Cibisatamab(Cibisatamab) - 药物靶点：CD3 x CEA_在研适应症：转移性结直肠癌，转移性微卫星稳定结直肠癌_专利_临床

概要

基本信息

药物类型

双特异性T细胞结合器

别名

CEA-TCB、Cibisatamab (USAN/INN)、CEA-CD3 TCB

+ [3]

靶点

CD3 x CEA

作用方式

刺激剂、抑制剂

作用机制

CD3刺激剂(T细胞表面糖蛋白CD3复合体刺激剂)、CEA抑制剂(癌胚抗原抑制剂)

治疗领域

肿瘤消化系统疾病

在研适应症

转移性结直肠癌转移性微卫星稳定结直肠癌

非在研适应症

局部晚期恶性实体瘤转移性非小细胞肺癌

原研机构

F. Hoffmann-La Roche Ltd.

在研机构

Hoffmann-La Roche, Inc.

非在研机构-

权益机构-

最高研发阶段临床1期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构/序列

Sequence Code 154482L

来源: *****

Sequence Code 154573H

来源: *****

Sequence Code 220669L

来源: *****

Sequence Code 9649700H

来源: *****

关联

7

项与 Cibisatamab 相关的临床试验

NCT04826003

/ Completed临床1期

An Open-Label, Multicenter, Phase Ib Study To Evaluate Safety, Pharmacokinetics, Pharmacodynamics, And Preliminary Anti-Tumor Activity Of RO7122290, A Fibroblast Activation Protein-A (FAP) Targeted 4-1BB Ligand (CD137L), In Combination With Cibisatamab With Obinutuzumab Pre-Treatment, In Participants With Previously Treated, Metastatic, Microsatellite-stable Colorectal Adenocarcinoma With High CEACAM5 Expression

This is an open-label, multicenter, Phase Ib study to determine the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) in the weekly (QW) and/or every 3 weeks (Q3W) regimens, safety, tolerability, PK, immunogenicity, PD profile and to evaluate preliminary anti-tumor activity of RO7122290 in combination with cibisatamab Q3W after pretreatment with obinutuzumab, in participants with previously treated metastatic, microsatellite-stable colorectal adenocarcinoma with high CEACAM5 expression

开始日期2021-07-14

申办/合作机构

Hoffmann-La Roche, Inc.

NCT03866239

/ Terminated临床1期

A Phase Ib, Multicenter, Open-Label Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of Cibisatamab in Combination With Atezolizumab After Pretreatment With Obinutuzumab in Patients With Previously Treated Metastatic, Microsatellite-Stable Colorectal Adenocarcinoma With High CEACAM5 Expression

CO40939 is a Phase Ib, open-label, multicenter, single-arm study designed to evaluate the safety, efficacy, pharmacokinetics, and immunogenicity of cibisatamab in combination with atezolizumab administered after pretreatment with obinutuzumab in patients with Stage IV microsatellite stable (MSS) metastatic colorectal cancer (mCRC) whose tumors have high carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) expression and who have progressed on two or more chemotherapy regimens. The study is composed of a safety run-in and an exploratory part.

开始日期2019-05-07

申办/合作机构

Hoffmann-La Roche, Inc.

NCT03337698

/ Terminated临床1/2期

A Phase Ib/II, Open-Label, Multicenter, Randomized Umbrella Study Evaluating The Efficacy And Safety Of Multiple Immunotherapy-Based Treatment Combinations In Patients With Metastatic Non-Small Cell Lung Cancer (Morpheus-Lung)

This study will evaluate the efficacy, safety, and pharmacokinetics of immunotherapy-based treatment combinations in participants with metastatic non-small cell lung cancer (NSCLC).
Two cohorts will be enrolled in parallel in this study: Cohort 1 will consist of participants with tumor PD-L1 expression who have received no prior systemic therapy for metastatic NSCLC, and Cohort 2 will consist of participants who experienced disease progression during or following treatment with a platinum-containing regimen and a PD-L1/PD-1 checkpoint inhibitor, given in combination as one line of therapy or as two separate lines of therapy, regardless of PD-L1 expression. In each cohort, eligible participants will initially be assigned to one of several treatment arms (Stage 1). Participants who experience disease progression, loss of clinical benefit, or unacceptable toxicity during Stage 1 may be eligible to continue treatment with a different treatment regimen (Stage 2).

开始日期2017-12-27

申办/合作机构

Hoffmann-La Roche, Inc.

100 项与 Cibisatamab 相关的临床结果

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100 项与 Cibisatamab 相关的转化医学

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100 项与 Cibisatamab 相关的专利（医药）

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21

项与 Cibisatamab 相关的文献（医药）

2023-11-01·CPT-Pharmacometrics & Systems Pharmacology

A model‐based approach leveraging in vitro data to support dose selection from the outset: A framework for bispecific antibodies in immuno‐oncology

Article

作者: Friberg, Lena E. ; Sánchez, Javier ; Gaillard, Brenda C. ; Marinho, Joana ; Frances, Nicolas ; Claus, Christina ; Jönsson, Siv ; Boehnke, Axel ; Albrecht, Rosmarie ; Tanos, Tamara ; McIntyre, Christine

Abstract:

FAP‐4‐1BBL is a bispecific antibody exerting 4‐1BB‐associated T‐cell activation only while simultaneously bound to the fibroblast activation protein (FAP) receptor, expressed on the surface of cancer‐associated fibroblasts. The trimeric complex formed when FAP‐4‐1BBL is simultaneously bound to FAP and 4‐1BB represents a promising mechanism to achieve tumor‐specific 4‐1BB stimulation. We integrated in vitro data with mathematical modeling to characterize the pharmacology of FAP‐4‐1BBL as a function of trimeric complex formation when combined with the T‐cell engager cibisatamab. This relationship was used to prospectively predict a range of clinical doses where trimeric complex formation is expected to be at its maximum. Depending on the dosing schedule and FAP‐4‐1BBL plasma: tumor distribution, doses between 2 and 145 mg could lead to maximum trimeric complex formation in the clinic. Due to the expected variability in both pharmacokinetic and FAP expression in the patient population, we predict that detecting a clear dose–response relationship would remain difficult without a large number of patients per dose level, highlighting that mathematical modeling techniques based on in vitro data could aid dose selection.

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

JAK and mTOR inhibitors prevent cytokine release while retaining T cell bispecific antibody in vivo efficacy

2区 · 医学

ArticleOA

作者: Larivière, Laurent ; Freimoser-Grundschober, Anne ; Odermatt, Alex ; Umana, Pablo ; Stern, Martin ; Zimmermann, Tina ; Haegel, Hélène ; Leclercq, Gabrielle ; Giusti, Anna Maria ; Schneider, Anneliese ; Sam, Johannes ; Bacac, Marina ; Klein, Christian ; Green, Luke ; Challier, John ; Toso, Alberto ; Pulko, Vesna ; Steinhoff, Nathalie

Background:

T cell engaging therapies, like chimeric antigen receptor T cells and T cell bispecific antibodies (TCBs), efficiently redirect T cells towards tumor cells, facilitating the formation of a cytotoxic synapse and resulting in subsequent tumor cell killing, a process that is accompanied by the release of cytokines. Despite their promising efficacy in the clinic, treatment with TCBs is associated with a risk of cytokine release syndrome (CRS). The aim of this study was to identify small molecules able to mitigate cytokine release while retaining T cell-mediated tumor killing.

Methods:

By screening a library of 52 Food and Drug Administration approved kinase inhibitors for their impact on T cell proliferation and cytokine release after CD3 stimulation, we identified mTOR, JAK and Src kinases inhibitors as potential candidates to modulate TCB-mediated cytokine release at pharmacologically active doses. Using an in vitro model of target cell killing by human peripheral blood mononuclear cells, we assessed the effects of mTOR, JAK and Src kinase inhibitors combined with 2+1 T cell bispecific antibodies (TCBs) including CEA-TCB and CD19-TCB on T cell activation, proliferation and target cell killing measured by flow cytometry and cytokine release measured by Luminex. The combination of mTOR, JAK and Src kinase inhibitors together with CD19-TCB was evaluated in vivo in non-tumor bearing stem cell humanized NSG mice in terms of B cell depletion and in a lymphoma patient-derived xenograft (PDX) model in humanized NSG mice in terms of antitumor efficacy.

Results:

The effect of Src inhibitors differed from those of mTOR and JAK inhibitors with the suppression of CD19-TCB-induced tumor cell lysis in vitro, whereas mTOR and JAK inhibitors primarily affected TCB-mediated cytokine release. Importantly, we confirmed in vivo that Src, JAK and mTOR inhibitors strongly reduced CD19-TCB-induced cytokine release. In humanized NSG mice, continuous treatment with a Src inhibitor prevented CD19-TCB-mediated B cell depletion in contrast to mTOR and JAK inhibitors, which retained CD19-TCB efficacy. Ultimately, transient treatment with Src, mTOR and JAK inhibitors minimally interfered with antitumor efficacy in a lymphoma PDX model.

Conclusions:

Taken together, these data support further evaluation of the use of Src, JAK and mTOR inhibitors as prophylactic treatment to prevent occurrence of CRS.

2022-01-01·Theranostics1区 · 医学

Three-dimensional colon cancer organoids model the response to CEA-CD3 T-cell engagers

1区 · 医学

ArticleOA

作者: Garasa, Saray ; Cirella, Asunta ; Olivera, Irene ; Teijeira, Alvaro ; Ochoa, Maria C ; Alvarez, Maite ; Klein, Christian ; Ponz, Mariano ; Cañamero, Marta ; Bacac, Marina ; Rodriguez-Ruiz, Maria E ; Luri, Carlos ; Sanmamed, Miguel F ; Migueliz, Itziar ; Melero, Ignacio ; Umaña, Pablo ; Rouzaut, Ana ; Karanikas, Vaios

Rationale: The CEA-CD3 T cell bispecific antibody cibisatamab (CEA-TCB) is currently undergoing clinical trials. Here we study its performance against three-dimensional tumor organoids in cocultures with T cells as compared to a higher affinity CEACAM5-CD3 (CEACAM5-TCB) bispecific antibody using time-lapse confocal microscopy. Methods: Pre-labelled spheroids derived from colon cancer cell lines and primary organoids derived from four colorectal cancer surgical specimens, which expressed different graded levels of CEA, were exposed in cocultures to T lymphocytes. Cocultures were treated with CEA-CD3 T-cell engagers and were followed by live confocal microscopy. Caspase 3 activation detected in real-time was used as an indicator of tumor cell death. Co-cultures were also set up with autologous tumor-associated fibroblasts to test the co-stimulatory effect of a fibroblast activated protein (FAP)- targeted 4-1BBL bispecific antibody fusion protein currently undergoing clinical trials. Results: Tumor-cell killing of 3D colon carcinoma cultures was dependent on the levels of surface CEA expression, in such a way that the lower affinity agent (CEA-TCB) did not mediate killing by human preactivated T cells below a certain CEA expression threshold, while the high affinity construct (CEACAM5-TCB) remained active on the low CEA expressing organoids. Modelling heterogeneity in the levels of CEA expression by coculturing CEA high and low organoids showed measurable but weak bystander killing. Cocultures of tumor organoids, autologous fibroblasts and T cells allowed to observe a costimulatory effect of anti-FAP-4-1BBL both to release IFNγ and to attain more efficacious tumor cell killing. Conclusion: Three-dimensional tumor cocultures with T cells using live confocal microscopy provide suitable models to test the requirements for colon-cancer redirected killing as elicited by CEA-targeted T-cell engagers undergoing clinical trials and treatment allow combinations to be tested in a relevant preclinical system.

37

项与 Cibisatamab 相关的新闻（医药）

2026-07-30

·北京医学感染与传染研究

自然医学 32卷 7期

Nature Medicine Volume 32 Issue 7 自然医学 32卷 7期 https://www.nature.com/nm/volumes/32/issues/7 Editorial（社论） 1 Oncology must confront hidden side effects 肿瘤学必须正视隐匿不良反应 Nature Medicine volume 32（7）, page 2321 News（新闻） 2 Taming the inflamed heart 调控炎症性心脏病变 Charlotte Harrison Nature Medicine volume 32（7）, pages 2322-2323 News Feature（新闻专题） 3 When the real world becomes the trial 当现实世界成为临床试验场域 Marianne Guenot Nature Medicine volume 32（7）, pages 2324–2327 Correspondence（读者来信） 4 What Galen’s dissections reveal about tacit learning in modern medical education 盖伦解剖研究对现代医学教育中默会学习的启示 Andres PelavskiGabriele TorcolettiOrly Lewis Nature Medicine volume 32（7）, pages 2328–2329 5 What Utah’s clinical AI sandbox reveals about independent oversight 犹他州临床人工智能沙箱对独立监管机制的启示 Rahul GorijavoluNikhil JaiswalLeo Anthony Celi Nature Medicine volume 32（7）, pages 2330–2332 6 A case of artificial intelligence-enhanced diagnostics leading to heart transplantation 人工智能辅助诊断促成心脏移植一例 Heidi S. HartmanJoshua FinerPierre Elias Nature Medicine volume 32（7）, pages 2333–2334 7 Unintended consequences of legacy oversight in digital medicine 数字医学领域传统监管模式带来的非预期后果 Jochen K. LennerzDaniela AllendeAnne M. Stowman Nature Medicine volume 32（7）, pages 2335–2337 8 Incretin therapies, nutrition and food insecurity in the UK 英国肠促胰素治疗、营养状况与粮食不安全问题 Marie SpreckleyCara F. RuggieroAdrian Brown Nature Medicine volume 32（7）, pages 2338–2339 World View（全球观点） 9 Manageable toxicity is not a label — it is an oxymoron 可控制毒性并非标签，而是矛盾表述 From the patient’s perspective, toxicity is manageable only when it is met with empathy. 从患者视角而言，只有饱含人文关怀，不良反应才谈得上可控。 Laura Book Nature Medicine volume 32（7）, page 2340 10 Downplaying toxicities in cancer drug trials is not acceptable 肿瘤药物临床试验中淡化不良反应不可取 Bishal Gyawali Nature Medicine volume 32（7）, page 2341 Comment（述评） 11 Wearables as personal health custodians 可穿戴设备：个人健康守护者 Lei LuJosip Car Nature Medicine volume 32（7）, pages 2342–2345 12 Australia legislates against genetic discrimination in life insurance 澳大利亚立法禁止人寿保险领域的基因歧视 Jane Tiller Nature Medicine volume 32（7）, pages 2346–2348 13 A roadmap to competitive preclinical packages 具备竞争力的临床前研究方案构建路线图 Mustafa KhasrawMegan C. BenzJose R. Conejo-Garcia Nature Medicine volume 32（7）, pages 2349–2352 14 Brain Health for Economic Resilience: a data-driven framework for the brain-positive economic transition 保障大脑健康助力经济韧性：推动益脑经济转型的数据驱动框架 Harris A. EyreRym AyadiSimon Fischer-Baum Nature Medicine volume 32（7）, pages 2353–2355 News & Views（新闻与观点） 15 Long-term health risks of e-cigarettes after smoking cessation 戒烟后使用电子烟的长期健康风险 Mahdi SheikhPamela M. Ling Nature Medicine volume 32（7）, pages 2356–2357 16 CAR T cells take on precancers CAR-T细胞靶向癌前病变 Eric M. JurgensSham Mailankody Nature Medicine volume 32（7）, pages 2358–2359 17 Lassa fever countermeasures gather pace 拉沙热防控举措加速推进 Daniel Jenkin Nature Medicine volume 32（7）, pages 2360–2361 18 Shifting the goalposts in obesity drug development 肥胖药物研发目标的重新界定 W. Timothy Garvey Nature Medicine volume 32（7）, pages pages 2362–2363 Research Briefings（研究简报） 19 General-purpose chatbots outperform clinical AI tools on physicians’ real-world questions 通用对话机器人在医师现实临床问题上表现优于专用临床人工智能工具 Nature Medicine volume 32（7）, pages 2364–2365 20 An AI framework for multi-disease detection via retinal imaging 基于视网膜影像的多疾病筛查人工智能框架 Nature Medicine volume 32（7）, pages 2366–2367 Perspectives（前瞻观点） 21 Immune aging biomarkers for clinical trials 适用于临床试验的免疫衰老生物标志物 Andrea CiprianoJamie JusticeChiara M. S. Herzog Nature Medicine volume 32（7）, pages 2368–2382 Review Articles（综述） 22 Biological aging clocks in health and disease 健康与疾病状态下的生物学衰老时钟 Tony Wyss-CorayEric J. Topol Nature Medicine volume 32（7）, pages 2383–2394 Matters Arising（学术争鸣） 23 Limited evidence of AI superiority in seasonal influenza vaccine strain selection 尚无充分证据证明人工智能在季节性流感疫苗毒株筛选中具备优势 Simon P. J. de JongColin A. Russell Nature Medicine volume 32（7）, pages 2395–2397 24 Reply to: Limited evidence of AI superiority in seasonal influenza vaccine strain selection 对《尚无充分证据证明人工智能在季节性流感疫苗毒株筛选中具备优势》一文的回应 Wenxian ShiJeremy WohlwendRegina Barzilay Nature Medicine volume 32（7）, pages 2398–2400 Brief Communications（简讯） 25 Spatiotemporal diffusion of the 2024 Oropouche outbreak in Cuba 2024年古巴奥罗普切热暴发的时空传播特征 Rosario GravierMelissa M. PerezMaria G. Guzman Nature Medicine volume 32（7）, pages 2401–2404 26 General-purpose large language models outperform specialized clinical AI tools on medical benchmarks 通用大语言模型在医学基准测试中优于专用临床人工智能工具 Krithik VishwanathAnton AlyakinEric Karl Oermann Nature Medicine volume 32（7）, pages 2405–2409 Articles（论著） 27 Electronic cigarette use after smoking cessation and lung cancer risk 戒烟后使用电子烟与肺癌风险 Yeon Wook KimEung Joo ParkChoon-Taek Lee Nature Medicine volume 32（7）, pages 2410–2419 28 Ciltacabtagene autoleucel in high-risk smoldering multiple myeloma: the CAR-PRISM phase 2 trial Ciltacabtagene autoleucel治疗高危冒烟型（无症状）多发性骨髓瘤：CAR-PRISMⅡ期临床试验 Omar NadeemDavid M. Cordas dos SantosIrene M. Ghobrial Nature Medicine volume 32（7）, pages 2420–2429 29 Cibisatamab and FAP-4-1BBL in microsatellite-stable colorectal cancer: a phase 1b trial Cibisatamab联合FAP-4-1BBL治疗微卫星稳定型结直肠癌：Ⅰb期临床试验 Ignacio MeleroTamara TanosVictor Moreno Nature Medicine volume 32（7）, pages 2430–2439 30 Teclistamab-based induction treatment in transplant-eligible, newly diagnosed multiple myeloma: a phase 2 trial 基于Teclistamab的诱导方案治疗适合移植初诊多发性骨髓瘤：Ⅱ期临床试验 Marc S. RaabNiels WeinholdK. Martin Kortüm Nature Medicine volume 32（7）, pages 2440–2448 31 Anti-LAG-3 with or without anti-PD-1 in recurrent glioblastoma: a phase 1 trial 抗LAG-3单抗联合或不联合抗PD-1单抗治疗复发性胶质母细胞瘤：Ⅰ期临床试验 Michael LimXiaobu YeStuart A. Grossman Nature Medicine volume 32（7）, pages 2449–2460 32 Neoadjuvant stereotactic body radiation therapy with durvalumab and oleclumab in ER+HER2− breast cancer: a randomized phase 2 trial 立体定向体部放疗联合度伐利尤单抗与奥来鲁单抗新辅助治疗ER阳性HER2阴性乳腺癌：随机Ⅱ期临床试验 Alex De CaluwéIsabelle DesmoulinsLaurence Buisseret Nature Medicine volume 32（7）, pages 2461–2472 33 Post-adjuvant chemotherapy in ctDNA-positive patients with resected colorectal cancer: a randomized phase 3 trial ctDNA阳性结直肠癌术后辅助化疗：随机Ⅲ期临床试验 Hideaki BandoJun WatanabeTakeshi Kato Nature Medicine volume 32（7）, pages 2473–2480 34 Multi-antigen-targeting T cells in pediatric central nervous system tumors: a phase 1 trial 多抗原靶向T细胞治疗儿童中枢神经系统肿瘤：Ⅰ期临床试验 Stephanie GomezRachel A. DiCioccioEugene I. Hwang Nature Medicine volume 32（7）, pages 2481–2493 35 AI framework for multidisease detection via retinal imaging 基于视网膜影像的多疾病筛查人工智能框架 Xiayin ZhangQinyi LiHonghua Yu Nature Medicine volume 32（7）, pages 2494–2503 36 Long-term independent use of an intracortical brain–computer interface for speech and cursor control 皮层内脑机接口用于语音与光标控制的长期独立应用研究 Nicholas S. CardTyler Singer-ClarkDavid M. Brandman Nature Medicine volume 32（7）, pages 2504–2510 37 Adjuvanted inactivated rabies virus-vectored Lassa virus vaccine in healthy adults: a phase 1 trial 含佐剂灭活狂犬病毒载体拉沙病毒疫苗在健康成人中的Ⅰ期临床试验 Justin R. OrtizDrishya KurupMatthias J. Schnell Nature Medicine volume 32（7）, pages 2511–2521 38 Favipiravir for Lassa fever: an open-label, randomized controlled phase 2 trial 法匹拉韦治疗拉沙热：开放标签随机对照Ⅱ期临床试验 Cyril EramehKevin OkwaraekeMirjam Groger Nature Medicine volume 32（7）, pages 2522–2532 39 Bispecific 10E8.4/iMab broadly neutralizing antibody in people with or without HIV-1: a partially randomized phase 1 trial 双特异性广谱中和抗体10E8.4/iMab在HIV-1感染者与健康人群中的部分随机Ⅰ期临床试验 Deborah A. TheodoreBryan T. MayerMagdalena E. Sobieszczyk Nature Medicine volume 32（7）, pages 2533–2545 40 15-strain live biotherapeutic product or same donor fecal microbiota transplant for recurrent Clostridioides difficile infection: a randomized phase 1b trial 15菌株活体生物制剂与同源供体粪菌移植治疗复发性艰难梭菌感染：随机Ⅰb期临床试验 Lukas BethlehemLorenza BartuAri Grinspan Nature Medicine volume 32（7）, pages 2546–2555 41 Innate immune responsiveness predicts enhanced cellular immunity and symptomatic disease after controlled human influenza infection 固有免疫应答水平可预测人工流感感染后细胞免疫增强与临床发病情况 Loukas PapargyrisJiayun XuChristopher Chiu Nature Medicine volume 32（7）, pages 2556–2569 42 Efficacy and target engagement of dopamine agonist pramipexole for anhedonic depression: a randomized placebo-controlled trial 多巴胺激动剂普拉克索治疗快感缺失型抑郁症的疗效与靶点作用验证：随机安慰剂对照试验 Filip VentorpMarie AspDaniel Lindqvist Nature Medicine volume 32（7）, pages 2570–2578 43 Spinal cord stimulation for upper limb motor function in people with chronic post-stroke hemiparesis: a feasibility trial 脊髓电刺激改善慢性卒中后偏瘫患者上肢运动功能：可行性临床试验 Roberto M. de FreitasShovan BhatiaMarco Capogrosso Nature Medicine volume 32（7）, pages 2579–2590 44 A neuroprosthesis for restoring hand movement and sensation in a person with complete tetraplegia 神经假体用于重建完全四肢瘫痪患者手部运动与感觉功能 Santosh ChandrasekaranSarah K. WandeltChad E. Bouton Nature Medicine volume 32（7）, pages pages2591–2601 45 Dual-target gene therapy in Parkinson’s disease: a multicenter phase 1 trial 双靶点基因疗法治疗帕金森病：多中心Ⅰ期临床试验 Mengyue NiuJifeng GuoJun Liu Nature Medicine volume 32（7）, pages 2602–2609 46 Abatacept versus hydroxychloroquine for prevention of rheumatoid arthritis in individuals with palindromic rheumatism: a randomized open-label trial 阿巴西普对比羟氯喹预防复发性风湿症进展为类风湿关节炎：随机开放标签试验 Raimon SanmartiCarolina Pérez-GarcíaIsabel Haro Nature Medicine volume 32（7）, pages 2610–2618 47 Oligonucleotide–siRNA conjugate for SOD1 amyotrophic lateral sclerosis: a phase 1 trial 寡核苷酸-siRNA偶联药物治疗SOD1相关肌萎缩侧索硬化：Ⅰ期临床试验 Weiqi ChenLingling JiangYilong Wang Nature Medicine volume 32（7）, pages 2619–2628 48 Multinational validation of the PREVENT and SCORE2心血管风险方程 across 6.4 million individuals 基于640万人群的多国验证：PREVENT与SCORE2心血管风险预测方程 Brendon L. NeuenRupert W. MajorVilmantas Giedraitis Nature Medicine volume 32（7）, pages 2629–2638 49 Cliramitug for depletion of cardiac amyloid transthyretin: long-term follow-up of the NI006-101 trial Cliramitug清除心脏转甲状腺素蛋白淀粉样物质：NI006-101试验长期随访结果 Peter C. KahrFabian aus dem SiepenPeter van der Meer Nature Medicine volume 32（7）, pages 2639–2646 50 Low-dose digoxin in patients with heart failure with reduced or mildly reduced ejection fraction: a randomized controlled trial 小剂量地高辛治疗射血分数降低或轻度降低心力衰竭：随机对照试验 D. J. van VeldhuisenM. RienstraP. van der Meer Nature Medicine volume 32（7）, pages 2647–2653 51 The microRNA inhibitor CDR132L in patients with reduced left ventricular ejection fraction after myocardial infarction: a randomized phase 2 trial 微小RNA抑制剂CDR132L治疗心肌梗死后左室射血分数降低患者：随机Ⅱ期临床试验 Johann BauersachsScott D. SolomonThomas Thum Nature Medicine volume 32（7）, pages 2654–2661 52 Semaglutide versus placebo in individuals with poor weight loss after bariatric surgery: a double-blinded, randomized, placebo-controlled trial 司美格鲁肽对比安慰剂治疗减重手术术后减重不佳人群：双盲随机安慰剂对照试验 Chloe StanleyRitwika MallikJanine Makaronidis Nature Medicine volume 32（7）, pages 2662–2672 53 Apitegromab for lean mass preservation during tirzepatide-induced weight loss: a randomized, double-blind, placebo-controlled phase 2 trial Apitegromab用于替尔泊肽减重过程中维持瘦体重：随机双盲安慰剂对照Ⅱ期临床试验 Richard E. PratleyDouglas Scott DenhamJing L. Marantz Nature Medicine volume 32（7）, pages 2673–2678 54 Orforglipron for maintenance of body weight reduction: the double-blind, randomized phase 3b ATTAIN-MAINTAIN trial Orforglipron用于维持减重效果：双盲随机Ⅲb期ATTAIN-MAINTAIN试验 Louis J. AronneDeborah B. HornNeena Xavier Nature Medicine volume 32（7）, pages 2679–2687 Amendments & Corrections（勘误与更正） 55 Author Correction: Teclistamab-based induction treatment in transplant-eligible, newly diagnosed multiple myeloma: a phase 2 trial 作者更正：基于Teclistamab的诱导方案治疗适合移植初诊多发性骨髓瘤：Ⅱ期临床试验 Marc S. RaabNiels WeinholdK. Martin Kortüm Nature Medicine volume 32（7）, page 2688 56 Author Correction: Digital AVATAR therapy for distressing voices in psychosis: the phase 2/3 AVATAR2 trial 作者更正：数字虚拟化身疗法治疗精神病幻听症状：Ⅱ/Ⅲ期AVATAR2临床试验 Philippa A. GaretyClementine J. EdwardsThomas Ward Nature Medicine volume 32（7）, page 2689 57 Author Correction: Global burden of amphetamine, cannabis, cocaine and opioid use in 204 countries, 1990–2023: a Global Burden of Disease Study 作者更正：1990–2023年204个国家苯丙胺、大麻、可卡因与阿片类物质使用的全球疾病负担研究 Jiseung KangHyeon Jin KimDong Keon Yon Nature Medicine volume 32（7）, page 2690 58 Retraction Note: Time-of-day immunochemotherapy in non-small cell lung cancer: a randomized phase 3 trial 撤稿声明：时辰免疫化疗治疗非小细胞肺癌：随机Ⅲ期临床试验 Zhe HuangLiang ZengYongchang Zhang Nature Medicine volume 32（7）, page 2691

2026-07-23

·北京医学感染与传染研究

自然医学 32卷 7期（2026年7月23日更新）

Nature Medicine Volume 32 Issue 7 自然医学 32卷 7期 https://www.nature.com/nm/volumes/32/issues/7 Editorial（社论） 1 Oncology must confront hidden side effects 肿瘤学必须正视隐匿不良反应 Nature Medicine volume 32（7）, page 2321 News（新闻） 2 Taming the inflamed heart 调控炎症性心脏病变 Charlotte Harrison Nature Medicine volume 32（7）, pages 2322-2323 News Feature（新闻专题） 3 When the real world becomes the trial 当现实世界成为临床试验场域 Marianne Guenot Nature Medicine volume 32（7）, pages 2324–2327 Correspondence（读者来信） 4 What Galen’s dissections reveal about tacit learning in modern medical education 盖伦解剖研究对现代医学教育中默会学习的启示 Andres PelavskiGabriele TorcolettiOrly Lewis Nature Medicine volume 32（7）, pages 2328–2329 5 What Utah’s clinical AI sandbox reveals about independent oversight 犹他州临床人工智能沙箱对独立监管机制的启示 Rahul GorijavoluNikhil JaiswalLeo Anthony Celi Nature Medicine volume 32（7）, pages 2330–2332 6 A case of artificial intelligence-enhanced diagnostics leading to heart transplantation 人工智能辅助诊断促成心脏移植一例 Heidi S. HartmanJoshua FinerPierre Elias Nature Medicine volume 32（7）, pages 2333–2334 7 Unintended consequences of legacy oversight in digital medicine 数字医学领域传统监管模式带来的非预期后果 Jochen K. LennerzDaniela AllendeAnne M. Stowman Nature Medicine volume 32（7）, pages 2335–2337 8 Incretin therapies, nutrition and food insecurity in the UK 英国肠促胰素治疗、营养状况与粮食不安全问题 Marie SpreckleyCara F. RuggieroAdrian Brown Nature Medicine volume 32（7）, pages 2338–2339 World View（全球观点） 9 Manageable toxicity is not a label — it is an oxymoron 可控制毒性并非标签，而是矛盾表述 From the patient’s perspective, toxicity is manageable only when it is met with empathy. 从患者视角而言，只有饱含人文关怀，不良反应才谈得上可控。 Laura Book Nature Medicine volume 32（7）, page 2340 10 Downplaying toxicities in cancer drug trials is not acceptable 肿瘤药物临床试验中淡化不良反应不可取 Bishal Gyawali Nature Medicine volume 32（7）, page 2341 Comment（述评） 11 Wearables as personal health custodians 可穿戴设备：个人健康守护者 Lei LuJosip Car Nature Medicine volume 32（7）, pages 2342–2345 12 Australia legislates against genetic discrimination in life insurance 澳大利亚立法禁止人寿保险领域的基因歧视 Jane Tiller Nature Medicine volume 32（7）, pages 2346–2348 13 A roadmap to competitive preclinical packages 具备竞争力的临床前研究方案构建路线图 Mustafa KhasrawMegan C. BenzJose R. Conejo-Garcia Nature Medicine volume 32（7）, pages 2349–2352 14 Brain Health for Economic Resilience: a data-driven framework for the brain-positive economic transition 保障大脑健康助力经济韧性：推动益脑经济转型的数据驱动框架 Harris A. EyreRym AyadiSimon Fischer-Baum Nature Medicine volume 32（7）, pages 2353–2355 News & Views（新闻与观点） 15 Long-term health risks of e-cigarettes after smoking cessation 戒烟后使用电子烟的长期健康风险 Mahdi SheikhPamela M. Ling Nature Medicine volume 32（7）, pages 2356–2357 16 CAR T cells take on precancers CAR-T细胞靶向癌前病变 Eric M. JurgensSham Mailankody Nature Medicine volume 32（7）, pages 2358–2359 17 Lassa fever countermeasures gather pace 拉沙热防控举措加速推进 Daniel Jenkin Nature Medicine volume 32（7）, pages 2360–2361 18 Shifting the goalposts in obesity drug development 肥胖药物研发目标的重新界定 W. Timothy Garvey Nature Medicine volume 32（7）, pages pages 2362–2363 Research Briefings（研究简报） 19 General-purpose chatbots outperform clinical AI tools on physicians’ real-world questions 通用对话机器人在医师现实临床问题上表现优于专用临床人工智能工具 Nature Medicine volume 32（7）, pages 2364–2365 20 An AI framework for multi-disease detection via retinal imaging 基于视网膜影像的多疾病筛查人工智能框架 Nature Medicine volume 32（7）, pages 2366–2367 Perspectives（前瞻观点） 21 Immune aging biomarkers for clinical trials 适用于临床试验的免疫衰老生物标志物 Andrea CiprianoJamie JusticeChiara M. S. Herzog Nature Medicine volume 32（7）, pages 2368–2382 Review Articles（综述） 22 Biological aging clocks in health and disease 健康与疾病状态下的生物学衰老时钟 Tony Wyss-CorayEric J. Topol Nature Medicine volume 32（7）, pages 2383–2394 Matters Arising（学术争鸣） 23 Limited evidence of AI superiority in seasonal influenza vaccine strain selection 尚无充分证据证明人工智能在季节性流感疫苗毒株筛选中具备优势 Simon P. J. de JongColin A. Russell Nature Medicine volume 32（7）, pages 2395–2397 24 Reply to: Limited evidence of AI superiority in seasonal influenza vaccine strain selection 对《尚无充分证据证明人工智能在季节性流感疫苗毒株筛选中具备优势》一文的回应 Wenxian ShiJeremy WohlwendRegina Barzilay Nature Medicine volume 32（7）, pages 2398–2400 Brief Communications（简讯） 25 Spatiotemporal diffusion of the 2024 Oropouche outbreak in Cuba 2024年古巴奥罗普切热暴发的时空传播特征 Rosario GravierMelissa M. PerezMaria G. Guzman Nature Medicine volume 32（7）, pages 2401–2404 26 General-purpose large language models outperform specialized clinical AI tools on medical benchmarks 通用大语言模型在医学基准测试中优于专用临床人工智能工具 Krithik VishwanathAnton AlyakinEric Karl Oermann Nature Medicine volume 32（7）, pages 2405–2409 Articles（论著） 27 Electronic cigarette use after smoking cessation and lung cancer risk 戒烟后使用电子烟与肺癌风险 Yeon Wook KimEung Joo ParkChoon-Taek Lee Nature Medicine volume 32（7）, pages 2410–2419 28 Ciltacabtagene autoleucel in high-risk smoldering multiple myeloma: the CAR-PRISM phase 2 trial Ciltacabtagene autoleucel治疗高危冒烟型（无症状）多发性骨髓瘤：CAR-PRISMⅡ期临床试验 Omar NadeemDavid M. Cordas dos SantosIrene M. Ghobrial Nature Medicine volume 32（7）, pages 2420–2429 29 Cibisatamab and FAP-4-1BBL in microsatellite-stable colorectal cancer: a phase 1b trial Cibisatamab联合FAP-4-1BBL治疗微卫星稳定型结直肠癌：Ⅰb期临床试验 Ignacio MeleroTamara TanosVictor Moreno Nature Medicine volume 32（7）, pages 2430–2439 30 Teclistamab-based induction treatment in transplant-eligible, newly diagnosed multiple myeloma: a phase 2 trial 基于Teclistamab的诱导方案治疗适合移植初诊多发性骨髓瘤：Ⅱ期临床试验 Marc S. RaabNiels WeinholdK. Martin Kortüm Nature Medicine volume 32（7）, pages 2440–2448 31 Anti-LAG-3 with or without anti-PD-1 in recurrent glioblastoma: a phase 1 trial 抗LAG-3单抗联合或不联合抗PD-1单抗治疗复发性胶质母细胞瘤：Ⅰ期临床试验 Michael LimXiaobu YeStuart A. Grossman Nature Medicine volume 32（7）, pages 2449–2460 32 Neoadjuvant stereotactic body radiation therapy with durvalumab and oleclumab in ER+HER2− breast cancer: a randomized phase 2 trial 立体定向体部放疗联合度伐利尤单抗与奥来鲁单抗新辅助治疗ER阳性HER2阴性乳腺癌：随机Ⅱ期临床试验 Alex De CaluwéIsabelle DesmoulinsLaurence Buisseret Nature Medicine volume 32（7）, pages 2461–2472 33 Post-adjuvant chemotherapy in ctDNA-positive patients with resected colorectal cancer: a randomized phase 3 trial ctDNA阳性结直肠癌术后辅助化疗：随机Ⅲ期临床试验 Hideaki BandoJun WatanabeTakeshi Kato Nature Medicine volume 32（7）, pages 2473–2480 34 Multi-antigen-targeting T cells in pediatric central nervous system tumors: a phase 1 trial 多抗原靶向T细胞治疗儿童中枢神经系统肿瘤：Ⅰ期临床试验 Stephanie GomezRachel A. DiCioccioEugene I. Hwang Nature Medicine volume 32（7）, pages 2481–2493 35 AI framework for multidisease detection via retinal imaging 基于视网膜影像的多疾病筛查人工智能框架 Xiayin ZhangQinyi LiHonghua Yu Nature Medicine volume 32（7）, pages 2494–2503 36 Long-term independent use of an intracortical brain–computer interface for speech and cursor control 皮层内脑机接口用于语音与光标控制的长期独立应用研究 Nicholas S. CardTyler Singer-ClarkDavid M. Brandman Nature Medicine volume 32（7）, pages 2504–2510 37 Adjuvanted inactivated rabies virus-vectored Lassa virus vaccine in healthy adults: a phase 1 trial 含佐剂灭活狂犬病毒载体拉沙病毒疫苗在健康成人中的Ⅰ期临床试验 Justin R. OrtizDrishya KurupMatthias J. Schnell Nature Medicine volume 32（7）, pages 2511–2521 38 Favipiravir for Lassa fever: an open-label, randomized controlled phase 2 trial 法匹拉韦治疗拉沙热：开放标签随机对照Ⅱ期临床试验 Cyril EramehKevin OkwaraekeMirjam Groger Nature Medicine volume 32（7）, pages 2522–2532 39 Bispecific 10E8.4/iMab broadly neutralizing antibody in people with or without HIV-1: a partially randomized phase 1 trial 双特异性广谱中和抗体10E8.4/iMab在HIV-1感染者与健康人群中的部分随机Ⅰ期临床试验 Deborah A. TheodoreBryan T. MayerMagdalena E. Sobieszczyk Nature Medicine volume 32（7）, pages 2533–2545 40 15-strain live biotherapeutic product or same donor fecal microbiota transplant for recurrent Clostridioides difficile infection: a randomized phase 1b trial 15菌株活体生物制剂与同源供体粪菌移植治疗复发性艰难梭菌感染：随机Ⅰb期临床试验 Lukas BethlehemLorenza BartuAri Grinspan Nature Medicine volume 32（7）, pages 2546–2555 41 Innate immune responsiveness predicts enhanced cellular immunity and symptomatic disease after controlled human influenza infection 固有免疫应答水平可预测人工流感感染后细胞免疫增强与临床发病情况 Loukas PapargyrisJiayun XuChristopher Chiu Nature Medicine volume 32（7）, pages 2556–2569 42 Efficacy and target engagement of dopamine agonist pramipexole for anhedonic depression: a randomized placebo-controlled trial 多巴胺激动剂普拉克索治疗快感缺失型抑郁症的疗效与靶点作用验证：随机安慰剂对照试验 Filip VentorpMarie AspDaniel Lindqvist Nature Medicine volume 32（7）, pages 2570–2578 43 Spinal cord stimulation for upper limb motor function in people with chronic post-stroke hemiparesis: a feasibility trial 脊髓电刺激改善慢性卒中后偏瘫患者上肢运动功能：可行性临床试验 Roberto M. de FreitasShovan BhatiaMarco Capogrosso Nature Medicine volume 32（7）, pages 2579–2590 44 A neuroprosthesis for restoring hand movement and sensation in a person with complete tetraplegia 神经假体用于重建完全四肢瘫痪患者手部运动与感觉功能 Santosh ChandrasekaranSarah K. WandeltChad E. Bouton Nature Medicine volume 32（7）, pages pages2591–2601 45 Dual-target gene therapy in Parkinson’s disease: a multicenter phase 1 trial 双靶点基因疗法治疗帕金森病：多中心Ⅰ期临床试验 Mengyue NiuJifeng GuoJun Liu Nature Medicine volume 32（7）, pages 2602–2609 46 Abatacept versus hydroxychloroquine for prevention of rheumatoid arthritis in individuals with palindromic rheumatism: a randomized open-label trial 阿巴西普对比羟氯喹预防复发性风湿症进展为类风湿关节炎：随机开放标签试验 Raimon SanmartiCarolina Pérez-GarcíaIsabel Haro Nature Medicine volume 32（7）, pages 2610–2618 47 Oligonucleotide–siRNA conjugate for SOD1 amyotrophic lateral sclerosis: a phase 1 trial 寡核苷酸-siRNA偶联药物治疗SOD1相关肌萎缩侧索硬化：Ⅰ期临床试验 Weiqi ChenLingling JiangYilong Wang Nature Medicine volume 32（7）, pages 2619–2628 48 Multinational validation of the PREVENT and SCORE2心血管风险方程 across 6.4 million individuals 基于640万人群的多国验证：PREVENT与SCORE2心血管风险预测方程 Brendon L. NeuenRupert W. MajorVilmantas Giedraitis Nature Medicine volume 32（7）, pages 2629–2638 49 Cliramitug for depletion of cardiac amyloid transthyretin: long-term follow-up of the NI006-101 trial Cliramitug清除心脏转甲状腺素蛋白淀粉样物质：NI006-101试验长期随访结果 Peter C. KahrFabian aus dem SiepenPeter van der Meer Nature Medicine volume 32（7）, pages 2639–2646 50 Low-dose digoxin in patients with heart failure with reduced or mildly reduced ejection fraction: a randomized controlled trial 小剂量地高辛治疗射血分数降低或轻度降低心力衰竭：随机对照试验 D. J. van VeldhuisenM. RienstraP. van der Meer Nature Medicine volume 32（7）, pages 2647–2653 51 The microRNA inhibitor CDR132L in patients with reduced left ventricular ejection fraction after myocardial infarction: a randomized phase 2 trial 微小RNA抑制剂CDR132L治疗心肌梗死后左室射血分数降低患者：随机Ⅱ期临床试验 Johann BauersachsScott D. SolomonThomas Thum Nature Medicine volume 32（7）, pages 2654–2661 52 Semaglutide versus placebo in individuals with poor weight loss after bariatric surgery: a double-blinded, randomized, placebo-controlled trial 司美格鲁肽对比安慰剂治疗减重手术术后减重不佳人群：双盲随机安慰剂对照试验 Chloe StanleyRitwika MallikJanine Makaronidis Nature Medicine volume 32（7）, pages 2662–2672 53 Apitegromab for lean mass preservation during tirzepatide-induced weight loss: a randomized, double-blind, placebo-controlled phase 2 trial Apitegromab用于替尔泊肽减重过程中维持瘦体重：随机双盲安慰剂对照Ⅱ期临床试验 Richard E. PratleyDouglas Scott DenhamJing L. Marantz Nature Medicine volume 32（7）, pages 2673–2678 54 Orforglipron for maintenance of body weight reduction: the double-blind, randomized phase 3b ATTAIN-MAINTAIN trial Orforglipron用于维持减重效果：双盲随机Ⅲb期ATTAIN-MAINTAIN试验 Louis J. AronneDeborah B. HornNeena Xavier Nature Medicine volume 32（7）, pages 2679–2687 Amendments & Corrections（勘误与更正） 55 Author Correction: Teclistamab-based induction treatment in transplant-eligible, newly diagnosed multiple myeloma: a phase 2 trial 作者更正：基于Teclistamab的诱导方案治疗适合移植初诊多发性骨髓瘤：Ⅱ期临床试验 Marc S. RaabNiels WeinholdK. Martin Kortüm Nature Medicine volume 32（7）, page 2688 56 Author Correction: Digital AVATAR therapy for distressing voices in psychosis: the phase 2/3 AVATAR2 trial 作者更正：数字虚拟化身疗法治疗精神病幻听症状：Ⅱ/Ⅲ期AVATAR2临床试验 Philippa A. GaretyClementine J. EdwardsThomas Ward Nature Medicine volume 32（7）, page 2689 57 Author Correction: Global burden of amphetamine, cannabis, cocaine and opioid use in 204 countries, 1990–2023: a Global Burden of Disease Study 作者更正：1990–2023年204个国家苯丙胺、大麻、可卡因与阿片类物质使用的全球疾病负担研究 Jiseung KangHyeon Jin KimDong Keon Yon Nature Medicine volume 32（7）, page 2690 58 Retraction Note: Time-of-day immunochemotherapy in non-small cell lung cancer: a randomized phase 3 trial 撤稿声明：时辰免疫化疗治疗非小细胞肺癌：随机Ⅲ期临床试验 Zhe HuangLiang ZengYongchang Zhang Nature Medicine volume 32（7）, page 2691

2026-07-20

·Organoids

同时接入血管、免疫与基质！首个“四位一体”肿瘤类器官，如何帮罗氏挑战高毒性靶点？

撰文：Sarah 编辑：Organoids 排版：Sarah Introduction 前言类器官技术的兴起，正在推动药企之间一条隐蔽的竞争线：谁能更早在人源模型中识别候选药物的疗效边界与安全风险，谁就更有机会在进入高成本临床试验之前，减少错误决策。年初，罗氏携手基因泰克于 bioRxiv 发表的预印本论文“Vascularized tumor organoids enable immunotherapy testing in tumor-remodeled stroma （血管化肿瘤类器官可在经肿瘤重塑的间质环境中开展免疫疗法评估）”，便是这一竞争趋势下的一项案例。该研究构建了名为 VascO 的血管肿瘤类器官体系，首次在类器官模型中实现了肿瘤-血管-基质-免疫细胞的功能性整合，旨在回应传统类器官在验证免疫疗法时的短板：真实治疗过程中，药物需要进入血液循环，激活或重定向 T 细胞；T 细胞依次完成血管壁黏附、跨内皮外渗和基质内迁移之后，才能接触肿瘤、形成免疫突触，最终造成杀伤。而单体类器官缺少这一组织与血管、间质、免疫细胞之间的互作，无法重现免疫疗法在实体瘤中必须经过的空间路径。因此，所得证据常缺乏研发决策亟需的可解释性。用以测试 VascO 的药物与罗氏自身的研发经历息息相关。其一沿自曾被罗氏推进临床、后因肠道毒性终止的 CEA-TCB 项目；其二则是在前者基础上改造的肿瘤激活型双抗，旨在保留肿瘤杀伤的同时降低正常组织毒性。换句话说，VascO 是由具体研发问题反向定义的验证工具。该项目由罗氏制药研究与早期开发部门（Pharma Research and Early Development，pRED）、基因泰克安全评估团队与罗氏人类生物学研究所（Institute of Human Biology，IHB）共同参与。IHB 于 2023 年成立，由时任 pRED 负责人的 Hans Clevers 推动，旨在将类器官等人源模型引入药物研发流程，更早评估候选药物的安全性、有效性及患者适配性。本文将以 VascO 这一具体案例为切入点，观察药企如何围绕真实研发问题设计模型，又如何将模型产生的读数转化为可复用、可比较、可支持研发决策的证据。 01 Organoids 免疫细胞抵达肿瘤之前，还需穿过血管和间质常规免疫共培养往往将 PBMC 等组分直接加入肿瘤类器官的培养体系；此类模型可以帮助研究者观测双抗的靶点识别、肿瘤接触与杀伤能力，却缺乏实体瘤治疗的关键前置环节：免疫细胞如何抵达肿瘤？在这一过程中，免疫细胞的血管递运、跨内皮外渗和基质内迁移，任一环节受阻，都可能限制最终药效。但现有血管化类器官往往服务于供氧或概念验证；放到验证免疫治疗的场景下，模型仍存在血管空间位置随机、与类器官接触不足、管腔过细以及递运受阻等问题。这背后是组装体面对临床转化时的共性问题：缺乏组分之间的互作关系与共生网络，因此在推演疾病进程、预判药物响应时难免有失偏颇。推荐阅读：组装体，正在为类器官补上“关系型证据” | Cell系列综述为提升模型的生物学相关性，IHB 团队对传统体系进行了工程化重构：打通肿瘤-血管接触面：类器官扩增完成后，清除残余 Matrigel。为微血管网络提供三维支架与力学环境：将类器官、内皮细胞和成纤维细胞包埋在超软纤维蛋白凝胶中，预防自组装过程中血管变细、管腔塌缩，以维持后续灌流免疫细胞所需的管径。划分肿瘤组织与循环系统：上述细胞-凝胶混合物被载入微流控芯片的三维组织区，两侧流体通道补种内皮细胞，构建给药 / 免疫细胞的血管入口，使输注物仅能通过血液循环接触肿瘤。在血管形成早期补充生长因子 VEGF-A 和 FGF-2，通过摇摆培养建立周期性流动，促进网络连接、维持管腔通畅。团队还以同一患者来源的健康结肠类器官构建了配对 VascO，与肿瘤 VascO 组成“肿瘤—正常组织”对照体系。图 | VascO 芯片示意图验证发现，VascO 可自发重建肿瘤上皮、血管与间质彼此塑造的组织关系：血管接入肿瘤：三维共聚焦成像显示，体系中的微血管大面积贴附肿瘤上皮，部分血管直接包裹类器官；荧光葡聚糖示踪进一步证实，脉管与外接流体通道形成贯通管腔，超过 95%的血管实现有效灌流。图 | 血管包裹肿瘤类器官；血管有效灌流肿瘤诱导血管重塑：肿瘤类器官促使内皮细胞活跃出芽并持续增殖；瘤周血管形成更多分支、节点和末梢，同时伴随血管渗漏增加。肿瘤重塑周边间质：健康成纤维细胞被诱导为肌成纤维型和炎症型两类癌相关成纤维细胞（CAF）状态，且这种调控呈现明显的患者异质性。微环境反哺肿瘤生长：撤除 Wnt3a、RSPO1、Noggin 等关键外源生长因子后，肿瘤类器官面积仍可在 7 天内增加约 2～6 倍；使用 VEGF-A/Ang2 双特异性抗体干预后，短期处理可降低血管渗漏，持续处理则同时抑制血管网络形成和肿瘤类器官扩增。至此，VascO 走完第一步：在模型中重建决定实体瘤免疫疗效的组织互作；下一步，团队要厘清这些互作如何解释候选药物的疗效与毒性。 02 Organoids 药企怎样借助模型优化候选分子？将 PBMC 沿 VascO 的侧道灌入体系，团队通过荧光信号标记与相应算法将免疫组分分为三类：血管黏附细胞仍贴在血管结构上；外渗细胞已位于血管边界之外；肿瘤接触细胞已与类器官发生接触。裂解型 Caspase-3 免疫荧光信号则用于衡量终点杀伤读数。图 | PBMC 的三种状态与终点凋亡标记由此，VascO 可观测免疫细胞的递运、浸润、肿瘤接触至最终杀伤的全过程，将 “免疫细胞能否有效抵达病灶” 转化为可分层评估的指标，帮助团队对药效开展归因。采用已有临床数据的初代 CEACAM5-TCB 进行模型校准：给药后，肿瘤 VascO 中可见 PBMC 外渗水平上升、免疫细胞接触肿瘤的概率提高，并伴随肿瘤细胞凋亡；在同源患者的健康结肠 VascO 中，则观测到显著免疫浸润与组织损伤，与该药物临床试验里出现的重度肠道毒性、治疗窗口狭窄的现象相互印证。在此基础上，团队继续评估蛋白酶激活型 Prot-CEACAM5-TCB：该分子的 CD3 结合区域处于遮蔽状态，进入肿瘤微环境后才会解除抑制。结果显示，新分子在保留肿瘤免疫浸润与杀伤效力的同时，对健康结肠组织的损伤显著减弱。图 | 一二代候选分子的疗效窗口对比依托同患者来源的“肿瘤-健康结肠”配对类器官体系，研究为双抗研发中长期存在的脱靶毒性（on-target, off-tumor toxicity）难题搭建了一套可嵌入研发管线的验证框架：先借助初代分子数据校准模型，再对比优化后的候选分子能否在肿瘤杀伤与正常组织损伤之间拉开差距。无独有偶，今年五月，罗氏 IHB 联合基因泰克在 Science Advances 刊发另一项研究，利用胰腺癌类器官与正常结肠类器官验证 FZD 靶向双抗的肿瘤选择性，同时将这套 “重寻治疗窗口” 的研究思路拓展至 FGFR1、EGFR 等多个具备开发潜力但风险较高的靶点（Kschonsak et al., 2026），再度印证了该配对体系在研发中的实际价值。 03 Organoids 复杂模型如何走出一次性项目？像 VascO 这样的复杂模型要沉淀为可跨项目复用的工具平台，还需一整套支撑体系。 IHB 的组织架构提供了一个观察样本。其探索生物学（Exploratory Biology）、转化生物工程（Translational Bioengineering）与计算生物学（Computational Biology）三个研究部门，大致覆盖了从人体生物学问题识别、模型构建，到复杂数据分析等不同任务。同时，IHB 的科研运营团队还设有类器官工业化（Organoid Industrialization）分支，围绕自动化制备、高内涵筛选推进人源模型的规模化应用。除此之外，IHB 参与建设了多项类器官图谱（Organoid Atlas），通过整合不同实验室、不同培养方案产生的类器官单细胞数据，并与人体组织及患者样本进行对照，为高度异质的类器官模型提供可横向比较的参照坐标。这些能力并非彼此平行的技术模块。它们共同连接起一条证据链：从管线提出问题，到模型生成实验读数，再到参照体系解释结果，最终将差异落到分子筛选、设计优化、安全风险判断或项目取舍之中。人源模型只有能够稳定、明确地回答这一系列问题，才能逐步进入研发团队的证据体系。多家大型药企都在针对人源模型推进类似的平台能力建设。诺华的“迷你心脏”平台最初也源自一个传统二维模型无法回答的心衰靶点问题。随后，团队陆续开发专用培养板、视频采集系统和数据分析工具，将实验规模从单个样本扩展至一次并行处理 96 个样本；该平台由此从单一问题定义的模型，走向靶点验证、候选分子筛选、心脏毒性研究等多个心血管疾病项目。总的来说，类器官进入药企研发流程，模型自身需要补齐与研究问题相关的关键组分和互作关系；应用端需要提前划定使用场景，明确模型究竟支持哪一种决策；在模型之上，还需建立参照坐标、数据分析、自动化生产和跨项目复用能力。 Organoids520，联系主编加入类器官培养同行交流圈一起探讨实验技术，分享领域最新动态免责声明本公众号发布的文章旨在分享、传递生物医药行业信息。文章内容仅代表作者观点，关于文中陈述、观点判断，本公众号均保持中立，不对所包含内容的准确性、可靠性或完整性提供任何明示或暗示的保证，亦不构成任何价值判断、投资建议或医疗指导，如有需求请咨询专业人士。本文仅作信息交流之目的，请读者仅作参考。如有侵权请联系我们，我们将会删除。如需原创文章授权请私信联系。参考资料 Wimmer, R., Krese, R., Henniger, L., et al. Vascularized tumor organoids enable immunotherapy testing in tumor-remodeled stroma. bioRxiv (2026). https://doi.org/10.64898/2026.01.23.701300 Kschonsak, Y. T., Liang, W.-C., Chan, J., et al. Tumor-targeted bispecific antibodies effectively inhibit oncogenic pathways while minimizing toxicity. Science Advances12, eadx3959 (2026). https://doi.org/10.1126/sciadv.adx3959 关注我们掌握类器官行业最新资讯往期推荐首家获批！教育部类器官资源库获人遗保藏行政许可，我国加快推进类器官资源共享从ISSCR 2026看类器官的转化落地：一场贯穿建模到应用的全链路改造，正在发生牛津团队开发骨髓类器官平台，为CAR-T临床前验证补上关键一环 | Science子刊香港大学周婕教授团队利用呼吸道类器官揭示对H5N1病毒的交叉免疫机制：突破传统评估瓶颈，开创流感抗体研发新纪元刚刚！国家药监局推进类器官、器官芯片应用试点！ Science新突破：南加大团队推进肾类器官标准化，专利已提交医保来了？肿瘤类器官药敏检测开始征求价格项目建议！耀速科技再获近2亿元融资：器官芯片能否反哺AI4S？考验才刚开始肠道芯片拿下2000万元订单！器官芯片开始比拼产品交付能力组装体，正在为类器官补上“关系型证据” | Cell系列综述美国打响临床研发提速战，资源加码类器官+器官芯片

100 项与 Cibisatamab 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
转移性非小细胞肺癌	临床2期	美国	Hoffmann-La Roche, Inc.	2017-12-27
转移性非小细胞肺癌	临床2期	澳大利亚	Hoffmann-La Roche, Inc.	2017-12-27
转移性非小细胞肺癌	临床2期	法国	Hoffmann-La Roche, Inc.	2017-12-27
转移性非小细胞肺癌	临床2期	以色列	Hoffmann-La Roche, Inc.	2017-12-27
转移性非小细胞肺癌	临床2期	韩国	Hoffmann-La Roche, Inc.	2017-12-27
转移性非小细胞肺癌	临床2期	西班牙	Hoffmann-La Roche, Inc.	2017-12-27
转移性非小细胞肺癌	临床2期	英国	Hoffmann-La Roche, Inc.	2017-12-27
转移性结直肠癌	临床1期	美国	Hoffmann-La Roche, Inc.	2019-05-07
转移性结直肠癌	临床1期	丹麦	Hoffmann-La Roche, Inc.	2019-05-07
转移性结直肠癌	临床1期	法国	Hoffmann-La Roche, Inc.	2019-05-07

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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


NCT04826003 (Pubmed \| Nat Med)	临床1期	转移性微卫星稳定结直肠癌三线 microsatellite-stable	52	Cibisatamab + FAP-4-1BBL (Microsatellite-stable metastatic colorectal cancer + Progressed after two or more prior therapies)	構膚憲積鏇衊積齋廠網(鏇願願繭餘築齋襯範積) = 範鹹鑰網願糧網獵製遞願艱膚願鏇窪顧築鏇衊 (製獵壓製鹹糧糧糧窪願 ) 更多	积极	2026-04-20
NCT04826003 (BP42675, AACR2026)	临床1期	转移性微卫星稳定结直肠癌三线 microsatellite-stable	51	Cibisatamab + FAP-4-1BBL	襯膚醖淵鹹繭鹽艱網繭(襯鹹鑰窪遞鹹製鑰範憲) = 簾觸膚範簾憲築築壓艱鏇憲築鬱淵網餘鹹壓遞 (襯鏇醖膚窪獵選遞製襯 ) 更多	积极	2026-04-20
NCT02324257 (ESMO2017) 人工标引	临床1期	结肠转移性腺癌 CEA Positive	45	RG7802 (CRC and At doses ≥ 60 mg)	餘夢鑰鏇繭觸網範糧糧(遞鏇繭窪廠壓夢積積廠) = In S1 (out of 59 pts > 40 mg), IRRs (24%) and diarrhea (7%). 齋鹹鑰廠齋窪顧獵構糧 (製壓憲鏇糧夢醖襯艱鑰 ) 更多	积极	2017-09-11
				Atezolizumab+RG7802 (CRC and At doses ≥ 60 mg)
NCT02650713 \| NCT02324257 (ASCO2017)	临床1期	转移性结直肠癌	-	CEA-CD3 TCB	餘鏇範襯願蓋糧夢衊鏇(蓋願夢願壓醖繭積願遞) = 醖簾鹹艱艱願鹹餘淵衊選糧淵積糧構鹽壓齋窪 (製衊壓製衊顧齋遞膚襯 ) 更多	-	2017-05-30
				Atezolizumab	餘鏇範襯願蓋糧夢衊鏇(蓋願夢願壓醖繭積願遞) = 糧窪憲餘糧齋願顧餘網選糧淵積糧構鹽壓齋窪 (製衊壓製衊顧齋遞膚襯 )