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更新于：2025-05-07

GPC3

更新于：2025-05-07

基本信息

别名

DGSX、glypican 3、glypican proteoglycan 3

+ [13]

简介

Cell surface proteoglycan (PubMed:14610063). Negatively regulates the hedgehog signaling pathway when attached via the GPI-anchor to the cell surface by competing with the hedgehog receptor PTC1 for binding to hedgehog proteins (By similarity). Binding to the hedgehog protein SHH triggers internalization of the complex by endocytosis and its subsequent lysosomal degradation (By similarity). Positively regulates the canonical Wnt signaling pathway by binding to the Wnt receptor Frizzled and stimulating the binding of the Frizzled receptor to Wnt ligands (PubMed:16227623, PubMed:24496449). Positively regulates the non-canonical Wnt signaling pathway (By similarity). Binds to CD81 which decreases the availability of free CD81 for binding to the transcriptional repressor HHEX, resulting in nuclear translocation of HHEX and transcriptional repression (By similarity). Inhibits the dipeptidyl peptidase activity of DPP4 (PubMed:17549790). Plays a role in limb patterning and skeletal development by controlling the cellular response to BMP4 (By similarity). Modulates the effects of growth factors BMP2, BMP7 and FGF7 on renal branching morphogenesis (By similarity). Required for coronary vascular development (By similarity). Plays a role in regulating cell movements during gastrulation (By similarity).

关联

147

项与 GPC3 相关的药物

GPC-3298306

靶点

GPC3

作用机制

GPC3调节剂

在研机构-

原研机构-

在研适应症

肝细胞癌 [+1]

非在研适应症-

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

PPMX-T001

靶点

GPC3

作用机制

GPC3调节剂

在研机构

Chugai Pharmaceutical Co., Ltd.

原研机构

Perseus Proteomics, Inc.

在研适应症

肝癌

非在研适应症-

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

ECT-204

靶点

GPC3

作用机制

GPC3调节剂 [+2]

在研机构

Eureka Therapeutics, Inc.

原研机构

Eureka Therapeutics, Inc.

在研适应症

晚期肝细胞癌 [+1]

非在研适应症-

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

103

项与 GPC3 相关的临床试验

NCT06198296

/ Not yet recruiting临床1期IIT

Immunotherapy for Adults with GPC3-Positive Solid Tumors Using Interleukin-15 and -21 Armored Glypican-3-Specific Chimeric Antigen Receptor Expressing Autologous T Cells

The body has different ways of fighting infection and disease. No single way seems perfect for fighting cancers. This research study combines two different ways of fighting cancer: antibodies and T cells.
Antibodies are types of proteins that protect the body from infectious diseases and possibly cancer. T cells, also called T lymphocytes, are special infection-fighting blood cells that can kill other cells, including cells infected with viruses and tumor cells. Both antibodies and T cells have been used to treat patients with cancers. They have shown promise but have not been strong enough to cure most patients.
In order to get them to kill cancers more effectively, in the laboratory, the study team inserted a new gene called a chimeric antigen receptor (CAR) into T cells that makes them recognize cancer cells and kill them. When inserted, this new CAR T cell can specifically recognize a protein found on solid tumors, called glypican-3 (GPC3). To make this GPC3-CAR more effective, the study team also added two genes called IL15 and IL21 that help CAR T cells grow better and stay in the blood longer so that they may kill tumors better. When the study team did this in the laboratory, they found that this mixture of GPC3-CAR,IL15 and IL21 killed tumor cells better when compared with CAR T cells that did not have IL15 plus IL21 in the laboratory. This study will use those cells, which are called 21.15.GPC3-CAR T cells, to treat patients with solid tumors that have GPC3 on their surface.
The study team also wanted to make sure that they could stop the 21.15.GPC3-CAR T cells from growing in the blood should there be any bad side effects. In order to do so, they inserted a gene called iCasp9 into the FAST-CAR T cells. This allows us the elimination of 21.15.GPC3-CAR T cells in the blood when the gene comes into contact with a medication called AP1903. The drug (AP1903) is an experimental drug that has been tested in humans with no bad side-effects. This drug will only be used to kill the T cells if necessary due to side effects .
The study team has treated patients with T cells that include GPC3. Patients have also been treated with IL-21 and with IL-15. Patients have not been treated with a combination of T cells that contain GPC3, IL-21 and IL-15. To summarize, this study will test the effect of 21.15.GPC3-CAR T cells in patients with solid tumors that express GPC3 on their surface.
The 21.15.GPC3-CAR T cells are an investigational product not yet approved by the Food and Drug Administration.

开始日期2026-01-01

申办/合作机构

Baylor College of Medicine

NCT06194461

/ Not yet recruitingN/A

A LOng-term Follow-up Master Protocol for Participants Who Received Cell or Gene Therapies in Other AstraZeneca StUdieS (LOCUS)

Master LTFU study will monitor the long-term safety and tolerability of cell or gene therapy study participants from AstraZeneca for up to 15 years post last cell or gene therapy treatment.

开始日期2025-09-17

申办/合作机构

AstraZeneca PLC

NCT06815432

/ Not yet recruiting临床1期IIT

GPC-3 Chimeric Antigen Receptor T Cells for Recurrent GPC-3 Positive Glioblastoma

The body has different ways of fighting infection and disease. No single way seems perfect for fighting cancers. This research study combines two different ways of fighting cancer: antibodies and T cells.
Antibodies are types of proteins that protect the body from infectious diseases and possibly cancer. T-cells, also called T lymphocytes, are special infection-fighting blood cells that can kill other cells, including cells infected with viruses and tumor cells. Both antibodies and T cells have been used to treat participants with cancers. They have shown promise, but have not been strong enough to cure most participants.
The study team has found from previous research that we can put a new gene (a tiny part of what makes-up DNA and carries the participants traits) into T cells that will make them recognize cancer cells and kill them. In the lab, the study team has made several genes called a chimeric antigen receptor (CAR), from an antibody called GC33. The antibody GC33 recognizes a protein found on the participants brain tumor. This CAR is called GPC3-CAR. To make this CAR more effective, the study has also added a gene that includes IL15. IL15 is a protein that helps CAR T cells grow better and stay in the blood longer so that they may kill tumors better. The mixture of GPC3-CAR and IL15 killed tumor cells better in the laboratory when compared with CAR T cells that did not have IL15. This study will test T cells with the IL15 GPC3-CAR (GO-CART T cells) in participants with GPC3-positive brain tumors.
T cells made to carry a gene called iCasp9 can be killed when they encounter a specific drug called AP1903. The study team will insert the iCasp9 and IL15 together into the T cells using a virus that has been made for this study. The drug (AP1903) is an experimental drug that has been tested in humans with no bad side-effects. The study team will use this drug to kill the T cells if necessary due to side effects.
This study will test T cells genetically engineered with a GPC3-CAR and IL15 (GO-CART T cells) in participants with GPC3-positive brain tumors.
The GO-CART T cells are an investigational product not approved by the Food and Drug Administration.

开始日期2025-04-03

申办/合作机构

Baylor College of Medicine

[+1]

100 项与 GPC3 相关的临床结果

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100 项与 GPC3 相关的转化医学

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0 项与 GPC3 相关的专利（医药）

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1,703

项与 GPC3 相关的文献（医药）

2025-10-01·Talanta

Dual-antibody functionalized transistor biosensor for specific diagnosis of liver cancer

Article

作者: Wang, Kaiwei ; Zhang, Guo-Jun ; Zhang, Wenhao ; Jiang, Boan ; Ding, Qiyue ; Cheng, Xiaolu ; Li, Yu-Tao ; Yu, Yi ; Yu, Xionghua ; Zhang, Guangxin

Selectively and sensitively detecting specific exosomal markers is critical for early diagnosis of liver cancer. However, identifying specific exosomal biomarkers and establishing accurate, convenient detection methods remain challenging. In this study, we used bioinformatics to identify the higher levels of EpCAM and GPC-3 proteins on liver cancer exosomes. These markers were used to create a dual-antibody functionalized transistor biosensor for precise detection of liver cancer exosomes. The techniques exhibited outstanding specificity and sensitivity. Detection thresholds in PBS and simulated plasma were established at 20 particles/μL and 47 particles/μL, respectively, facilitating the distinction of liver cancer cell-derived exosomes from those originating from various other cancer cells. Furthermore, in clinical samples testing, this approach not only distinguished clinical samples among liver cancer patients and healthy individuals, but also demonstrated the ability to differentiate liver cancer from other types of tumors, achieving a precision and accuracy rate of 100 %. The developed biosensor demonstrates excellent potential for clinical application and this work offers a promising and effective approach for cancer diagnosis.

2025-08-01·Tissue and Cell

Glypican3 and serglycin as potential biomarkers involved in the pathogenesis of ovarian endometriosis

Article

作者: Hassanein, Hasnaa Hassan ; WalyEldeen, Amr Ahmed ; Hassan, Hebatallah ; Ibrahim, Sherif Abdelaziz ; Taha, Ahmed Abdelrahem Ahmed ; Sayed, Rasha Mohamed Samir

Endometriosis, a non-malignant gynecological disorder characterized by debilitating symptoms, displays several cancer-like characteristics, including metastatic behavior and extracellular matrix (ECM) remodeling. The dynamics of ECM are largely influenced by proteoglycans (PGs), a family of glycosaminoglycan (GAG)-decorated proteins known for their regulatory impact on cellular behavior through ECM modulation. This study aimed to investigate the dysregulated expression of 20 PG genes in ovarian endometrioma (n = 24) in comparison to eutopic endometrial tissue samples (n = 16) from patients diagnosed with ovarian endometriosis, employing quantitative real-time PCR (qPCR) and immunohistochemistry (IHC). qPCR screening identified four upregulated PG genes-glypican 3 (GPC3), decorin (DCN), serglycin (SRGN), and glypican 5 (GPC5)-whereas 16 PG genes were found to be downregulated. In ovarian endometrioma, relative to eutopic endometrial tissue, GPC3 and SRGN expression were further verified to be significantly overexpressed by 18.6-fold (P < 0.05) and 6.7-fold (P < 0.01), respectively, whereas brevican (BCAN) and syndecan 4 (SDC4) were markedly downregulated by approximately 90 % and 86 %, respectively (both P < 0.001). IHC staining further validated the significant overexpression of GPC3 protein in ovarian endometrioma compared to eutopic and control endometrial tissues (P < 0.0001). In-silico analysis using the Enrichr database identified enriched functional pathways associated with the top overexpressed genes, such as hypoxia, glycolysis, and WNT signaling, known to be implicated in endometriosis. These findings suggest that the overexpression of GPC3 and SRGN may contribute to the pathogenesis of ovarian endometrioma, highlighting their potential as biomarkers and therapeutic targets for this disease.

2025-07-01·Modern Pathology

A Deep Learning Model of Histologic Tumor Differentiation as a Prognostic Tool in Hepatocellular Carcinoma

Article

作者: Graham, Rondell P ; Nazli, Saadiya ; Patil, Ameya ; DaCosta, Adilson ; Hasan, Bashar ; Lau, Chun ; Elhalaby, Rofyda ; Moreira, Roger K ; Sivasubramaniam, Priya ; Smith, Lindsey ; Cannon, Andrew ; Elessawy, Nada ; Shabaan, Abdelrahman ; Park, Byoung Uk ; Hartley, Christopher P

Tumor differentiation represents an important driver of the biological behavior of various forms of cancer. Histologic features of tumor differentiation in hepatocellular carcinoma (HCC) include cytoarchitecture, immunohistochemistry profile, and reticulin framework. In this study, we evaluate the performance of an artificial intelligence (AI)-based model in quantifying features of HCC tumor differentiation and predicting cancer-related outcomes. We developed a supervised AI model using a cloud-based, deep learning platform to quantify histologic features of HCC differentiation, including various morphologic parameters (nuclear density, area, circularity, chromatin pattern, and pleomorphism), mitotic figures, immunohistochemistry markers (HepPar 1 and glypican-3), and reticulin expression. We applied this AI model to patients undergoing HCC curative resection and assessed whether AI-based features added value to standard clinical and pathologic data in predicting HCC-related outcomes. Ninety-nine HCC resection specimens were included. Three AI-based histologic variables were most relevant to HCC prognostic assessment: (1) percentage of tumor occupied by neoplastic nuclei (nuclear area percent), (2) quantitative reticulin expression in the tumor, and (3) HepPar 1 low (ie, expressed in <50% of the tumor)/glypican-3-positive immunophenotype. Statistical models that included these AI-based variables outperformed models with combined clinical pathologic features for overall survival (C-indexes of 0.81 vs 0.68), disease-free survival (C-indexes of 0.73 vs 0.68), metastasis (C-indexes of 0.78 vs 0.65), and local recurrence (C-indexes of 0.72 vs 0.68) for all cases, with similar results in the subgroup analysis of World Health Organization grade 2 HCCs. Our AI model serves as a proof of concept that HCC differentiation can be objectively quantified digitally by assessing a combination of biologically relevant histopathologic features. In addition, several AI-derived features were independently predictive of HCC-related outcomes in our study population, most notably nuclear area percent, hepar-low/glypican-3-negative phenotype, and decreasing levels of reticulin expression, highlighting the relevance of quantitative analysis of tumor differentiation features in this context.

553

项与 GPC3 相关的新闻（医药）

2025-04-29

·PipelineReview

Bayer Initiates Phase I Study Targeting GPC3 With Actinium-225 Radiopharmaceutical in Patients With Advanced Hepatocellular Carcinoma

WHIPPANY, NJ, USA I April 29, 2025 I Bayer announced today initiation of a Phase I clinical trial with 225 Ac-GPC3 (BAY 3547926), an investigational targeted alpha radiopharmaceutical being developed to treat tumors expressing Glypican-3 (GPC3) in patients with advanced hepatocellular carcinoma (HCC). Oncofetal protein GPC3 is a membrane-associated proteoglycan which is overexpressed in 70-75% of HCC lesions making it an attractive target for targeted radionuclide therapy. 1,2 The first-in-human, dose escalation study ( NCT06764316 ) will evaluate the safety, tolerability and preliminary efficacy of BAY 3547926 alone, and as a combination therapy in patients with advanced HCC. “Hepatocellular carcinoma continues to be a devastating disease for millions of patients and a pressing unmet need in cancer care. The launch of the Phase I trial using the 225 Ac-GPC3 radionuclide therapy marks an important milestone in our commitment to develop new medicines targeting cancer cells with high effect size and precision to improve the lives of people living with cancer,” said Dominik Ruettinger, M.D., Ph.D., Global Head of Research and Early Development for Oncology at Bayer’s Pharmaceuticals Division. “Through continued research innovation we can unlock the full potential of targeted alpha therapies which is an emerging class of targeted radionuclide therapy and a strategic focus area for Bayer’s precision oncology development portfolio.” Liver cancer, including hepatocellular carcinoma, is the third leading cause of cancer-related deaths in the world with almost 900,000 new cases annually. 3 It is the most rapidly growing cause of cancer deaths in the US accounting for approximately 2% of new cases and 5% of cancer deaths. 4 Despite recent scientific advancements, many doctors are not satisfied with the therapeutic benefits from the currently available treatments. Targeted alpha therapy (TAT) has the potential to address high unmet medical need across various cancer types. Bayer’s growing TAT portfolio combines alpha particle-emitting radionuclides with different targeting moieties. 225 Ac-GPC3 is the third TAT program in clinical development and the first investigational targeted radiopharmaceutical for Bayer in HCC. The newly disclosed targeted alpha conjugate joins 225 Ac-Pelgifatamab and 225 Ac-PSMA-Trillium, which are currently in Phase I clinical trials in patients with advanced metastatic castration resistant prostate cancer. On April 28, 2025 Bayer introduced 225 Ac-GPC3 in an oral presentation during the “New Drugs on the Horizon” session at the AACR (American Association of Cancer Research) Annual Meeting, showcasing preclinical characterization of the asset including the low uptake and fast clearance from normal organs as well as induction of tumor regression in in vivo models. Recognition in this special symposium highlights the company’s commitment for precision oncology development portfolio. About BAY 3547926 BAY 3547926 is an investigational targeted alpha radiopharmaceutical being developed to treat tumors expressing Glypican-3 (GPC3) in patients with advanced hepatocellular carcinoma (HCC). It is composed of a GPC3 targeting high affinity antibody radiolabeled with actinium-225 ( 225 Ac). 225 Ac-GPC3 delivers highly potent alpha-particles to the GPC3-expressing cancer cells, with the potential to inducing DNA double-strand breaks, reducing cancer cell viability which may potentially cause anti-tumor activity. About Targeted Alpha Therapy Targeted alpha therapy (TAT) is an emerging class of radionuclide therapy that can be used against a variety of tumors. It delivers alpha particle radiation directly to the tumor inside the body, either via its bone-seeking property (radium-223) or by combining alpha radionuclides, such as actinium-225, with specific targeting moieties. Actinium-225 is an alpha particle–emitting radionuclide with a 9.9-day half-life. Alpha particles deposit highly ionizing radiation over a short range. This localized delivery of the radioactive payload induces irreparable DNA double-strand breaks, often resulting in cell death. At the same time, because the energy travels a short range, damage to nearby normal tissues is much reduced. 5,6,7 About Oncology at Bayer Bayer is committed to delivering science for a better life by advancing a portfolio of innovative treatments. The company has the passion and determination to develop new medicines that help improve and extend the lives of people living with cancer. The oncology franchise at Bayer includes several marketed products across diverse indications and multiple compounds in different stages of clinical development. We have a wealth of expertise in areas including Tumor Cell Intrinsic Pathways, Targeted Radionuclide Therapies, and selective Next-Generation Immuno-Oncology. With our portfolio we are advancing cancer treatments from early to metastatic stage, with the goal of extending survival while limiting side effects for the cancer patients we serve. About Bayer Bayer is a global enterprise with core competencies in the life science fields of health care and nutrition. In line with its mission, “Health for all, Hunger for none,” the company’s products and services are designed to help people and the planet thrive by supporting efforts to master the major challenges presented by a growing and aging global population. Bayer is committed to driving sustainable development and generating a positive impact with its businesses. At the same time, the Group aims to increase its earning power and create value through innovation and growth. The Bayer brand stands for trust, reliability and quality throughout the world. In fiscal 2024, the Group employed around 93,000 people and had sales of 46.6 billion euros. R&D expenses amounted to 6.2 billion euros. For more information, go to www.bayer.com . Find more information at https://pharma.bayer.com/ . Follow us on Facebook: http://www.facebook.com/bayer . SOURCE: Bayer

临床1期

2025-04-25

·肿瘤界

CAR-T细胞疗法在实体瘤治疗中的进展与挑战

点击蓝字关注我们前言近年来，嵌合抗原受体T细胞（CAR-T）疗法在血液系统肿瘤的治疗中取得了巨大成功，但其在实体瘤中的治疗却遇到了诸多挑战。其中，抗原异质性以及肿瘤微环境的免疫抑制特性等难题是影响CAR-T治疗实体瘤疗效不佳的主要罪魁。随着一些肿瘤新抗原的深入发掘与CAR-T细胞改造技术的突破，CAR-T细胞疗法在肺癌、胃癌、肝癌等实体瘤治疗领域取得了一些突破和进展。本文梳理了目前CAR-T细胞疗法在多种实体瘤中的临床研究进展与面临的挑战。CAR-T细胞疗法的核心原理CAR-T细胞疗法是目前临床恶性肿瘤治疗中探索最多的免疫细胞疗法，其原理是在T细胞上组装一个能特异识别肿瘤抗原，并且激活T细胞的嵌合抗原受体（CAR）分子。CAR分子结构由3部分组成：胞外区是一个单链抗体可变区（ScFv），能特异识别肿瘤抗原；跨膜区常用CD8或CD28分子穿膜区作为胞内与胞外连接桥梁；胞内区结构根据CAR-T技术的更新迭代略有不同，目前临床使用最多的二代CAR的胞内区包含一个共刺激结构域（CD28或41BB）和CD3ζ结构域。简而言之，CAR-T细胞疗法是应用基因修饰技术制备表达嵌合抗原受体的T淋巴细胞（CAR-T细胞），CAR-T细胞经体外扩增后回输至患者体内，起到增强效应T细胞的靶向性、杀伤性和持久性的作用。CAR-T细胞疗法在实体瘤领域的进展随着CAR-T细胞疗法研究的深入，实体瘤领域的细胞疗法研发呈现快速增长趋势。靶点的多样化成为一大特点，其中EGFR、glypican 3（GPC3）、CLDN18.2和皮素（MSLN）成为CAR-T细胞试验中的热门靶点。1 肺癌（1）靶向EGFR的CAR-T细胞疗法表皮生长因子受体（EGFR）在多种癌症类型中高表达，靶向EGFR的CAR-T细胞免疫疗法为肺癌治疗提供了新的策略和希望。一项纳入了9例晚期复发/难治性非小细胞肺癌（NSCLC）患者的临床研究（NCT03182816）显示，EGFR靶向的CAR-T细胞疗法的中位无进展生存期（PFS）为7.13个月，中位总生存期（OS）为15.63个月。（2）靶向GPC3的CAR-T细胞疗法磷脂酰肌醇蛋白聚糖3（glypican 3，GPC3）在调控细胞生长和分化方面起重要作用，在肺鳞癌（54%）中有一定程度表达。近日，由上海市胸科医院肿瘤科学科带头人陆舜教授作为主要研究者（PI）发起的全球首个靶向GPC3自体CAR-T细胞疗法C-CAR031治疗晚期鳞状细胞肺癌的临床研究，已顺利完成首例患者回输。陆舜教授表示："这是一次极具挑战性的创新尝试——将靶向GPC3的新一代CAR-T技术应用于肺癌治疗。首例患者的成功回输验证了临床转化的可行性，为既往PD-1耐药、驱动基因阴性患者开辟了‘第三种武器’的可能性。随着后续剂量探索和疗效观察的推进，我们期待能重塑晚期鳞状细胞肺癌的治疗格局。"2 肝癌靶向GPC3的CAR-T细胞疗法CAR-T细胞疗法在肝细胞癌（HCC）治疗中也显示出令人鼓舞的结果。GPC3在70%-80%的HCC中过表达，而在健康组织中几乎不存在，被认为是HCC的潜在治疗靶点。在Ⅰ期临床试验（NCT05103631和NCT04377932）中，GPC3靶向CAR-T疗法治疗HCC的疾病控制率（DCR）达到66%，抗肿瘤应答率为33%；令人兴奋的是，另一项Ⅰ期研究（NCT05155189）显示，GPC3靶向CAR-T疗法C-CAR031的DCR为90.9%，ORR为50.0%。3 胃癌靶向CLDN18.2的CAR-T细胞疗法紧密连接蛋白剪接变异体2（Claudin18.2，CLDN18.2）在正常细胞中表达高度受限，但在胃癌、胰腺癌等恶性肿瘤中特异性高表达，这使得CLDN18.2成为胃癌治疗的潜在靶点。CT041是一种靶向CLDN18.2的CAR-T细胞药物，其在临床试验中展现出令人鼓舞的结果。在一项由研究者发起的临床试验（NCT03874897）中，CT041在表达CLDN18.2的晚期胃肠道肿瘤中显示出治疗潜力，并且安全性可控。在该试验中，98例接受治疗的患者的客观缓解率（ORR）和疾病控制率（DCR）分别为38.8%和91.8%。CT041在胃癌亚组中疗效更显著，ORR和DCR分别达到了57.4%和83.0%，中位PFS时间为5.8个月，中位OS时间为9.7个月，取得令人鼓舞的疗效。4 卵巢癌间皮素（MSLN）是实体瘤细胞治疗领域的常见靶点，在70%的卵巢癌中高度表达。值得关注的是，在近期的一项临床试验（NCT01583686）中，接受MSLN靶向CAR-T细胞输注后，患者的6个月总生存率为70.2%，无进展生存期为5.8个月，13%的患者经历了可逆的≥3级CRS反应。5 脑胶质瘤CAR-T细胞疗法在脑胶质瘤中的应用正在迅速发展。靶向EGFR和IL-13Rα2的双特异性CAR-T细胞鞘内给药，观察到短暂肿瘤消退；靶向B7-H3的CAR-T细胞疗法的中位总OS为20.3个月，12个月总生存率为83.3%；靶向GD2的CAR-T细胞疗法达到了50%的部分缓解（PR）率。尽管上述CAR-T细胞疗法在一些实体瘤患者中展示出了治疗潜力，但其在整体实体瘤中的临床疗效仍有待提升。CAR-T细胞治疗实体瘤面临的挑战实体瘤的CAR-T疗法仍然面临诸多挑战，CAR-T细胞在实体瘤中疗效不佳的因素包括：T细胞耗竭。持续暴露于肿瘤抗原导致CAR-T细胞抗肿瘤活性下降并耗竭。非肿瘤靶向毒性。实体瘤异质性高，不同肿瘤细胞的蛋白表达特征各异，缺乏肿瘤特异性抗原。实体瘤靶点多为肿瘤相关抗原，而这些靶点在正常组织细胞中也有表达，因此CAR-T细胞可能会误伤正常组织，引发On-target off-tumor（非肿瘤靶向）毒性。CAR-T细胞无法有效浸润肿瘤组织。相较于血液肿瘤，实体瘤具有物理屏障，加之CAR-T细胞迁移所依赖的趋化因子表达下调或不表达，不利于CAR-T细胞的渗透、迁移和浸润。免疫抑制性的肿瘤微环境。实体瘤微环境缺氧、免疫抑制代谢物水平高，不利于免疫效应细胞存活，且肿瘤微环境中免疫抑制细胞和分子的存在会抑制CAR-T细胞的免疫反应。结语CAR-T细胞疗法作为一种革命性的肿瘤治疗手段，在血液肿瘤领域取得令人瞩目进展的同时，实体瘤领域也在不断探索更多的可能。随着对肿瘤免疫微环境、肿瘤靶点的深入研究，CAR-T细胞的改造和设计不断优化，CAR-T细胞有望在更多实体瘤类型的临床治疗中取得突破性进展，为更多肿瘤患者带来新的希望。然而，CAR-T疗法在实体瘤的治疗仍面临诸多挑战，包括CAR-T细胞改造、特异性靶点挖掘、免疫抑制性肿瘤微环境改善等问题。未来，仍需要持续开展研究以优化治疗方案，比如CAR-T细胞治疗与其它治疗方案的联合应用，以满足癌症患者的临床需求。期待CAR-T疗法克服现有瓶颈，成为肿瘤治疗领域的重要支柱。推荐阅读● 一文读懂CAR-T疗法● 收藏必备！一文读懂细胞疗法(汇总篇)声明：本文由“肿瘤界”整理与汇编，欢迎分享转载，如需使用本文内容，请务必注明出处。参考文献：1. 中国肿瘤整合诊治技术指南(CACA)—免疫治疗2. Zhang, Y., Zhang, Z., Ding, Y. et al. Phase I clinical trial of EGFR-specific CAR-T cells generated by the piggyBac transposon system in advanced relapsed/refractory non-small cell lung cancer patients. J Cancer Res Clin Oncol 147, 3725–3734 (2021).3. Steffin, D., Ghatwai, N., Montalbano, A. et al. Interleukin-15-armoured GPC3 CAR T cells for patients with solid cancers. Nature 637, 940–946 (2025). https://doi-org.libproxy1.nus.edu.sg/10.1038/s41586-024-08261-8https://ascopubs-org.libproxy1.nus.edu.sg/doi/10.1200/JCO.2024.42.16_suppl.40194. Qi, C., Liu, C., Gong, J. et al. Claudin18.2-specific CAR T cells in gastrointestinal cancers: phase 1 trial final results. Nat Med 30, 2224–2234 (2024). https://doi-org.libproxy1.nus.edu.sg/10.1038/s41591-024-03037-z5. CAR-T therapy in solid tumors.Du, Bing et al.Cancer Cell, Volume 43, Issue 4, 665 - 679.6. Bagley, S.J., Logun, M., Fraietta, J.A. et al. Intrathecal bivalent CAR T cells targeting EGFR and IL13Rα2 in recurrent glioblastoma: phase 1 trial interim results. Nat Med 30, 1320–1329 (2024). https://doi-org.libproxy1.nus.edu.sg/10.1038/s41591-024-02893-z7. Yang Zhang et al. Safety and efficacy of B7-H3 targeting CAR-T cell therapy for patients with recurrent GBM.. JCO 42, 2062-2062(2024).DOI:10.1200/JCO.2024.42.16_suppl.2062编辑：商陆审核：lagertha

细胞疗法免疫疗法临床研究

2025-04-24

·同写意

邦耀生物刘明耀、杜冰教授团队《Cancer Cell 》重磅综述：CAR-T攻克实体瘤，未来可期！

免疫疗法细胞疗法临床研究临床结果