British Journal of Cancer最新文献

The pronounced cytotoxic effects of chimeric antigen receptor T cells targeting B7-H3 in organoids and liver xenografts derived from colorectal cancer patients. 靶向B7-H3的嵌合抗原受体T细胞在结直肠癌患者的类器官和肝脏异种移植中显著的细胞毒性作用。

IF 6.8 1区医学

British Journal of Cancer Pub Date : 2025-07-28 DOI: 10.1038/s41416-025-03114-1

Yuling Sheng, Li Yan, Qi Liu, Yifan Peng, Jingyun Tan, Wenhua Li, Wei Mao, Wenqing Wei, Yanyun Chang, Linlin Cao, Yi Tan, Yanlin Xiao, Wenyong Zhang, Jing Gao, Yang Xu, Changzheng Du

{"title":"The pronounced cytotoxic effects of chimeric antigen receptor T cells targeting B7-H3 in organoids and liver xenografts derived from colorectal cancer patients.","authors":"Yuling Sheng, Li Yan, Qi Liu, Yifan Peng, Jingyun Tan, Wenhua Li, Wei Mao, Wenqing Wei, Yanyun Chang, Linlin Cao, Yi Tan, Yanlin Xiao, Wenyong Zhang, Jing Gao, Yang Xu, Changzheng Du","doi":"10.1038/s41416-025-03114-1","DOIUrl":"https://doi.org/10.1038/s41416-025-03114-1","url":null,"abstract":"Background: The application of chimeric antigen receptor (CAR)-T cells in solid tumors is hindered due to the lack of specific tumor antigen and limited clinical efficacy. Our aim is to develop and validate novel CAR-T cell therapy against metastatic colorectal cancer (CRC).Methods: By analyzing the expression of B7-H3 in CRC tissue and cell lines using immunohistochemistry (IHC) and flow cytometry, respectively, we identified B7-H3 as a potential target in CRC. We thereby developed CAR-T cells targeting B7-H3 (B7-H3 CAR-T) and evaluated their anti-tumor activity in vitro and in vivo, using patient-derived organoids (PDOs) and xenograft (PDX) models to validate its translational potential.Results: In our cohort of 170 CRC patients, B7-H3 was significantly upregulated in CRC tumors compared to paratumor tissue, as determined by IHC staining. When co-cultured with CRC cells or PDOs, B7-H3 CAR-T cells exhibited a dose-dependent cytotoxicity in vitro. Furthermore, B7-H3 CAR-T cells effectively controlled tumor growth and metastasis in vivo, significantly prolonging survival time for the tumor-burden mice through cytotoxic killing and potential immune regulatory effects, demonstrated in both CRC cell-based and PDX-based metastatic models.Conclusions: These findings underscore the potential efficacy of B7-H3 CAR-T cells for treating metastatic CRC and highlight its translational value.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144728064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Enhanced HER2 internalization by clathrin-dependent endocytosis in non-small cell lung cancer positive for HER2 mutations. 在HER2突变阳性的非小细胞肺癌中，通过网格蛋白依赖的内吞作用增强HER2内化。

IF 6.8 1区医学

British Journal of Cancer Pub Date : 2025-07-28 DOI: 10.1038/s41416-025-03126-x

Atsushi Shimauchi, Eiji Iwama, Ritsu Ibusuki, Hirono Tsutsumi, Daisuke Shibahara, Kohei Otsubo, Yasuto Yoneshima, Kentaro Tanaka, Isamu Okamoto

{"title":"Enhanced HER2 internalization by clathrin-dependent endocytosis in non-small cell lung cancer positive for HER2 mutations.","authors":"Atsushi Shimauchi, Eiji Iwama, Ritsu Ibusuki, Hirono Tsutsumi, Daisuke Shibahara, Kohei Otsubo, Yasuto Yoneshima, Kentaro Tanaka, Isamu Okamoto","doi":"10.1038/s41416-025-03126-x","DOIUrl":"https://doi.org/10.1038/s41416-025-03126-x","url":null,"abstract":"Background: HER2-targeted antibody-drug conjugates (ADCs) have shown marked efficacy for HER2 mutation-positive non-small cell lung cancer (NSCLC). The intracellular trafficking of mutant HER2 has remained to be fully elucidated, however.Methods: HER2 dynamics were examined in cells expressing wild-type (WT) or mutant HER2 with the use of live cell imaging and an in situ proximity ligation assay. Proteins related to mutant HER2 trafficking were identified by liquid chromatography and tandem mass spectrometry.Results: HER2 internalization was enhanced in NSCLC cells expressing mutant HER2 compared with those expressing HER2(WT). Homodimers of HER2(WT) were localized mainly at the cell surface, whereas those of mutant HER2 were present mostly in the cytoplasm. Knockdown of EGFR or HER3 suppressed internalization of HER2(WT) but not that of mutant HER2. The enhanced internalization of mutant HER2 was mediated by clathrin-dependent endocytosis, as was reflected by increased binding of the ubiquitin ligase c-Cbl to mutant HER2 and its consequent ubiquitination, and was attenuated by treatment with zongertinib, a HER2-specific tyrosine kinase inhibitor.Conclusions: Upregulation of HER2 phosphorylation promotes internalization of mutant HER2 mediated by clathrin-dependent endocytosis, likely contributing to the efficacy of HER2-targeted ADCs in NSCLC positive for HER2 mutations.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144728063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cumulative incidence and survival outcomes of brain metastases in sarcoma: a large single center retrospective analysis. 脑转移性肉瘤的累积发病率和生存结局：一项大型单中心回顾性分析。

IF 6.4 1区医学

British Journal of Cancer Pub Date : 2025-07-26 DOI: 10.1038/s41416-025-03111-4

Ayah Erjan, Kurl Jamora, Enrique Gutierrez, Anna Santiago, Adeodatus Vito Nicanor, Barbara-Ann Millar, Normand Laperriere, Tatiana Conrad, Dana Keilty, Philip Wong, Peter Chung, Charles Catton, David Kirsch, David B Shultz

{"title":"Cumulative incidence and survival outcomes of brain metastases in sarcoma: a large single center retrospective analysis.","authors":"Ayah Erjan, Kurl Jamora, Enrique Gutierrez, Anna Santiago, Adeodatus Vito Nicanor, Barbara-Ann Millar, Normand Laperriere, Tatiana Conrad, Dana Keilty, Philip Wong, Peter Chung, Charles Catton, David Kirsch, David B Shultz","doi":"10.1038/s41416-025-03111-4","DOIUrl":"https://doi.org/10.1038/s41416-025-03111-4","url":null,"abstract":"Background: The incidence and predictors of brain metastases (BrM) from sarcoma remain poorly characterized. We aimed to determine the cumulative incidence (CuI) and risk factors for BrM.Methods: We retrospectively analyzed data from all sarcoma patients who presented to our center (2006-2023). CuI was calculated from initial presentation to BrM, stratified by key variables. Univariable (UVA) and multivariable competing risk regression analyses (MVA) were conducted to identify risk factors.Results: Among 5110 sarcoma patients, 117 developed BrM. CuI rates were 1.8%, 2.4%, and 2.9% at 24, 48, and 72 months, respectively, within a median onset of 17 months. On UVA, intrathoracic primary site, alveolar soft part (ASPS), epithelioid, intimal and Rhabdomyosarcoma histologies, and stage IV at diagnosis were associated with increased CuI, while age ≥59, retroperitoneal origin and liposarcoma were associated with decreased CuI. On MVA the following remained correlated to BrM incidence: intrathoracic primary (HR 5.13), ASPS (HR 4.2), age ≥59 years (HR 0.45) and liposarcoma (HR 0.11); 44.3% presented with solitary BrM. Median survival post-BrM diagnosis was 6 months.Conclusion: BrM risk in sarcoma varies by age, histology, and tumor location. Solitary metastases were common in our BrM cohort, and OS post-BrM was poor.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A cancer-associated TP53 synonymous mutation induces synthesis of the p53 isoform p53/47. 癌症相关的TP53同义突变诱导p53异构体p53/47的合成。

IF 6.4 1区医学

British Journal of Cancer Pub Date : 2025-07-26 DOI: 10.1038/s41416-025-03127-w

Rhythm Sajwan, Lixiao Wang, Olivera Casar-Borota, Konstantinos Karakostis, Sa Chen, Robin Fahraeus, Xiaolian Gu, Sivakumar Vadivel Gnanasundram

{"title":"A cancer-associated TP53 synonymous mutation induces synthesis of the p53 isoform p53/47.","authors":"Rhythm Sajwan, Lixiao Wang, Olivera Casar-Borota, Konstantinos Karakostis, Sa Chen, Robin Fahraeus, Xiaolian Gu, Sivakumar Vadivel Gnanasundram","doi":"10.1038/s41416-025-03127-w","DOIUrl":"https://doi.org/10.1038/s41416-025-03127-w","url":null,"abstract":"Background: Synonymous mutations (SMs) change the mRNA nucleotide sequences without altering the corresponding amino acid sequence and are usually overlooked due to their perceived lack of influence on protein function. However, emerging reports suggest that SMs play a significant role in disease development and progression.Methods: Whole exome sequencing, RNA-sequencing, and droplet digital PCR were performed to identify the SMs from the malignant glioma patients. MutaRNA was used to predict the effect of SMs on RNA structure in silico. SHAPE-MaP was performed to probe and assess the effect of SMs on RNA structure in-cellulo.Results: Here, we report that a Cancer-Associated SM in TP53 codon valine 203 (CASM203) results in the induction of the alternative translation initiated p53 protein isoform, p47. In-cell high-throughput RNA structural mapping showed that CASM203 mimics the Protein Kinase RNA-Like ER Kinase (PERK)-mediated p53 mRNA secondary structure that induces p47 expression of during the unfolded protein response (UPR).Conclusions: Overall, the single gain-of-function SM mimics the UPR-mediated p53 stress response, by generating RNA secondary structures akin to the PERK-mediated p53 mRNA structural switch. This illustrates the link between RNA structures and cellular biology and underscores the importance of SMs in cancer biology and their potential to further refine genetic diagnostics.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Impact of gut microbiome on radiotherapy and immunotherapy efficacy in microsatellite-stable colorectal cancer: role of propionic acid and B. fragilis. 肠道微生物组对微卫星稳定型结直肠癌放疗和免疫治疗效果的影响：丙酸和脆弱芽孢杆菌的作用

IF 6.4 1区医学

British Journal of Cancer Pub Date : 2025-07-26 DOI: 10.1038/s41416-025-03105-2

Lu Yu, Qiqing Guo, Xinyi Gu, Zihuan Wang, Jiaying Li, Xusheng Wang, Zi Xu, Yafang Wang, Yuqin Zhang, Yaowei Zhang, Yanqing Ding, Zhenhui Chen, Keli Chen, Yi Ding

{"title":"Impact of gut microbiome on radiotherapy and immunotherapy efficacy in microsatellite-stable colorectal cancer: role of propionic acid and B. fragilis.","authors":"Lu Yu, Qiqing Guo, Xinyi Gu, Zihuan Wang, Jiaying Li, Xusheng Wang, Zi Xu, Yafang Wang, Yuqin Zhang, Yaowei Zhang, Yanqing Ding, Zhenhui Chen, Keli Chen, Yi Ding","doi":"10.1038/s41416-025-03105-2","DOIUrl":"https://doi.org/10.1038/s41416-025-03105-2","url":null,"abstract":"Background: Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related deaths worldwide. While immunotherapy is effective in microsatellite instability-high (MSI-H) CRC, its benefits in microsatellite-stable (MSS) CRC are limited. Radiotherapy may modify the immune microenvironment in MSS-CRC, enhancing immunotherapy efficacy, but individual responses vary.Methods: We employed MSS-CRC mouse models to examine the effects of combined radiotherapy and immunotherapy, with and without antibiotics (ABX). Various analyses, including metagenomic, nontargeted metabolomic, and gas chromatography-mass spectrometry (GC-MS), were performed to identify factors influencing treatment outcomes. Flow cytometry, immunohistochemistry and in vivo antibody blockade experiments assessed the role of metabolites and bacteria on CD8+ T cell infiltration and treatment responses, complemented by transcriptomic sequencing and molecular biology experiments.Results: Our analyses identified propionic acid and Bacteroides fragilis (B. fragilis) as crucial factors enhancing the efficacy of combined therapies in MSS-CRC. Both propionic acid and B. fragilis improved CD8+ T cell infiltration and treatment outcomes, with molecular assays indicating that propionic acid facilitates H3K14 acetylation, activating the Meox1-Cxcr6/Ccl5 axis.Conclusions: This study highlights the pivotal role of the gut microbiome, specifically propionic acid and B. fragilis, in modulating the efficacy of combined radiotherapy and immunotherapy in MSS-CRC.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Retraction Note: miR-21, miR-17 and miR-19a induced by phosphatase of regenerating liver-3 promote the proliferation and metastasis of colon cancer. 注：再生肝-3磷酸酶诱导的miR-21、miR-17和miR-19a促进结肠癌的增殖和转移。

IF 6.4 1区医学

British Journal of Cancer Pub Date : 2025-07-25 DOI: 10.1038/s41416-025-03135-w

J Zhang, Z Xiao, D Lai, J Sun, C He, Z Chu, H Ye, S Chen, J Wang

引用次数: 0

Postdiagnosis physical activity is associated with improved survival in prostate cancer patients treated with surgery but not with radiation therapy. 前列腺癌患者接受手术治疗后的身体活动与生存率的提高有关，但与放射治疗无关。

IF 6.4 1区医学

British Journal of Cancer Pub Date : 2025-07-23 DOI: 10.1038/s41416-025-03123-0

Ki-Yong An, Justin Y Jeon, Fernanda Z Arthuso, Qinggang Wang, Christine M Friedenreich, Kerry S Courneya

{"title":"Postdiagnosis physical activity is associated with improved survival in prostate cancer patients treated with surgery but not with radiation therapy.","authors":"Ki-Yong An, Justin Y Jeon, Fernanda Z Arthuso, Qinggang Wang, Christine M Friedenreich, Kerry S Courneya","doi":"10.1038/s41416-025-03123-0","DOIUrl":"https://doi.org/10.1038/s41416-025-03123-0","url":null,"abstract":"Background: The effects of exercise on cancer outcomes may differ depending on its positioning within different cancer treatment combinations. We examined whether the associations between physical activity (PA) and cancer outcomes varied by cancer treatment modality or timing of PA.Methods: We conducted a secondary analysis of the Prostate Cancer Cohort Study consisting of 830 men in Alberta, Canada with newly diagnosed prostate cancer. Lifetime prediagnosis PA was assessed by an in-person interview shortly after diagnosis whereas postdiagnosis PA was assessed at 2-3 year intervals by an in-person interview (first follow-up) or self-report (second and third follow-ups). Cox proportional hazards regression models were used to test interactions between PA and treatment modalities for disease-free survival, overall survival, and prostate cancer-specific disease-free survival.Results: Postdiagnosis vigorous PA significantly interacted with surgery (p < 0.001) and radiotherapy (p = 0.003). Specifically, patients who had surgery experienced a 61% lower likelihood of a disease-free survival event if they engaged in any versus no postdiagnosis vigorous PA (HR = 0.39, 95% CI = 0.27-0.57). Conversely, patients who received radiotherapy did not experience any benefit from postdiagnosis vigorous PA (HR = 1.14, 95% CI = 0.88-1.47).Conclusions: The role of PA as a treatment for prostate cancer may depend on its combination and sequencing with other treatments.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697667","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

T cell engagers: expanding horizons in oncology and beyond. T细胞接合者：拓展肿瘤学及其他领域的视野。

IF 6.4 1区医学

British Journal of Cancer Pub Date : 2025-07-23 DOI: 10.1038/s41416-025-03125-y

Gulsah Albayrak, Peter Kok-Ting Wan, Kerry Fisher, Leonard W Seymour

{"title":"T cell engagers: expanding horizons in oncology and beyond.","authors":"Gulsah Albayrak, Peter Kok-Ting Wan, Kerry Fisher, Leonard W Seymour","doi":"10.1038/s41416-025-03125-y","DOIUrl":"https://doi.org/10.1038/s41416-025-03125-y","url":null,"abstract":"Background/introduction: T cell engagers (TCEs) are engineered immunotherapeutic molecules designed to direct the body's immune system against tumour or infected cells by bridging T cells and their targets, triggering potent cytotoxic responses. Over the past decade, TCE-based therapies have gained momentum in oncology, resulting in several FDA approvals for haematologic malignancies and showing growing promise in solid tumours.Objective: This review elaborates on TCE mechanisms of action, emphasising their ability to activate T cells, target tumour antigens, and modulate the tumour microenvironment.Methods/results: We also delve into the clinical outcomes demonstrating TCE efficacy, alongside challenges such as cytokine release syndrome, antigen heterogeneity, and short half-lives. Recent advances in TCE design have incorporated multispecific constructs and conditional activation strategies and expansion in target molecules has enabled broadening applications to non-oncology indications like autoimmune and infectious diseases. Moreover, the use of artificial intelligence (AI) has also accelerated TCE discovery by identifying favourable epitope interactions, reducing immunogenicity risks, and enhancing overall design efficiency.Conclusions: Looking further, these advances open up a new era to redefine success for TCEs in both cancer and beyond, offering hope for more effective, safer immunotherapies.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The colorectal liver metastasis growth pattern phenotype is not dependent on genotype. 结直肠肝转移生长模式表型不依赖于基因型。

IF 6.4 1区医学

British Journal of Cancer Pub Date : 2025-07-23 DOI: 10.1038/s41416-025-03103-4

Diederik J Höppener, Sanne M L Verheul, Pieter M H Nierop, Florian E Buisman, Boris Galjart, Saskia M Wilting, Siân A Pugh, Susan D Richman, Vinod P Balachandran, William R Jarnagin, T Peter Kingham, Peter B Vermeulen, Jinru Shia, Philip Quirke, John A Bridgewater, Timothy S Maughan, Bas Groot Koerkamp, Dirk J Grünhagen, Cornelis Verhoef, John N Primrose, Michael I D'Angelica

{"title":"The colorectal liver metastasis growth pattern phenotype is not dependent on genotype.","authors":"Diederik J Höppener, Sanne M L Verheul, Pieter M H Nierop, Florian E Buisman, Boris Galjart, Saskia M Wilting, Siân A Pugh, Susan D Richman, Vinod P Balachandran, William R Jarnagin, T Peter Kingham, Peter B Vermeulen, Jinru Shia, Philip Quirke, John A Bridgewater, Timothy S Maughan, Bas Groot Koerkamp, Dirk J Grünhagen, Cornelis Verhoef, John N Primrose, Michael I D'Angelica","doi":"10.1038/s41416-025-03103-4","DOIUrl":"https://doi.org/10.1038/s41416-025-03103-4","url":null,"abstract":"Background: The histopathological growth patterns (HGPs) of colorectal cancer liver metastases broadly classify patients into two groups post-liver metastasectomy, with encapsulated HGP indicating a more favourable prognosis. The potential association between HGPs and specific mutations is poorly understood.Methods: Using next-generation sequencing data of 461 resected patients (104 patients with encapsulated versus 357 patients with non-encapsulated HGP), 19 putative colorectal cancer driver genes, tumour mutational burden (TMB), and microsatellite instability (MSI) or POLE mediated hypermutation were compared.Results: Most putative drivers, including KRAS (q = 0.89), NRAS (q = 0.98),) and BRAF (q = 0.97)), were not associated with HGP. However, mutations in B2M and PTEN were associated with a encapsulated phenotype (7% vs. 0%, q = 0.001, and 9% vs. 2%, q = 0.02, respectively). TMB was higher in encapsulated patients (median 5.8 vs. 5.1 mutations per megabase, p = 0.009). Multivariable overall survival analysis corrected for genetic and patient factors confirmed that the encapsulated phenotype was an independent prognostic factor (adjusted hazard ratio, 0.60; 95% confidence interval: 0.36-0.99). Upon stratified analysis, all identified genetic associations were equivocal between the cohorts.Conclusions: While an association between genetic drivers of adaptive immune responses seems probable and could explain a minority of encapsulated patients, these results primarily demonstrate that HGP phenotype is independent of the tumour genotype.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A phase 1b, multicentre, dose escalation, safety and pharmacokinetics study of tilvestamab (BGB149) in relapsed, platinum-resistant, high-grade serous ovarian cancer (PROC) patients. tilvestamab （BGB149）用于复发、铂耐药、高级别浆液性卵巢癌（PROC）患者的1b期、多中心、剂量递增、安全性和药代动力学研究

IF 6.4 1区医学

British Journal of Cancer Pub Date : 2025-07-22 DOI: 10.1038/s41416-025-03090-6

Kenneth Sooi, Tuan Zea Tan, Jae-Weon Kim, Jung Yun Lee, Byoung-Gie Kim, David Micklem, Akil Jackson, David J Pinato, Charlie Gourley, Rebecca Kristeleit, Sarah P Blagden, Line Bjorge, David Shao Peng Tan

{"title":"A phase 1b, multicentre, dose escalation, safety and pharmacokinetics study of tilvestamab (BGB149) in relapsed, platinum-resistant, high-grade serous ovarian cancer (PROC) patients.","authors":"Kenneth Sooi, Tuan Zea Tan, Jae-Weon Kim, Jung Yun Lee, Byoung-Gie Kim, David Micklem, Akil Jackson, David J Pinato, Charlie Gourley, Rebecca Kristeleit, Sarah P Blagden, Line Bjorge, David Shao Peng Tan","doi":"10.1038/s41416-025-03090-6","DOIUrl":"https://doi.org/10.1038/s41416-025-03090-6","url":null,"abstract":"Background: Tilvestamab is a highly selective humanised immunoglobulin G1 anti-AXL monoclonal antibody. This phase 1 study evaluated its optimal dose, safety, tolerability, immunogenicity and pharmacokinetics (PK) in relapsed platinum-resistant HGSOC patients.Methods: Patients received tilvestamab in three dose levels (1 mg/kg, 3 mg/kg and 5 mg/kg) via IV infusion every 2 weeks. Primary objectives included safety, tolerability and PK. Exploratory objectives included overall response, progression-free survival (PFS) and quality-of-life measures. Pharmacodynamic included AXL expression, gene and protein changes by transcriptomic and proteomic analysis.Results: Between 25 February 2021 and 4 February 2022, 16 patients were enroled across 8 sites in Singapore, Korea, United Kingdom, and Norway. Median treatment duration was 6.1 weeks. Grade 3 or higher treatment-emergent adverse events occurred in 62.5% patients, but none were tilvestamab-related. Common events included fatigue (38%), anorexia (38%) infections (31%), anaemia (25%) and dyspnoea (25%). No objective responses were observed, but 7 (44%) had stable disease at 6 weeks. PK showed dose-proportional exposure and steady-state by the second dose. Pharmacodynamic analyses revealed reduced fibrosis-related gene signatures and AXL protein expression. Epithelial-mesenchymal transition reversal was seen in 2 patients.Conclusion: Tilvestamab was well-tolerated and further studies to examine the efficacy of AXL inhibition in other indications are required.Clinical trial registration: This trial is registered at https://clinicaltrials.gov .Registration number: NCT04893551. EudraCT Number: 2020-001382-36.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0