病理生理学角度看，BP并非由于药物本身直接毒性导致的过敏反应，而是一种由免疫异常活化触发的、针对表皮与真皮交界处半桥粒结构成分（主要是BP180，亦称胶原XVII）的自身免疫性疾病。研究显示，这种免疫靶向攻击通常源于肿瘤抗原与正常皮肤抗原之间的“交叉反应” 。在非小细胞肺癌、恶性黑色素瘤等多种肿瘤组织表面，同样表达有BP180或类似的半桥粒蛋白。当PD-1/PD-L1抑制剂打破体内的免疫耐受、重新激活抗肿瘤T细胞和B细胞时，这些高度活跃的免疫细胞在清除肿瘤细胞的同时，也会无选择性地攻击正常皮肤中的BP180蛋白。这种免疫系统“杀敌八百，自损一千”的机制，导致表皮真皮粘连受损，进而在补体活化及炎性细胞浸润的作用下导致表皮下水疱的形成。这也合理解释了为什么在许多回顾性队列中，出现BP的不良反应往往与患者较好的肿瘤总体生存率和治疗应答存在正向相关。水疱大面积爆发对抗肿瘤决策构成严峻考验规范化分级管理至关重要在肿瘤免疫治疗期间，一旦确诊为BP，不仅意味着患者必须忍受皮损带来的痛苦，更有可能使整个抗肿瘤治疗停滞不前。回顾性临床研究指出，BP具有高度的持久性和复发倾向，往往会导致很高比例的肿瘤患者面临免疫治疗暂时中断甚至永久停药的结局，从而给患者的整体生存预后蒙上阴影。因此，在多学科联合诊疗（MDT）模式下，如何在有效控制水疱、缓解瘙痒的同时尽量维持抗肿瘤免疫活性，极其考验医生的临床平衡艺术。根据国际现行不良反应管理推荐，对免疫相关BP必须实施精细化的分级管理。对于轻度（1级，受累皮损面积拓展阅读在传统的 irAEs 临床处置中，系统性应用大剂量糖皮质激素被视为快速扑灭过度免疫反应的基石。然而，对于本身免疫功能低下的晚期肿瘤患者而言，长期大剂量使用糖皮质激素犹如一把双刃剑。这不仅会带来代谢紊乱、严重感染以及骨质疏松等严重的系统性副作用，更令肿瘤科医生担忧的是，系统性大范围的免疫抑制剂可能从根本上“对冲”或“扼杀”PD-1/PD-L1抑制剂带来的抗肿瘤效应，最终导致肿瘤进展或免疫耐受失败。基于这一严峻的临床痛点，学术界正在寻找一种“精准打击”的替代疗法，力求在控制皮肤水疱的同时，不削弱抗肿瘤 T 细胞的功能。在这一背景下，靶向特定细胞因子的生物制剂治疗方案开始受到广泛关注。多中心观察性队列研究提示，针对Th2通路中关键因子IL-4/IL-13的受体拮抗剂度普利尤单抗（Dupilumab），以及针对 IgE 的单克隆抗体奥马珠单抗（Omalizumab），在治疗免疫相关BP中展现出了极具前景的临床获益。由于BP的表皮下水疱形成过程高度依赖于Th2型炎症因子的活化及 IgE 介导的嗜酸性粒细胞脱颗粒，这些特异性生物制剂能够靶向阻断这一特定炎性瀑布反应，同时避免了对发挥抗肿瘤作用的Th1和CD8+ T细胞产生广泛抑制。这种不牺牲肿瘤免疫反应的“靶向皮肤耐受”疗法，有望在未来重塑中重度免疫相关皮肤毒性的治疗格局，成为更安全、不削弱免疫治疗疗效的一线联合干预手段。观点评述肿瘤免疫治疗相关的大疱性类天疱疮（BP）绝非单纯的“皮疹”小问题，它是一个具有独特免疫生物学特征的交叉医学课题，深刻体现了抗肿瘤免疫活性与自体免疫耐受之间的博弈。首先，临床实践中最迫切的需求是关口前移和多学科深度融合。由于BP发病机制的特殊性，非特异性的前驱期瘙痒往往是干预的最佳时机。肿瘤科医生在随访时，应常规进行精准的皮肤症状评估，切忌将所有的皮肤发红、发痒简单粗暴地当作普通湿疹或斑丘疹处理。若在非水疱期便能邀请皮肤科医生深度介入，通过早期局部足量糖皮质激素控制局部微环境，甚至有望截断其向大面积爆发期演变，最大限度地规避被迫停用免疫药物给患者抗肿瘤大局带来的系统性风险。然而，我们亦必须认识到，目前关于免疫相关BP的证据链条仍存在明显的局限性。当前的大多数诊疗推荐主要建立在小样本回顾性观察、病例系列或借鉴经典自发性BP的治疗方案之上，仍缺乏大规模、多中心、前瞻性控制的随机对照临床研究。在实际临床操作中，对于生物制剂的应用时机、激素的最佳减量路径，以及如何在量化层面上评估免疫抑制治疗对肿瘤长期总体生存率（OS）的影响，依旧缺乏金标准。未来的研究重点，应当致力于通过精确的液体活检、自身抗体动态监测等转化医学工具，建立起能够预测免疫相关BP发生的高危分子标志物，并在 MDT框架下制定出一套兼顾“皮肤屏障恢复”与“肿瘤持久缓解”双重获益的个体化精准治疗共识。 ---------------------------------- ☆ 本文仅供医疗卫生等专业人士参考参考文献 [1] Lopez AT, Khanna T, Antonov N, Audrey-Bayan C, Geskin L. A review of bullous pemphigoid associated with PD-1 and PD-L1 inhibitors. Int J Dermatol. 2018;57(6):664-669. [2] Siegel J, Totonchy M, Damsky W, et al. Bullous disorders associated with anti-PD-1 and anti-PD-L1 therapy: A retrospective analysis evaluating the clinical and histopathologic features, frequency, and impact on cancer therapy. J Am Acad Dermatol. 2018;79(6):1081-1088. [3] Kawsar A, Edwards C, Patel P, et al. Checkpoint inhibitor-associated bullous cutaneous immune-related adverse events: a multicentre observational study. Br J Dermatol. 2022;187(6):981-987.

2026-08-27

·肿瘤头条

别把“水疱”当成普通皮疹！警惕肿瘤免疫治疗背后隐匿的“大疱性类天疱疮”

作者导语随着以PD-1/PD-L1抑制剂为代表的免疫检查点抑制剂（ICIs）在临床的广泛应用，肿瘤治疗进入了免疫时代。然而，伴随而来的免疫相关不良反应（irAEs）也给临床医生带来了全新的挑战。在众多irAEs中，皮肤毒性是最常见且发生最早的副反应之一。尽管临床医生对常规的斑丘疹、瘙痒或苔藓样皮损等早已不陌生，但在面对免疫治疗引发的“大疱性类天疱疮”（Bullous Pemphigoid, BP）这一罕见却病情严重的自身免疫性皮肤病时，却常因早期诊断意识不足而面临“漏诊”或“误诊”的困局。 BP的典型表现为全身突发张力性水疱和剧烈瘙痒，如不及时识别并有效干预，极易因水疱破溃导致继发感染或低蛋白血症，甚至被迫终止极具临床获益的肿瘤免疫治疗。更具欺骗性的是，这类患者在水疱出现之前的数周乃至数月，往往仅表现为非特异性的皮肤瘙痒或湿疹样红斑，常被临床医生当成“普通皮肤过敏”进行简单处理。本文将结合国际权威循证医学证据，系统梳理免疫治疗相关BP的临床识别要点、发病机制及现代管理策略，旨在提升多学科诊疗背景下对这一不良反应的精准化管理水平。早期症状极具欺骗性非特异性瘙痒往往是BP的“前驱信号” 许多临床医生习惯于将“突发满身水疱”作为大疱性类天疱疮（BP）的唯一诊断线索。然而，由免疫制剂引发的BP在起病过程上具有明显的特殊性与隐匿性。权威研究表明，免疫相关BP在进展为典型水疱之前，往往存在一个漫长且极具迷惑性的“前驱期”，其主要临床表现仅为持续加重的皮肤瘙痒、湿疹样皮损或荨麻疹样风团。这种非特异性的皮肤改变，在临床表现上与其他低级别的免疫皮肤毒性（如普通的斑丘疹或皮炎）几乎无法区分。如果接诊医生在此阶段缺乏警惕，仅给予常规的抗组胺药物或弱效局部激素治疗，往往难以遏制病情的持续进展。随着体内自身抗体滴度的累积，患者常在数周至数月后，在红斑或原本正常的皮肤上突然爆发大量张力性、壁厚且不易破裂的水疱，此时才被确诊为BP。这意味着，对于接受免疫治疗的肿瘤患者，任何常规对症治疗无效、顽固且持续恶化的皮肤瘙痒和非特异性红斑，都不能仅简单地归为“一过性药物过敏”，而必须将其视为BP的潜在“前驱信号”。及时的皮肤科联络会诊及必要的皮肤活检，是避免其演变为大面积表皮剥脱性损害的黄金干预窗口。并非简单的药物过敏其本质是抗肿瘤免疫对皮肤半桥粒结构的“交叉攻击” 理解免疫治疗相关BP的发病机制，有助于临床医生深刻认识这一疾病的顽固性。从病理生理学角度看，BP并非由于药物本身直接毒性导致的过敏反应，而是一种由免疫异常活化触发的、针对表皮与真皮交界处半桥粒结构成分（主要是BP180，亦称胶原XVII）的自身免疫性疾病。研究显示，这种免疫靶向攻击通常源于肿瘤抗原与正常皮肤抗原之间的“交叉反应”。在非小细胞肺癌、恶性黑色素瘤等多种肿瘤组织表面，同样表达有BP180或类似的半桥粒蛋白。当PD-1/PD-L1抑制剂打破体内的免疫耐受、重新激活抗肿瘤T细胞和B细胞时，这些高度活跃的免疫细胞在清除肿瘤细胞的同时，也会无选择性地攻击正常皮肤中的BP180蛋白。这种免疫系统“杀敌八百，自损一千”的机制，导致表皮真皮粘连受损，进而在补体活化及炎性细胞浸润的作用下导致表皮下水疱的形成。这也合理解释了为什么在许多回顾性队列中，出现BP的不良反应往往与患者较好的肿瘤总体生存率和治疗应答存在正向相关。水疱大面积爆发对抗肿瘤决策构成严峻考验规范化分级管理至关重要在肿瘤免疫治疗期间，一旦确诊为BP，不仅意味着患者必须忍受皮损带来的痛苦，更有可能使整个抗肿瘤治疗停滞不前。回顾性临床研究指出，BP具有高度的持久性和复发倾向，往往会导致很高比例的肿瘤患者面临免疫治疗暂时中断甚至永久停药的结局，从而给患者的整体生存预后蒙上阴影。因此，在多学科联合诊疗（MDT）模式下，如何在有效控制水疱、缓解瘙痒的同时尽量维持抗肿瘤免疫活性，极其考验医生的临床平衡艺术。根据国际现行不良反应管理推荐，对免疫相关BP必须实施精细化的分级管理。对于轻度（1级，受累皮损面积<10%且无水疱）患者，通常首选高强度局部糖皮质激素（如丙酸氯倍他索乳膏）外用，并可在密切监测下继续抗肿瘤免疫治疗。而对于中至重度（2-3级，出现明显张力性水疱或累及皮损面积≥10%）的患者，则应当机立断暂停免疫治疗，并系统性给予中至大剂量糖皮质激素（如泼尼松 0.5-1.0 mg/kg/d）治疗。当出现皮损泛发或激素依赖/不耐受的情况时，应积极引入系统性二线免疫抑制剂，以协助病情的安全过度。拓展阅读在传统的irAEs临床处置中，系统性应用大剂量糖皮质激素被视为快速扑灭过度免疫反应的基石。然而，对于本身免疫功能低下的晚期肿瘤患者而言，长期大剂量使用糖皮质激素犹如一把双刃剑。这不仅会带来代谢紊乱、严重感染以及骨质疏松等严重的系统性副作用，更令肿瘤科医生担忧的是，系统性大范围的免疫抑制剂可能从根本上“对冲”或“扼杀”PD-1/PD-L1抑制剂带来的抗肿瘤效应，最终导致肿瘤进展或免疫耐受失败。基于这一严峻的临床痛点，学术界正在寻找一种“精准打击”的替代疗法，力求在控制皮肤水疱的同时，不削弱抗肿瘤 T 细胞的功能。在这一背景下，靶向特定细胞因子的生物制剂治疗方案开始受到广泛关注。多中心观察性队列研究提示，针对Th2通路中关键因子IL-4/IL-13的受体拮抗剂度普利尤单抗（Dupilumab），以及针对IgE的单克隆抗体奥马珠单抗（Omalizumab），在治疗免疫相关BP中展现出了极具前景的临床获益。由于BP的表皮下水疱形成过程高度依赖于Th2型炎症因子的活化及IgE介导的嗜酸性粒细胞脱颗粒，这些特异性生物制剂能够靶向阻断这一特定炎性瀑布反应，同时避免了对发挥抗肿瘤作用的Th1和CD8+ T细胞产生广泛抑制。这种不牺牲肿瘤免疫反应的“靶向皮肤耐受”疗法，有望在未来重塑中重度免疫相关皮肤毒性的治疗格局，成为更安全、不削弱免疫治疗疗效的一线联合干预手段。观点评述肿瘤免疫治疗相关的大疱性类天疱疮（BP）绝非单纯的“皮疹”小问题，它是一个具有独特免疫生物学特征的交叉医学课题，深刻体现了抗肿瘤免疫活性与自体免疫耐受之间的博弈。首先，临床实践中最迫切的需求是关口前移和多学科深度融合。由于BP发病机制的特殊性，非特异性的前驱期瘙痒往往是干预的最佳时机。肿瘤科医生在随访时，应常规进行精准的皮肤症状评估，切忌将所有的皮肤发红、发痒简单粗暴地当作普通湿疹或斑丘疹处理。若在非水疱期便能邀请皮肤科医生深度介入，通过早期局部足量糖皮质激素控制局部微环境，甚至有望截断其向大面积爆发期演变，最大限度地规避被迫停用免疫药物给患者抗肿瘤大局带来的系统性风险。然而，我们亦必须认识到，目前关于免疫相关BP的证据链条仍存在明显的局限性。当前的大多数诊疗推荐主要建立在小样本回顾性观察、病例系列或借鉴经典自发性BP的治疗方案之上，仍缺乏大规模、多中心、前瞻性控制的随机对照临床研究。在实际临床操作中，对于生物制剂的应用时机、激素的最佳减量路径，以及如何在量化层面上评估免疫抑制治疗对肿瘤长期总体生存率（OS）的影响，依旧缺乏金标准。未来的研究重点，应当致力于通过精确的液体活检、自身抗体动态监测等转化医学工具，建立起能够预测免疫相关BP发生的高危分子标志物，并在MDT框架下制定出一套兼顾“皮肤屏障恢复”与“肿瘤持久缓解”双重获益的个体化精准治疗共识。 ---------------------------------- ☆本文仅供医疗卫生等专业人士参考参考文献 [1] Lopez AT, Khanna T, Antonov N, Audrey-Bayan C, Geskin L. A review of bullous pemphigoid associated with PD-1 and PD-L1 inhibitors. Int J Dermatol. 2018;57(6):664-669. [2] Siegel J, Totonchy M, Damsky W, et al. Bullous disorders associated with anti-PD-1 and anti-PD-L1 therapy: A retrospective analysis evaluating the clinical and histopathologic features, frequency, and impact on cancer therapy. J Am Acad Dermatol. 2018;79(6):1081-1088. [3] Kawsar A, Edwards C, Patel P, et al. Checkpoint inhibitor-associated bullous cutaneous immune-related adverse events: a multicentre observational study. Br J Dermatol. 2022;187(6):981-987.

100 项与 Sym-021 相关的药物交易

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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
晚期恶性实体瘤	临床1期	美国	Institut Servier de Medecine Translationnelle SARL	2021-10-15
晚期恶性实体瘤	临床1期	加拿大	Institut Servier de Medecine Translationnelle SARL	2021-10-15
胆管癌	临床1期	美国	Servier Symphogen A/S	2020-10-12
胆管癌	临床1期	加拿大	Servier Symphogen A/S	2020-10-12
胆管癌	临床1期	法国	Servier Symphogen A/S	2020-10-12
胆管癌	临床1期	西班牙	Servier Symphogen A/S	2020-10-12
食管鳞状细胞癌	临床1期	美国	Servier Symphogen A/S	2020-10-12
食管鳞状细胞癌	临床1期	加拿大	Servier Symphogen A/S	2020-10-12
食管鳞状细胞癌	临床1期	法国	Servier Symphogen A/S	2020-10-12
食管鳞状细胞癌	临床1期	西班牙	Servier Symphogen A/S	2020-10-12

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临床结果

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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


NCT05162755	临床1期	实体瘤末线 \| 二线 \| 三线	41	Sym025	糧觸觸壓襯網蓋願餘網(鹽積膚範艱衊鏇窪鹽簾) = 築窪膚廠鏇齋鬱鬱鹹齋廠選簾鹽憲醖鹽餘窪簾 (廠積夢觸選壓壓廠憲壓 ) 更多	积极	2024-11-05
				Sym021+Sym025	糧觸觸壓襯網蓋願餘網(鹽積膚範艱衊鏇窪鹽簾) = 顧淵衊餘簾夢網鏇糧網廠選簾鹽憲醖鹽餘窪簾 (廠積夢觸選壓壓廠憲壓 ) 更多
NCT03489343 \| NCT03311412 \| NCT03489369 (ESMO2020)	临床1期	转移性肿瘤 \| 晚期恶性实体瘤 \| 淋巴瘤	-	Sym021	鑰夢鏇構積艱膚膚鏇獵(糧膚顧獵鹹製選選願憲) = Sym021, Sym022 and Sym023 alone and Sym021 in combination with either Sym022 or Sym023 were well tolerated with AE profiles typical of immune checkpoint inhibitors 觸淵淵鬱觸獵壓餘淵願 (鏇蓋襯網廠遞膚範衊製 )	-	2020-09-20
				Sym022
AUA2020	N/A	泌尿生殖系统肿瘤 HLA-I genotypes \| HLA-C genotypes \| KIR ligands ... 更多	51	anti-PD-1 drugs (HLA-A2 supertype)	衊糧遞願齋醖淵齋鬱壓(窪網製糧選膚蓋積淵觸) = 膚簾構餘淵壓壓鏇簾簾選艱蓋憲蓋網艱鑰憲鏇 (範醖齋築廠觸憲獵鬱夢 )	-	2020-04-01
				anti-PD-1 drugs (Patients without HLA-A2 supertype)	衊糧遞願齋醖淵齋鬱壓(窪網製糧選膚蓋積淵觸) = 衊獵選遞鬱願淵顧積艱選艱蓋憲蓋網艱鑰憲鏇 (範醖齋築廠觸憲獵鬱夢 )