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

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）

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 ; Hong, Jiaxin ; Zhang, Sheng ; 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.

2019-01-01·Theranostics1区 · 医学

CD4⁺ and CD8a⁺ PET imaging predicts response to novel PD-1 checkpoint inhibitor: studies of Sym021 in syngeneic mouse cancer models

1区 · 医学

ArticleOA

作者: Kristensen, Lotte K ; Kragh, Michael ; Melander, Maria C ; Galler, Gunther R ; Lantto, Johan ; Kjaer, Andreas ; Nielsen, Carsten H ; Horak, Ivan D ; Fröhlich, Camilla ; Christensen, Camilla ; Poulsen, Thomas T

Predicting the outcome of immunotherapy is essential for efficient treatment. The recent clinical success of immunotherapy is increasingly changing the paradigm of cancer treatment. Accordingly, the development of immune-based agents is accelerating and the number of agents in the global immuno-oncology pipeline has grown 60-70% over the past year. However, despite remarkable clinical efficacy in some patients, only few achieve a lasting clinical response. Treatment failure can be attributed to poorly immunogenic tumors that do not attract tumor infiltrating lymphocytes (TILs). Therefore, we developed positron emission tomography (PET) radiotracers for non-invasive detection of CD4⁺ and CD8a⁺ TILs in syngeneic mouse tumor models for preclinical studies. Methods: Seven syngeneic mouse tumor models (B16F10, P815, CT26, MC38, Renca, 4T1, Sa1N) were quantified for CD4⁺ and CD8a⁺ TILs using flow cytometry and immunohistochemistry (IHC), as well as for tumor growth response to Sym021, a humanized PD-1 antibody cross-reactive with mouse PD-1. Radiotracers were generated from F(ab)'2 fragments of rat-anti-mouse CD4 and CD8a antibodies conjugated to the p-SCN-Bn-Desferrioxamine (SCN-Bn-DFO) chelator and radiolabeled with Zirconium-89 (⁸⁹Zr-DFO-CD4/⁸⁹Zr-DFO-CD8a). Tracers were optimized for in vivo PET/CT imaging in CT26 tumor-bearing mice and specificity was evaluated by depletion studies and isotype control imaging. ⁸⁹Zr-DFO-CD4 and ⁸⁹Zr-DFO-CD8a PET/CT imaging was conducted in the panel of syngeneic mouse models prior to immunotherapy with Sym021. Results: Syngeneic tumor models were characterized as "hot" or "cold" according to number of TILs determined by flow cytometry and IHC. ⁸⁹Zr-DFO-CD4 and ⁸⁹Zr-DFO-CD8a were successfully generated with a radiochemical purity >99% and immunoreactivity >85%. The optimal imaging time-point was 24 hours post-injection of ~1 MBq tracer with 30 µg non-labeled co-dose. Reduced tumor and spleen uptake of ⁸⁹Zr-DFO-CD8a was observed in CD8a⁺ depleted mice and the uptake was comparable with that of isotype control (⁸⁹Zr-DFO-IgG2b) confirming specificity. PET imaging in syngeneic tumor models revealed a varying maximum tumor-to-heart ratio of ⁸⁹Zr-DFO-CD4 and ⁸⁹Zr-DFO-CD8a across tumor types and in-between subjects that correlated with individual response to Sym021 at day 10 relative to start of therapy (p=0.0002 and p=0.0354, respectively). The maximum ⁸⁹Zr-DFO-CD4 tumor-to-heart ratio could be used to stratify mice according to Sym021 therapy response and overall survival was improved in mice with a ⁸⁹Zr-DFO-CD4 ratio >9 (p=0.0018). Conclusion: We developed ⁸⁹Zr-DFO-CD4 and ⁸⁹Zr-DFO-CD8a PET radiotracers for specific detection and whole-body assessment of CD4⁺ and CD8a⁺ status. These radiotracers can be used to phenotype preclinical syngeneic mouse tumor models and to predict response to an immune checkpoint inhibitor. We foresee development of such non-invasive in vivo biomarkers for prediction and evaluation of clinical efficacy of immunotherapeutic agents, such as Sym021.

项与 Sym-021 相关的新闻（医药）

2026-01-30

·研日新

研日新 ·4| 01月30日肿瘤内科 | 皮肤科 | 精神科

精选医学文献查看更多，请点击"阅读原文" 1. Cemiplimab in the treatment of cutaneous squamous cell carcinoma. [Carcinoma] 综述 | Immunotherapy | 2026-01-29 | IF 10.3 AI西米普利单抗为皮肤鳞状细胞癌提供了高效、安全的治疗选择，尤其在晚期及围手术期治疗中展现出显著临床价值。摘要Immune checkpoint inhibitors (ICIs) have significantly transformed the treatment landscape of cutaneous squamous cell carcinoma (CSCC). Cemiplimab, a human IgG4 monoclonal antibody to the programmed death-1 (PD-1) receptor, has shown impressive response rates and durable disease control in patients with advanced CSCC, alongside a manageable safety profile. More recently, cemiplimab has demonstrate... 阅读原文 2. Systemic immune correlates of long-term survival after Delta-24-RGD based on the Therapeutic Adenovirus for Recurrent Glioblastoma Effect Trial (TARGET). [Glioblastoma] Clinical cancer research : an official journal of the American Association for Cancer Research | 2026-01-29 | IF 10.0 AIDelta-24-RGD治疗后早期的抗腺病毒抗体及活化CD8+ NKT样细胞水平，可作为预测复发性高级别胶质瘤患者长期生存的潜在生物标志物。摘要To evaluate the combination of intra-tumoral Delta-24-RGD and subcutaneous interferon gamma (IFN-g) in patients with high grade glioma (HGG), based on the rationale that augmenting the immune response with IFN-g will increase the efficacy of Delta-24-RGD treatment. In this Phase 1b, multicenter, randomized trial (NCT02197169), we evaluated the combination of intratumorally injected Delta-24-RGD wi... 阅读原文 3. Transarterial Chemoembolization Modulates the Exosomal miR-32-5p/cGAS-STING Axis Mediated Macrophage Ferroptosis, Triggers Immune Remodeling, and Enhances Anti-PD-1/L1 Efficacy in HCC. [Carcinoma] Research (Washington, D.C.) | 2026-01-29 | IF 8.5 AI外泌体miR-32-5p通过诱导TAMs铁死亡和激活cGAS-STING通路重塑免疫微环境，为TACE耐药HCC患者联合抗PD-L1治疗提供了新的增效策略。摘要Hepatocellular carcinoma (HCC) is a cancer type that causes a high rate of cancer death in the world. The standard therapy plan of intermediate and advanced stages of the HCC is transarterial chemoembolization (TACE). The treatment effectiveness is, however, limited because of the heterogeneity of tumors and the resistance to drugs. This paper shows that the HCC patients with TACE resistance alter... 阅读原文 4. Lactoferrin reduces febrile neutropenia in children receiving chemotherapy for hematologic malignancies: a randomized, placebo-controlled trial. [Neutropenia] Haematologica | 2026-01-29 | IF 8.2 AI乳铁蛋白能有效降低血液肿瘤患儿化疗期间的发热性中性粒细胞减少风险，为临床提供一种安全的辅助预防策略。摘要Not available. 5. Brain-Resident MAIT Cells Infiltrate GL261 Tumors, and Activated MAIT Cell Signatures Are Associated With Improved Outcomes in Glioma. [Glioblastoma] Neurology(R) neuroimmunology & neuroinflammation | 2026-01-29 | IF 7.5 AI脑驻留MAIT细胞通过产生IL-17和IFN-γ在高级别胶质瘤中发挥保护作用，其活化特征与患者预后改善相关，提示其可能成为胶质瘤免疫治疗的新靶点。摘要Mucosal-associated invariant T (MAIT) cells are unconventional T cells with emerging roles in antitumor immunity. Their phenotype in the brain and potential role in immunity to gliomas-including lower-grade (WHO grades I and II) and higher-grade gliomas such as grades III and IV (glioblastoma)-remain poorly defined. We assessed the role of MAIT cells in glioma using publicly available transcriptom... 阅读原文 6. Comment on 'Contrasting Survival Outcomes and Patient Characteristics in 5,815 Patients with Stage II and III Melanoma: A Nationwide Population-Based Registry Study from Sweden'. [Melanoma] The British journal of dermatology | 2026-01-29 | IF 11.0 AI该评论强调了基于人群登记数据的黑色素瘤研究对临床实践的价值，提示医生需结合分期和患者特征优化个体化治疗策略。 7. Prevalence and psychosocial correlates of apathy in psoriasis: A cross-sectional study. [Psoriasis] 信函 | Journal of the European Academy of Dermatology and Venereology : JEADV | 2026-01-29 | IF 8.4 AI银屑病患者中冷漠症状常见且与抑郁、焦虑显著相关，临床医生应将其纳入常规评估并考虑心理干预。 8. Identification and Pre-clinical Evaluation of a Novel GD2 Antibody-Drug Conjugate for Solid Tumors in Children and Adults. [Melanoma] Molecular cancer therapeutics | 2026-01-29 | IF 5.3 AI该新型GD2 ADC通过独特机制降低神经毒性，为GD2阳性实体瘤患者提供了更安全有效的潜在治疗选择。摘要The ganglioside GD2 is an attractive cancer target due to its high expression in neuroblastoma and other solid tumors, with limited normal tissues distribution. Despite regulatory approvals of three anti-GD2 antibodies, clinical efficacy remains limited by neurotoxicity, suboptimal affinity for ADCC, and immunogenicity. Developing a highly effective, less toxic anti-GD2 agent remains an unmet need... 阅读原文 9. Fecal microbiota transplantation plus immunotherapy in non-small cell lung cancer and melanoma: the phase 2 FMT-LUMINate trial. [Melanoma] Nature medicine | 2026-01-28 | IF 58.7 AIFMT联合免疫治疗可显著提高NSCLC和黑色素瘤患者的客观缓解率，其疗效可能与清除肠道有害菌群密切相关。摘要Immune checkpoint inhibitors (ICI) have improved outcomes for patients with non-small cell lung cancer (NSCLC) and melanoma, yet over half of patients exhibit primary resistance. Fecal microbiota transplantation (FMT) may overcome resistance to anti-programmed cell death protein 1 (PD-1) therapy. The clinical activity and safety of FMT plus anti-PD-1 in NSCLC or anti-PD-1 plus anti-cytotoxic T-lym... 阅读原文 10. Lipid nanoparticle-based non-viral in situ gene editing of congenital ichthyosis-causing mutations in human skin models. [Skin Diseases] Cell stem cell | 2026-01-28 | IF 19.8 AI该研究为先天性鱼鳞病等遗传性皮肤病提供了安全有效的原位基因编辑治疗新策略，有望实现从症状管理到基因根治的突破性转变。摘要Autosomal recessive congenital ichthyosis (ARCI) refers to a group of rare, highly debilitating skin disorders that significantly impair patients' quality of life and lack any effective treatment options. Here, we report clinically relevant in situ correction of the most common ARCI-causing mutation, TGM1 c.877-2A>G, a splice-site aberration, in human disease models. Targeted skin barrier modulati... 阅读原文 11. Diagnostic tests for autism spectrum disorder (ASD) in preschool children. [Autism Spectrum Disorder] The Cochrane database of systematic reviews | 2026-01-29 | IF 8.8 AI该综述将为临床医生提供学龄前ASD诊断工具的准确性证据，辅助选择最适工具并理解其在不同亚组中的表现。摘要This is a protocol for a Cochrane Review (diagnostic). The objectives are as follows: Primary objectives To evaluate the diagnostic accuracy of widely used ASD diagnostic tools (specifically CARS, GARS, ADOS, ADI-R, DISCO, 3di) in preschool children, compared with multidisciplinary team clinical judgement. We aim to: summarise sensitivity, specificity, and other accuracy measures for each ASD diag... 阅读原文 12. Chemosensing of an Autism Biomarker, Gamma-Aminobutyric Acid, by Electropolymerized Molecularly Imprinted Polymers. [Autism Spectrum Disorder] ACS sensors | 2026-01-29 | IF 8.2 AI该研究开发的EIS-MIP化学传感器为床旁自闭症生物标志物GABA的快速、高灵敏度检测提供了新工具，具有显著的临床转化潜力。摘要We electrochemically synthesized molecularly imprinted polymer (MIP) films and simultaneously deposited them onto an interdigitated electrode array (IDEA) and a classical Pt disk electrode to devise chemosensors for the selective determination of gamma-aminobutyric acid (GABA), a biomarker of autism spectrum disorder. p-Bis(2,2'-bithien-5-yl)methyl phenol 2-hydroxy acetamide ether wa... 阅读原文 13. New Pharmacological Treatment Approaches for Schizophrenia: Navigating the Post-iclepertin Landscape. [Schizophrenia] 综述 | CNS drugs | 2026-01-29 | IF 7.4 AI在艾克利培汀失败后，非多巴胺能机制（如KarXT）及血清素-多巴胺调节剂成为新希望，但需克服高安慰剂反应以提升临床试验效能。摘要Schizophrenia is a complex psychiatric disorder, with cognitive impairment representing a critical unmet medical need. Current treatments primarily address positive symptoms, failing to effectively improve cognitive function and negative symptoms. This narrative review examines the current landscape of novel schizophrenia therapeutics following the discontinuation of iclepertin development, critic... 阅读原文 14. Useful considerations for treating migraine in patients with autism. [Autism Spectrum Disorder] Headache | 2026-01-29 | IF 7.3 AI临床医生需针对自闭症患者的感官敏感和沟通特点，制定个体化偏头痛治疗方案，以提升疗效与安全性。 15. Early interventions for first onset of symptoms of mental health conditions: an umbrella review of systematic reviews. [Bipolar Disorder] BMC medicine | 2026-01-29 | IF 7.0 AI精神病早期干预证据相对充分，但进食障碍、抑郁、焦虑等其他疾病的高质量证据仍严重不足，临床需关注现有有效方法并推动更多研究。摘要Early intervention following mental health symptom onset has great potential in reducing the long-term burden on individuals, families and friends, and society. The main focus in service development and research has been on early intervention in psychosis, but advances have been made for some other mental health difficulties. We aimed to take stock of existing evidence regarding effectiveness, imp... 阅读原文 16. Conformation of CD40LG and ANXA5 as Key Events of 2,7-Dibromocarbazole-Induced Cardiotoxicity Using in Vivo and in Vitro Models. [Cardiotoxicity] Environmental science & technology | 2026-01-29 | IF 10.8 AI该研究揭示了2,7-二溴咔唑通过AhR激活及下游CD40LG/ANXA5通路诱导心脏毒性的机制，为环境污染物相关心肌损伤的早期预警和干预提供了潜在靶点。摘要Polyhalogenated carbazoles (PHCZs) are emerging dioxin-like compounds (DLCs) with uncertain toxicological effects. Cardiotoxicity caused by DLCs has been well-characterized within the framework of an adverse outcome pathway, demonstrating consistent aryl hydrocarbon receptor (AhR) activation as the molecular initiating event. However, the downstream key events (KEs) contributing to PHCZ-induced ca... 阅读原文 17. [Oncologic surgery in the context of immunotherapy, neoadjuvant treatment and HPV : Clinical, immunological and translational aspects]. [Papillomavirus Infections] 综述 | HNO | 2026-01-29 | IF 10.6 AI新辅助免疫治疗联合手术正重塑头颈癌治疗格局，临床医生需整合免疫病理标志物与影像学评估，以精准筛选患者并优化多模式治疗策略。摘要Head and neck oncological surgery has long been guided by stable therapeutic principles; however, advances in tumor immunology, the emergence of neoadjuvant immunotherapy and the distinct biology of human papillomavirus (HPV)-associated carcinomas are driving a paradigm shift. This article summarizes current developments and underlying biological mechanisms, focusing on biomarkers for patient sele... 阅读原文 18. Randomized trial of low-dose -, ultrasound assisted thrombolysis or heparin for pulmonary embolism. [Pulmonary Embolism] Cardiovascular research | 2026-01-29 | IF 10.2 AI对于急性中高危肺栓塞患者，低剂量溶栓可有效降低血栓负荷，但超声辅助途径并未优于静脉给药，且需警惕出血风险增加。摘要Intermediate high-risk pulmonary embolism is associated with increased risk of hemodynamic deterioration and death, but balancing risk of thrombolytics or catheter-based treatment and efficacy has been challenging. This trial compared the additional efficacy of catheter-based ultrasound low-dose thrombolysis (USAT) over intravenous low-dose thrombolysis or heparin alone. In an investigator-initiat... 阅读原文 19. Genetic associations of circulating plasma proteins with cardiometabolic diseases. [Venous Thromboembolism] Genome biology | 2026-01-29 | IF 10.1 AI本研究为心血管疾病伴代谢紊乱的精准治疗提供了新的潜在靶点（如INHBC、APOH、DUSP13B），并验证了PCSK9等已知靶点的遗传学基础，有助于指导个体化药物研发与临床决策。摘要Cardiovascular disease is the leading cause of death worldwide, and its risk is closely linked to metabolic abnormalities. Through summary-data-based mendelian randomization and colocalization analysis, we investigate the causal relationships between plasma proteins, six cardiovascular diseases (atrial fibrillation, coronary artery disease, heart failure, venous thromboembolism, peripheral artery ... 阅读原文 20. Correction for Hou et al., Therapeutic restoration of mitochondria-endoplasmic reticulum cross talk for osteoarthritis. [Osteoarthritis] Published Erratum | Proceedings of the National Academy of Sciences of the United States of America | 2026-01-29 | IF 9.4 AI该更正强调了科研数据完整性的重要性，提醒临床医生在阅读文献时需关注潜在的数据错误，并关注线粒体-内质网交互作用作为骨关节炎治疗新靶点的潜力。免责声明：仅供学术交流参考，不构成任何医学建议或诊疗指导

临床研究免疫疗法

2026-01-29

·奇点网

《自然·医学》：拐点降临！科学家首次证实，粪菌移植抗癌的关键，在于清除患者体内有害细菌

*仅供医学专业人士阅读参考通过粪菌移植改善癌症免疫治疗效果的研究，终于又迎来了一个里程碑事件。今天，伦敦健康科学中心Saman Maleki Vareki领衔的团队[1]，以及蒙特利尔大学中心医院Arielle Elkrief领衔的研究团队[2]，背靠背在顶级医学期刊Nature Medicine上发表两篇研究论文。这两项临床试验首次发现，口服健康供体来源的粪菌胶囊，可以改善免疫检查点抑制剂治疗晚期肾癌、非小细胞肺癌和黑色素瘤的效果和安全性。尤其值得注意的是，这些研究还揭示了粪菌移植改善免疫治疗效果的潜在机制——粪菌移植清除了基线时存在的有害细菌。这一发现的重要意义不言而喻，它会将我们的关注点从粪菌移植引入哪些有益菌，转变为粪菌移植消除了哪些有害菌。这一转变，有望催生新的精准治疗方案。科学家发现肠道菌群影响免疫治疗效果的时间并不长。2015年11月，《科学》杂志发表的两篇重磅研究论文首次指出：基于癌症小鼠模型的研究发现，肠道微生物会影响免疫检查点抑制剂的效果[3,4]。这一发现在免疫治疗领域“一石激起千层浪”，有不少研究人员质疑这两个基于小鼠的研究成果的可靠性。然而，仅仅两年之后的2017年底，《科学》杂志又接连发表三篇研究论文，驱散了质疑声。研究人员在分析PD-1抑制剂治疗不同癌症患者的数据之后，发现肠道微生物的组成确实与免疫治疗的疗效相关[5-7]。自此，调节肠道微生物组成，就成了改善免疫治疗效果的潜在方案。时间来到2021年2月，两项1期临床试验首次证实，来自对PD-1抗体治疗有反应患者的粪菌移植（FMT），可以克服黑色素瘤对免疫检查点抑制剂的原发性或获得性耐药[8,9]；到2023年7月，一项1期临床试验证实，健康供体来源的粪菌可以降低黑色素瘤患者对PD-1抑制剂治疗的原发性耐药[10]。一扇新的大门正在徐徐打开。然而，这个领域仍然存在很多问题。除了黑色素瘤之外，粪菌移植对其他癌症有类似的效果吗？除了PD-1抑制剂之外，对其他免疫检查点抑制剂有类似的效果吗？粪菌移植带来改善的分子机制又是什么？咱们先来看Vareki团队的研究成果。他们发起了一个名为PERFORM的开放标签、单中心、1期临床试验，旨在评估健康供体粪菌移植胶囊（LND101）联合免疫检查点抑制剂治疗初治转移性肾细胞癌患者的安全性、可行性和初步活性。试验共纳入20名患者，他们接受封装好的粪菌胶囊，随后联合使用CTLA-4抑制剂伊匹木单抗/PD-1抑制剂纳武利尤单抗、帕博利珠单抗/阿昔替尼或帕博利珠单抗/仑伐替尼。研究的主要终点是安全性，定义为免疫相关不良事件（irAE）的发生率和严重程度；次要终点包括客观缓解率（ORR）、肠道微生物组和免疫相关性，以及患者报告的生活质量；探索性终点包括无进展生存期（PFS）和总生存期（OS）。总的来说，PERFORM试验达到了安全性终点，没有观察到与粪菌移植相关的严重毒性。在可评估的患者中，ORR为50%（9/18），其中11%达到完全缓解。研究还发现，较高的微生物多样性和抗炎菌群的维持，与更轻的毒性和更好的治疗反应相关。据了解，这也是科学家首次证实，在接受粪菌移植和免疫检查点抑制剂治疗的转移性肾细胞癌患者中，成功且持久地维持多样化的抗炎微生物群与改善临床疗效和降低毒性相关。接下来是Elkrief团队的2期临床试验FMT-LUMINate。FMT-LUMINate是一项多中心、开放标签、2期临床试验，评估健康供体来源的粪菌胶囊（LND101）联合免疫检查点抑制剂治疗非小细胞肺癌（20例，LND101联合PD-1抑制剂）和黑色素瘤（20例，LND101联合CTLA-4抑制剂/PD-1抑制剂）的一线临床活性。研究的主要终点是非小细胞肺癌队列的ORR；次要终点包括黑色素瘤队列的ORR、安全性、供体-宿主微生物组相似性等。从研究结果来看，非小细胞肺癌队列的ORR达到80%，远高于既往报道的历史数据（39%至46%），达到了主要终点；黑色素瘤队列的ORR为75%，也超过了既往数据。安全性分析显示，粪菌胶囊被认为在两个队列中均是安全的。最值得关注的是机制研究。一开始，Elkrief团队认为粪菌移植能够将供体来源的“有益”细菌引入，并定植到患者的微生物群中，从而重塑微生物生态系统，进而促进抗肿瘤免疫。然而，在分析宏基因组测序数据后，他们确实发现应答者在粪菌移植后肠道微生物组组成发生了显著改变，但是仅凭来自供体的菌株移植无法解释应答。简单来说，患者的应答情况似乎与移植的菌群无关。这一发现一度让Elkrief团队感觉走进了死胡同[11]。百般无奈之下，他们只能放弃关注患者在接受粪菌移植后获得了哪些细菌，而是分析与基线相比有哪些细菌发生了变化[11]。这一思路的转变，让他们看到了那些很容易被忽视的、在粪菌移植后“消失”的细菌。分析结果显示，与不响应治疗的患者相比，响应治疗的患者有一些在治疗前存在的肠菌消失了，尤其是Enterocloster citroniae、E. lavalensis和Clostridium innocuum。值得注意的是，Elkrief团队在回头分析2021年和2023年的三个临床研究数据后，也发现类似的结果。为了进一步证实上述相关关系背后是否存在因果关系，Elkrief团队又回到小鼠研究，证实当粪菌移植与免疫检查点抑制剂联合使用时，清除有害物种是实现全部治疗效果的必要条件。从代谢和免疫的角度来看，那些被清除的有害细菌能维持免疫抑制的代谢和免疫环境，从而损害免疫检查点抑制剂的疗效。总的来说，伦敦健康科学中心团队和蒙特利尔大学中心医院团队的这两项研究成果表明，健康供体来源的粪菌移植可以改善免疫检查点抑制剂治疗肾癌、非小细胞肺癌和黑色素瘤的疗效，且安全性良好。更重要的是，研究还揭示了粪菌移植改善免疫检查点抑制剂治疗效果的潜在机制，为供体选择、生物标志物开发和下一代微生物疗法的设计，提供了一个可操作的框架。最后，欢迎大家关注我们在小宇宙上的播客栏目——药研片语，和我们一起关注未来药物研发的趋势~参考文献：[1].Fernandes, R., Jabbarizadeh, B., Rajeh, A. et al. Fecal microbiota transplantation plus immunotherapy in metastatic renal cell carcinoma: the phase 1 PERFORM trial. Nat Med (2026). https://doi.org/10.1038/s41591-025-04183-8[2].Duttagupta, S., Messaoudene, M., Hunter, S. et al. Fecal microbiota transplantation plus immunotherapy in non-small cell lung cancer and melanoma: the phase 2 FMT-LUMINate trial. Nat Med (2026). https://doi.org/10.1038/s41591-025-04186-5[3].Vétizou M, Pitt JM, Daillère R, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science. 2015;350(6264):1079-1084. doi:10.1126/science.aad1329[4].Sivan A, Corrales L, Hubert N, et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science. 2015;350(6264):1084-1089. doi:10.1126/science.aac4255[5].Routy B, Le Chatelier E, Derosa L, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2018;359(6371):91-97. doi:10.1126/science.aan3706[6].Gopalakrishnan V, Spencer CN, Nezi L, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science. 2018;359(6371):97-103. doi:10.1126/science.aan4236[7].Matson V, Fessler J, Bao R, et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science. 2018;359(6371):104-108. doi:10.1126/science.aao3290[8].Davar D, Dzutsev AK, McCulloch JA, et al. Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients. Science. 2021;371(6529):595-602. doi:10.1126/science.abf3363[9].Baruch EN, Youngster I, Ben-Betzalel G, et al. Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients. Science. 2021;371(6529):602-609. doi:10.1126/science.abb5920[10].Routy B, Lenehan JG, Miller WH Jr, et al. Fecal microbiota transplantation plus anti-PD-1 immunotherapy in advanced melanoma: a phase I trial. Nat Med. 2023;29(8):2121-2132. doi:10.1038/s41591-023-02453-x[11].https://communities.springernature.com/posts/behind-the-paper-the-art-of-losing-how-loss-of-immunosuppressive-bacteria-shapes-immunotherapy-response本文作者丨BioTalker

2026-01-29

·爱医时空

华西医院丁振宇教授团队：启动全球首个个体化新抗原DC疫苗+卡瑞利珠单抗的随机对照临床研究，为局晚期不可切食管鳞癌维持治疗提供新方案

前言近日，四川大学华西医院丁振宇教授团队发起的一项“个性化新抗原DC疫苗联合卡瑞利珠单抗用于局部晚期不可切除食管鳞癌根治性治疗后的维持治疗（CHANT-241）：一项随机对照试验的方案”发表在《Frontiers in Immunology》1。这是全球首个针对局部晚期不可切除食管鳞癌患者，在根治性放化疗后采用个性化新抗原树突状细胞疫苗（Neo-DCVac）联合卡瑞利珠单抗作为维持治疗的随机、开放标签、II期临床研究。该研究旨在探索个体化免疫治疗在食管鳞癌维持治疗中的疗效与安全性，有望为这类患者提供全新的精准治疗选择。 CHANT-241研究方案发表于Frontiers in Immunology 研究背景食管鳞状细胞癌（ESCC）是我国高发的消化道恶性肿瘤，约占全球发病与死亡病例的50%以上2-4。由于早期症状隐匿，多数患者确诊时为局部晚期或转移性，根治性放化疗（CRT）是不可切除患者的标准方案，但CRT后易快速复发/远处转移，且目前无标准维持治疗方案，预后极差5。近年研究发现，免疫检查点抑制剂（ICIs）有望成为ESCC的维持治疗选择。多项II/III期临床试验（如ESCORT-CRT、KEYNOTE-975等）正在评估其疗效，初步提示ICIs在根治性治疗后可能发挥重要作用。此前ESCORT-1st、ESCORT-RWS等研究也已证实卡瑞利珠单抗在晚期食管癌中的疗效与安全性。肿瘤疫苗作为精准免疫治疗的重要方向，可激活或增强机体自身抗肿瘤免疫应答，其中个性化新抗原疫苗靶向肿瘤特有的基因突变，能诱导肿瘤特异性T细胞应答，避免对正常组织的免疫损伤。而ESCC具有高肿瘤突变负荷（TMB），富含新抗原，为该疫苗提供了理想靶点；树突状细胞（DC）作为核心抗原呈递细胞，可通过MHC分子激活CD8⁺和CD4⁺ T细胞，有效启动适应性免疫应答6-13。基于前期研究基础，丁振宇教授团队创新性地提出：在根治性放化疗后，采用个体化新抗原DC疫苗联合PD-1抑制剂（卡瑞利珠单抗）作为维持治疗，有望进一步提升免疫系统的抗肿瘤能力，降低复发风险，改善患者长期生存。研究设计 CHANT-241研究是一项前瞻性、随机、开放标签、单中心II期临床试验（NCT06675201），旨在评估Neo-DCVac联合卡瑞利珠单抗在局部晚期不可切除ESCC患者根治性放化疗后维持治疗中的疗效与安全性。本研究共纳入165例经病理学确诊的局部晚期不可切除ESCC患者，所有患者已完成根治性放化疗（或放化疗联合免疫治疗），且在重新评估时无进展。按2:1随机分组，试验组经三个阶段，阶段一疫苗制备期：患者先接受2-3个周期的卡瑞利珠单抗诱导治疗；后进入阶段二初始接种期：分别在第1、2、4、6、8周接种新抗原DC疫苗，并同时每4周给予一次卡瑞利珠单抗；最后进入阶段三加强接种期：患者每4周同时接受疫苗与卡瑞利珠单抗治疗。对照组患者则仅每4周接受卡瑞利珠单抗单药治疗。两组治疗将持续至多12个月，直至出现疾病进展、不可耐受的毒性反应或其他研究终止标准。治疗期间将定期进行影像学评估。外周血样本将在基线、初始接种期结束后2周和6个月，以及疾病进展时采集，用于ctDNA等分析。研究意义与展望目前，国内外尚未见同类个性化新抗原DC疫苗用于食管鳞癌维持治疗的临床研究报道。CHANT-241试验的启动，标志着我国在实体瘤个体化免疫治疗领域迈出重要一步。若该研究取得阳性结果，将为局部晚期不可切除食管鳞癌患者提供：全新的维持治疗策略，从“标准化疗/免疫”迈向“精准疫苗+免疫”的个体化模式；潜在的生存获益，通过激活患者自身免疫系统，实现长期抗肿瘤免疫记忆；可靠的生物标志物体系，指导未来个体化免疫治疗的精准实施。患者招募信息 CHANT-241研究目前正在四川大学华西医院开展，现面向社会招募符合条件的患者。研究者介绍丁振宇教授教授，主任医师，博士生导师四川大学华西医院肿瘤中心副主任，肿瘤学教研室主任长期从事肿瘤生物治疗的临床转化研究，擅长肺癌、食管癌的综合治疗，负责多项2-3期GCP临床研究及IIT研究项目。作为负责人承担国家重大新药创制项目、自然科学基金，教育部博士点基金，医学科学院临床孵化项目、四川省科技厅重点项目等多项研究项目。现专注于肿瘤特异性疫苗及细胞治疗北京肿瘤防治学会食管癌专委会青委会副主委，四川省老年医学会肿瘤康复治疗专委会主委，西部精神病学会胸部肿瘤MDT青委会主委人卫社肿瘤学八年制规划教材第三版编委兼秘书以第一或通讯作者于STTT（封面文章，高被引），Nat Comm，JITC，Br J Cance，Int J Surg等杂志发表论文40余篇陈月云教授四川大学华西医院肿瘤科主治医师/助理研究员博士，博士后在站第9届CSCO“35 under 35”优秀青年肿瘤医生中国医药生物技术协会生物制药技术技术分会委员四川省医创会肿瘤生物分会秘书兼委员入选2023级国家博士后研究人员计划，承担中国博士后面上基金和省自然科学基金各1项，获得了2024年FACO青年旅行基金资助，参与国家重点研发、国自然面上项目和四川省重点研发项目各1项以第一作者及共同第一作者在Br J Cancer，JITC等杂志发表10+篇SCI论文作为Sub-PI参与几十项I-III期GCP临床研究及IIT临床研究项目，相关研究在ASCO GI、AACR、JSCO、ISDE及CSCO国际会议进行口头报告及壁报展示，并获得了2025届ESTRO大会的TOP 5%摘要参考文献（上下滑动查看）： [1] Chen Y, Zheng Y, Shi H, et al. 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[10] Dhodapkar MV, Steinman RM, Krasovsky J, Munz C, Bhardwaj N. Antigenspecific inhibition of effector T cell function in humans after injection of immature dendritic cells. J Exp Med. (2001) 193:233–8. doi: 10.1084/jem.193.2.233. [11] 7. Palucka K, Banchereau J. Cancer immunotherapy via dendritic cells. Nat Rev Can. (2012) 12:265–77. doi: 10.1038/nrc3258. [12] Palucka K, Banchereau J, Mellman I. Designing vaccines based on biology of human dendritic cell subsets. Immunity. (2010) 33:464–78. doi: 10.1016/ j.immuni.2010.10.007. [13] Laidlaw BJ, Craft JE, Kaech SM. The multifaceted role of CD4(+) T cells in CD8 (+) T cell memory. Nat Rev Immunol. (2016) 16:102–11. doi: 10.1038/nri.2015.10. * 本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息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，如果该信息被用于资讯以外的目的，本公众号及作者不承担相关责任。更多前沿学术内容，敬请关注“爱医时空”！

疫苗临床2期免疫疗法临床1期

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	Symphogen A/S	2020-10-12
胆管癌	临床1期	加拿大	Symphogen A/S	2020-10-12
胆管癌	临床1期	法国	Symphogen A/S	2020-10-12
胆管癌	临床1期	西班牙	Symphogen A/S	2020-10-12
Vater壶腹癌	临床1期	美国	Symphogen A/S	2020-10-12
Vater壶腹癌	临床1期	加拿大	Symphogen A/S	2020-10-12
Vater壶腹癌	临床1期	法国	Symphogen A/S	2020-10-12
Vater壶腹癌	临床1期	西班牙	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	鬱鑰築憲網構網顧繭醖(範鏇襯遞鏇壓顧鹽鑰繭) = 壓襯衊願夢壓鹽廠憲製簾獵糧鹹窪蓋鹽艱鹹襯 (糧憲積遞壓遞夢積鹽鑰 ) 更多	积极	2024-11-05
				Sym021+Sym025	鬱鑰築憲網構網顧繭醖(範鏇襯遞鏇壓顧鹽鑰繭) = 簾製構膚憲鏇觸衊蓋齋簾獵糧鹹窪蓋鹽艱鹹襯 (糧憲積遞壓遞夢積鹽鑰 ) 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	壓鹽選襯夢齋願鹽壓壓(鏇餘製憲構願鬱衊繭醖) = 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 餘構顧鹹蓋觸衊鬱齋構 (選鑰膚艱蓋鹽憲鹽壓廠 )	-	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)	鑰鏇艱簾網壓鬱範鹹夢(積蓋鏇糧範願繭遞選壓) = 顧選構襯窪構遞膚襯糧築簾窪顧窪廠衊鹽鏇窪 (壓鹹鏇壓壓顧艱顧齋醖 )	-	2020-04-01
				anti-PD-1 drugs (Patients without HLA-A2 supertype)	鑰鏇艱簾網壓鬱範鹹夢(積蓋鏇糧範願繭遞選壓) = 衊顧糧觸網壓鹹壓衊鹹築簾窪顧窪廠衊鹽鏇窪 (壓鹹鏇壓壓顧艱顧齋醖 )