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Efficacy and safety of lenvatinib combined with anti-PD-1 antibodies plus GEMOX chemotherapy as non-first-line systemic therapy in advanced gallbladder cancer. 来伐替尼联合抗PD-1抗体加GEMOX化疗作为晚期胆囊癌非一线系统疗法的有效性和安全性。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-10-03 DOI: 10.1007/s00262-024-03831-1
Yang Tan, Kai Liu, Chengpei Zhu, Shanshan Wang, Yunchao Wang, Jingnan Xue, Cong Ning, Nan Zhang, Jiashuo Chao, Longhao Zhang, Junyu Long, Xiaobo Yang, Daobing Zeng, Lijin Zhao, Haitao Zhao

Background: Lenvatinib, programmed cell death 1 (PD-1) antibodies, and gemcitabine and oxaliplatin (GEMOX) chemotherapy have shown significant antitumor activity as first-line therapy against biliary tract cancer. This study evaluated their efficacy and safety as non-first-line therapy in advanced gallbladder cancer (GBC).

Methods: Patients with advanced GBC who received lenvatinib combined with anti-PD-1 antibodies and GEMOX chemotherapy as a non-first-line therapy were retrospectively analyzed. The primary endpoints were overall survival (OS) and progression-free survival (PFS), and the secondary endpoints were objective response rate (ORR) and safety.

Results: A total of 36 patients with advanced GBC were included in this study. The median follow-up time was 11.53 (95% confidence interval (CI): 2.2-20.9) months, and the ORR was 36.1%. The median OS and PFS were 15.1 (95% CI: 3.2-26.9) and 6.1 (95% CI: 4.9-7.2) months, respectively. The disease control rate (DCR) and clinical benefit rate (CBR) were 75% and 61.1%, respectively. Subgroup analysis demonstrated that patients with programmed cell death-ligand 1 (PD-L1) expression had significantly longer PFS and OS than those without PD-L1 expression. Additionally, patients with a neutrophil-lymphocyte ratio (NLR) < 5.57 had a longer OS than those with an NLR ≥ 5.57. All patients experienced adverse events (AEs), with 61.1% experiencing grade 3 or 4 AEs, including myelosuppression (13.9%) and fatigue (13.3%), alanine transaminase or aspartate transaminase levels (8.3%), and diarrhea (8.3%). No grade 5 AEs were reported.

Conclusion: Anti-PD-1 antibodies combined with lenvatinib and GEMOX chemotherapy are effective and well-tolerated as a non-first-line therapy in advanced GBC. PD-L1 expression and baseline NLR may potentially predict treatment efficacy.

背景:伦伐替尼、程序性细胞死亡1(PD-1)抗体以及吉西他滨和奥沙利铂(GEMOX)化疗作为胆道癌的一线疗法已显示出显著的抗肿瘤活性。本研究评估了它们作为晚期胆囊癌(GBC)非一线疗法的有效性和安全性:回顾性分析了接受来伐替尼联合抗PD-1抗体和GEMOX化疗作为非一线疗法的晚期胆囊癌患者。主要终点是总生存期(OS)和无进展生存期(PFS),次要终点是客观反应率(ORR)和安全性:本研究共纳入了36名晚期GBC患者。中位随访时间为11.53个月(95%置信区间(CI):2.2-20.9),ORR为36.1%。中位OS和PFS分别为15.1个月(95% 置信区间:3.2-26.9)和6.1个月(95% 置信区间:4.9-7.2)。疾病控制率(DCR)和临床获益率(CBR)分别为75%和61.1%。亚组分析显示,有程序性细胞死亡配体1(PD-L1)表达的患者的PFS和OS明显长于无PD-L1表达的患者。此外,中性粒细胞-淋巴细胞比值(NLR)结论也表明,PD-L1表达的患者的PFS和OS明显长于无PD-L1表达的患者:抗PD-1抗体联合来伐替尼和GEMOX化疗作为晚期GBC的非一线疗法有效且耐受性良好。PD-L1 表达和基线 NLR 有可能预测疗效。
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引用次数: 0
Development and validation of a new tool to estimate early mortality in patients with advanced cancer treated with immunotherapy. 开发并验证用于估算接受免疫疗法的晚期癌症患者早期死亡率的新工具。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-10-03 DOI: 10.1007/s00262-024-03836-w
Andrea De Giglio, Alessandro Leonetti, Francesca Comito, Daria Maria Filippini, Veronica Mollica, Karim Rihawi, Marianna Peroni, Giulia Mazzaschi, Ilaria Ricciotti, Francesca Carosi, Andrea Marchetti, Matteo Rosellini, Ambrogio Gagliano, Valentina Favorito, Elisabetta Nobili, Francesco Gelsomino, Barbara Melotti, Paola Valeria Marchese, Francesca Sperandi, Alessandro Di Federico, Sebastiano Buti, Fabiana Perrone, Francesco Massari, Maria Abbondanza Pantaleo, Marcello Tiseo, Andrea Ardizzoni

Background: Immune checkpoint inhibitors (ICIs) are standard treatments for advanced solid cancers. Resistance to ICIs, both primary and secondary, poses challenges, with early mortality (EM) within 30-90 days indicating a lack of benefit. Prognostic factors for EM, including the lung immune prognostic index (LIPI), remain underexplored.

Methods: We performed a retrospective, observational study including patients affected by advanced solid tumors, treated with ICI as single agent or combined with other agents. Logistic regression models identified factors associated with EM and 90-day progression risks. A nomogram for predicting 90-day mortality was built and validated within an external cohort.

Results: In total, 637 patients received ICIs (single agent or in combination with other drugs) for advanced solid tumors. Most patients were male (61.9%), with NSCLC as the prevalent tumor (61.8%). Within the cohort, 21.3% died within 90 days, 8.4% died within 30 days, and 34.5% experienced early progression. Factors independently associated with 90-day mortality included ECOG PS 2 and a high/intermediate LIPI score. For 30-day mortality, lung metastasis and a high/intermediate LIPI score were independent risk factors. Regarding early progression, high/intermediate LIPI score was independently associated. A predictive nomogram for 90-day mortality combining LIPI and ECOG PS achieved an AUC of 0.76 (95% CI 0.71-0.81). The discrimination ability of the nomogram was confirmed in the external validation cohort (n = 255) (AUC 0.72, 95% CI 0.64-0.80).

Conclusion: LIPI and ECOG PS independently were able to estimate 90-day mortality, with LIPI also demonstrating prognostic validity for 30-day mortality and early progression.

背景:免疫检查点抑制剂(ICIs免疫检查点抑制剂(ICIs)是晚期实体瘤的标准疗法。对 ICIs 的耐药性(包括原发性和继发性)带来了挑战,30-90 天内的早期死亡率(EM)表明缺乏获益。包括肺免疫预后指数(LIPI)在内的EM预后因素仍未得到充分探讨:我们进行了一项回顾性观察研究,研究对象包括晚期实体瘤患者,他们接受了 ICI 单药治疗或与其他药物联合治疗。逻辑回归模型确定了与EM和90天进展风险相关的因素。建立了预测90天死亡率的提名图,并在外部队列中进行了验证:共有 637 名晚期实体瘤患者接受了 ICIs(单药或与其他药物联用)治疗。大多数患者为男性(61.9%),主要肿瘤为 NSCLC(61.8%)。在队列中,21.3%的患者在90天内死亡,8.4%的患者在30天内死亡,34.5%的患者病情出现早期进展。与90天死亡率独立相关的因素包括ECOG PS 2和高/中LIPI评分。就30天死亡率而言,肺转移和高/中LIPI评分是独立的风险因素。在早期进展方面,高/中LIPI评分是独立的相关因素。结合 LIPI 和 ECOG PS 的 90 天死亡率预测提名图的 AUC 为 0.76(95% CI 0.71-0.81)。外部验证队列(n = 255)证实了该提名图的区分能力(AUC 0.72,95% CI 0.64-0.80):结论:LIPI和ECOG PS能够独立估算90天死亡率,LIPI还显示出对30天死亡率和早期进展的预后有效性。
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引用次数: 0
Effectiveness, safety, and biomarker analysis of lenvatinib plus toripalimab as chemo-free therapy in advanced intrahepatic cholangiocarcinoma: a real-world study. 来伐替尼联合托瑞帕利单抗作为晚期肝内胆管癌免化疗疗法的有效性、安全性和生物标志物分析:一项真实世界研究。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-10-03 DOI: 10.1007/s00262-024-03841-z
Shanshan Wang, Jiashuo Chao, Hao Wang, Shuofeng Li, Yunchao Wang, Chengpei Zhu, Nan Zhang, Mingjian Piao, Xu Yang, Kai Liu, Ziyu Xun, Xinting Sang, Xiaobo Yang, Weidong Duan, Haitao Zhao

Background: Treatment options for advanced intrahepatic cholangiocarcinoma (ICC) are currently limited. Chemo-containing regimens are the mainstay treatments but associated with notable toxicity, poor tolerance, and reduced compliance, necessitating exploration of alternative therapies. Lenvatinib plus PD-1 inhibitors has shown substantial clinical activity in preliminary studies. This study aimed to assess the effectiveness and safety of lenvatinib plus toripalimab (a novel PD-1 antibody) as chemo-free therapy in advanced ICC.

Methods: This retrospective study included consecutive advanced ICC patients receiving lenvatinib plus toripalimab between February 2019 and December 2023. The main outcomes were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety. Prognostic factors and exploratory analyses for genetic alternations were also conducted.

Results: A total of 78 patients were included, with a median follow-up of 25.9 months. Median OS and PFS were 11.3 (95% CI: 9.5-13.1) and 5.4 (95% CI: 3.8-7.0) months, respectively. ORR was 19.2% and DCR was 75.6%. The incidence of grade 3 or 4 adverse events (AEs) was 50.0%, with no grade 5 AEs reported. Patients with normal baseline CA19-9 levels exhibited a higher ORR (p = 0.011), longer PFS (11.5 versus 4.6 months; HR 0.47; p=0.005), and OS (21.0 versus 9.7 months; HR 0.43; p=0.003). The presence of IDH1 mutations correlated with increased ORR (60.0% versus 8.9%, p=0.016).

Conclusion: Lenvatinib plus toripalimab represents an effective and well-tolerated chemo-free therapeutic option for advanced ICC. Baseline CA19-9 levels and IDH1 mutations may serve as predictive treatment-related biomarkers.

背景:晚期肝内胆管癌(ICC)的治疗方案目前很有限。含化疗方案是主流治疗方法,但毒性显著、耐受性差、依从性低,因此有必要探索替代疗法。伦伐替尼联合PD-1抑制剂已在初步研究中显示出巨大的临床活性。本研究旨在评估来伐替尼联合托瑞帕单抗(一种新型PD-1抗体)作为晚期ICC免化疗疗法的有效性和安全性:这项回顾性研究纳入了2019年2月至2023年12月期间接受来伐替尼联合托瑞帕利单抗治疗的连续晚期ICC患者。主要结果为总生存期(OS)、无进展生存期(PFS)、客观反应率(ORR)、疾病控制率(DCR)和安全性。此外,还对预后因素和基因变异进行了探索性分析:共纳入 78 名患者,中位随访时间为 25.9 个月。中位OS和PFS分别为11.3个月(95% CI:9.5-13.1)和5.4个月(95% CI:3.8-7.0)。ORR为19.2%,DCR为75.6%。3级或4级不良事件(AE)发生率为50.0%,无5级不良事件报告。基线CA19-9水平正常的患者具有更高的ORR(p = 0.011)、更长的PFS(11.5个月对4.6个月;HR 0.47;p=0.005)和OS(21.0个月对9.7个月;HR 0.43;p=0.003)。IDH1突变与ORR增加相关(60.0%对8.9%,P=0.016):结论:伦伐替尼联合托瑞帕利单抗是治疗晚期ICC的一种有效且耐受性良好的无化疗方案。基线CA19-9水平和IDH1突变可作为与治疗相关的预测性生物标志物。
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引用次数: 0
A random survival forest-based pathomics signature classifies immunotherapy prognosis and profiles TIME and genomics in ES-SCLC patients. 基于随机生存森林的病理组学特征可对ES-SCLC患者的免疫疗法预后进行分类,并对TIME和基因组学进行分析。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-10-03 DOI: 10.1007/s00262-024-03829-9
Yuxin Jiang, Yueying Chen, Qinpei Cheng, Wanjun Lu, Yu Li, Xueying Zuo, Qiuxia Wu, Xiaoxia Wang, Fang Zhang, Dong Wang, Qin Wang, Tangfeng Lv, Yong Song, Ping Zhan

Background: Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor with high mortality, and only a limited subset of extensive-stage SCLC (ES-SCLC) patients demonstrate prolonged survival under chemoimmunotherapy, which warrants the exploration of reliable biomarkers. Herein, we built a machine learning-based model using pathomics features extracted from hematoxylin and eosin (H&E)-stained images to classify prognosis and explore its potential association with genomics and TIME.

Methods: We retrospectively recruited ES-SCLC patients receiving first-line chemoimmunotherapy at Nanjing Jinling Hospital between April 2020 and August 2023. Digital H&E-stained whole-slide images were acquired, and targeted next-generation sequencing, programmed death ligand-1 staining, and multiplex immunohistochemical staining for immune cells were performed on a subset of patients. A random survival forest (RSF) model encompassing clinical and pathomics features was established to predict overall survival. The function of putative genes was assessed via single-cell RNA sequencing.

Results and conclusion: During the median follow-up period of 12.12 months, 118 ES-SCLC patients receiving first-line immunotherapy were recruited. The RSF model utilizing three pathomics features and liver metastases, bone metastases, smoking status, and lactate dehydrogenase, could predict the survival of first-line chemoimmunotherapy in patients with ES-SCLC with favorable discrimination and calibration. Underlyingly, the higher RSF-Score potentially indicated more infiltration of CD8+ T cells in the stroma as well as a greater probability of MCL-1 amplification and EP300 mutation. At the single-cell level, MCL-1 was associated with TNFA-NFKB signaling and apoptosis-related processes. Hopefully, this noninvasive model could act as a biomarker for immunotherapy, potentially facilitating precision medicine in the management of ES-SCLC.

背景:小细胞肺癌(SCLC)是一种侵袭性很强的神经内分泌肿瘤,死亡率很高,只有少数广泛期SCLC(ES-SCLC)患者在化疗免疫治疗下能延长生存期,因此需要探索可靠的生物标志物。在此,我们利用从苏木精和伊红(H&E)染色图像中提取的病理组学特征建立了一个基于机器学习的模型,对预后进行分类,并探索其与基因组学和TIME的潜在关联:我们回顾性地招募了2020年4月至2023年8月期间在南京金陵医院接受一线化疗免疫治疗的ES-SCLC患者。我们采集了数字化H&E染色的全切片图像,并对部分患者进行了靶向新一代测序、程序性死亡配体-1染色和免疫细胞多重免疫组化染色。建立了一个包含临床和病理组学特征的随机生存森林(RSF)模型来预测总生存率。通过单细胞RNA测序评估了推测基因的功能:在中位随访期12.12个月期间,共招募了118名接受一线免疫疗法的ES-SCLC患者。利用三个病理组学特征和肝转移、骨转移、吸烟状态及乳酸脱氢酶的RSF模型,可以预测ES-SCLC患者一线化疗免疫治疗的生存率,并具有良好的区分度和校准性。RSF-Score越高,表明基质中CD8+ T细胞浸润越多,MCL-1扩增和EP300突变的可能性越大。在单细胞水平上,MCL-1 与 TNFA-NFKB 信号转导和细胞凋亡相关过程有关。希望这种非侵入性模型能成为免疫疗法的生物标记物,从而促进ES-SCLC治疗的精准医疗。
{"title":"A random survival forest-based pathomics signature classifies immunotherapy prognosis and profiles TIME and genomics in ES-SCLC patients.","authors":"Yuxin Jiang, Yueying Chen, Qinpei Cheng, Wanjun Lu, Yu Li, Xueying Zuo, Qiuxia Wu, Xiaoxia Wang, Fang Zhang, Dong Wang, Qin Wang, Tangfeng Lv, Yong Song, Ping Zhan","doi":"10.1007/s00262-024-03829-9","DOIUrl":"10.1007/s00262-024-03829-9","url":null,"abstract":"<p><strong>Background: </strong>Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor with high mortality, and only a limited subset of extensive-stage SCLC (ES-SCLC) patients demonstrate prolonged survival under chemoimmunotherapy, which warrants the exploration of reliable biomarkers. Herein, we built a machine learning-based model using pathomics features extracted from hematoxylin and eosin (H&E)-stained images to classify prognosis and explore its potential association with genomics and TIME.</p><p><strong>Methods: </strong>We retrospectively recruited ES-SCLC patients receiving first-line chemoimmunotherapy at Nanjing Jinling Hospital between April 2020 and August 2023. Digital H&E-stained whole-slide images were acquired, and targeted next-generation sequencing, programmed death ligand-1 staining, and multiplex immunohistochemical staining for immune cells were performed on a subset of patients. A random survival forest (RSF) model encompassing clinical and pathomics features was established to predict overall survival. The function of putative genes was assessed via single-cell RNA sequencing.</p><p><strong>Results and conclusion: </strong>During the median follow-up period of 12.12 months, 118 ES-SCLC patients receiving first-line immunotherapy were recruited. The RSF model utilizing three pathomics features and liver metastases, bone metastases, smoking status, and lactate dehydrogenase, could predict the survival of first-line chemoimmunotherapy in patients with ES-SCLC with favorable discrimination and calibration. Underlyingly, the higher RSF-Score potentially indicated more infiltration of CD8<sup>+</sup> T cells in the stroma as well as a greater probability of MCL-1 amplification and EP300 mutation. At the single-cell level, MCL-1 was associated with TNFA-NFKB signaling and apoptosis-related processes. Hopefully, this noninvasive model could act as a biomarker for immunotherapy, potentially facilitating precision medicine in the management of ES-SCLC.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11448477/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Toripalimab combined with definitive chemoradiotherapy for locally advanced cervical squamous cell carcinoma patients (TRACE): A single-arm, phase I/II trial. 局部晚期宫颈鳞状细胞癌患者托利帕利单抗联合放化疗(TRACE):单臂 I/II 期试验。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-10-03 DOI: 10.1007/s00262-024-03823-1
Dan Ou, Rong Cai, Wei-Xiang Qi, Can Cui, Lu Cao, Shu-Bei Wang, Huan Li, Tao Ma, Ying Miao, Cheng Xu, Gang Cai, Wei-Guo Cao, Yun-Sheng Gao, Jia-Yi Chen, Hao-Ping Xu

Purpose: This phase I/II trial (ChiCTR2000032879) assessed the safety and efficacy of toripalimab combined with chemoradiotherapy for locally advanced cervical squamous cell carcinoma.

Methods and materials: Twenty-two patients, regardless of their programmed death ligand-1 (PD-L1) status, received toripalimab combined with concurrent chemoradiotherapy (CCRT). CCRT included cisplatin (40 mg/m2, once weekly for 5 weeks), radiotherapy (45-50.4 Gy/25-28 Fx, 5 fractions weekly), followed by brachytherapy (24-30 Gy/3-5 Fx) and toripalimab (240 mg, intravenous) on days 1, 22 and 43 during CCRT. The primary endpoints were safety and 2-year progression-free survival (PFS). The secondary endpoints included 2-year local control (LC), local regional control and overall survival (OS).

Results: All patients successfully completed CCRT and toripalimab treatment. Grade III and higher adverse events (AEs) were observed in 11 patients (11/22, 50%), and no patient experienced grade V AEs. The objective response rate (ORR) was 100%. At the data cutoff (June 30, 2023), the median follow-up was 31.8 months (9.5 to 37.8 months). The 2-year PFS rate was 81.8%. The 2-year LC and local regional control rates were both 95.5%, and the 2-year OS rate was 90.9%.

Conclusions: Toripalimab combined with CCRT achieved good tolerance and showed promising anti-tumor effects in patients with locally advanced cervical cancer.

目的:这项I/II期试验(ChiCTR2000032879)评估了托利帕利单抗联合化放疗治疗局部晚期宫颈鳞癌的安全性和有效性:22名患者,无论其程序性死亡配体-1(PD-L1)状态如何,均接受了托利帕利单抗联合同期化放疗(CCRT)。CCRT包括顺铂(40 mg/m2,每周一次,持续5周)、放疗(45-50.4 Gy/25-28 Fx,每周5次),然后是近距离放射治疗(24-30 Gy/3-5 Fx),以及在CCRT期间的第1、22和43天使用托利帕利单抗(240 mg,静脉注射)。主要终点是安全性和两年无进展生存期(PFS)。次要终点包括2年局部控制(LC)、局部区域控制和总生存期(OS):所有患者都顺利完成了CCRT和托瑞帕利单抗治疗。11名患者(11/22,50%)出现了III级及以上不良反应(AEs),没有患者出现V级不良反应。客观反应率(ORR)为100%。截至数据截止日(2023 年 6 月 30 日),中位随访时间为 31.8 个月(9.5 至 37.8 个月)。2年PFS率为81.8%。2年LC和局部区域控制率均为95.5%,2年OS率为90.9%:结论:托利帕利单抗联合CCRT对局部晚期宫颈癌患者具有良好的耐受性和抗肿瘤效果。
{"title":"Toripalimab combined with definitive chemoradiotherapy for locally advanced cervical squamous cell carcinoma patients (TRACE): A single-arm, phase I/II trial.","authors":"Dan Ou, Rong Cai, Wei-Xiang Qi, Can Cui, Lu Cao, Shu-Bei Wang, Huan Li, Tao Ma, Ying Miao, Cheng Xu, Gang Cai, Wei-Guo Cao, Yun-Sheng Gao, Jia-Yi Chen, Hao-Ping Xu","doi":"10.1007/s00262-024-03823-1","DOIUrl":"10.1007/s00262-024-03823-1","url":null,"abstract":"<p><strong>Purpose: </strong>This phase I/II trial (ChiCTR2000032879) assessed the safety and efficacy of toripalimab combined with chemoradiotherapy for locally advanced cervical squamous cell carcinoma.</p><p><strong>Methods and materials: </strong>Twenty-two patients, regardless of their programmed death ligand-1 (PD-L1) status, received toripalimab combined with concurrent chemoradiotherapy (CCRT). CCRT included cisplatin (40 mg/m<sup>2</sup>, once weekly for 5 weeks), radiotherapy (45-50.4 Gy/25-28 Fx, 5 fractions weekly), followed by brachytherapy (24-30 Gy/3-5 Fx) and toripalimab (240 mg, intravenous) on days 1, 22 and 43 during CCRT. The primary endpoints were safety and 2-year progression-free survival (PFS). The secondary endpoints included 2-year local control (LC), local regional control and overall survival (OS).</p><p><strong>Results: </strong>All patients successfully completed CCRT and toripalimab treatment. Grade III and higher adverse events (AEs) were observed in 11 patients (11/22, 50%), and no patient experienced grade V AEs. The objective response rate (ORR) was 100%. At the data cutoff (June 30, 2023), the median follow-up was 31.8 months (9.5 to 37.8 months). The 2-year PFS rate was 81.8%. The 2-year LC and local regional control rates were both 95.5%, and the 2-year OS rate was 90.9%.</p><p><strong>Conclusions: </strong>Toripalimab combined with CCRT achieved good tolerance and showed promising anti-tumor effects in patients with locally advanced cervical cancer.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447187/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
PD-1 blockade does not improve efficacy of EpCAM-directed CAR T-cell in lung cancer brain metastasis. PD-1阻断不能提高EpCAM引导的CAR T细胞对肺癌脑转移的疗效。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-10-03 DOI: 10.1007/s00262-024-03837-9
Jens Blobner, Laura Dengler, Constantin Eberle, Julika J Herold, Tao Xu, Alexander Beck, Anton Mühlbauer, Katharina J Müller, Nico Teske, Philipp Karschnia, Dominic van den Heuvel, Ferdinand Schallerer, Hellen Ishikawa-Ankerhold, Niklas Thon, Joerg-Christian Tonn, Marion Subklewe, Sebastian Kobold, Patrick N Harter, Veit R Buchholz, Louisa von Baumgarten

Background: Lung cancer brain metastasis has a devastating prognosis, necessitating innovative treatment strategies. While chimeric antigen receptor (CAR) T-cell show promise in hematologic malignancies, their efficacy in solid tumors, including brain metastasis, is limited by the immunosuppressive tumor environment. The PD-L1/PD-1 pathway inhibits CAR T-cell activity in the tumor microenvironment, presenting a potential target to enhance therapeutic efficacy. This study aims to evaluate the impact of anti-PD-1 antibodies on CAR T-cell in treating lung cancer brain metastasis.

Methods: We utilized a murine immunocompetent, syngeneic orthotopic cerebral metastasis model for repetitive intracerebral two-photon laser scanning microscopy, enabling in vivo characterization of red fluorescent tumor cells and CAR T-cell at a single-cell level over time. Red fluorescent EpCAM-transduced Lewis lung carcinoma cells (EpCAM/tdtLL/2 cells) were implanted intracranially. Following the formation of brain metastasis, EpCAM-directed CAR T-cell were injected into adjacent brain tissue, and animals received either anti-PD-1 or an isotype control.

Results: Compared to controls receiving T-cell lacking a CAR, mice receiving EpCAM-directed CAR T-cell showed higher intratumoral CAR T-cell densities in the beginning after intraparenchymal injection. This finding was accompanied with reduced tumor growth and translated into a survival benefit. Additional anti-PD-1 treatment, however, did not affect intratumoral CAR T-cell persistence nor tumor growth and thereby did not provide an additional therapeutic effect.

Conclusion: CAR T-cell therapy for brain malignancies appears promising. However, additional anti-PD-1 treatment did not enhance intratumoral CAR T-cell persistence or effector function, highlighting the need for novel strategies to improve CAR T-cell therapy in solid tumors.

背景:肺癌脑转移的预后极具破坏性,因此需要创新的治疗策略。虽然嵌合抗原受体(CAR)T细胞在血液恶性肿瘤中显示出良好的前景,但它们在实体瘤(包括脑转移瘤)中的疗效却受到免疫抑制性肿瘤环境的限制。PD-L1/PD-1 通路抑制 CAR T 细胞在肿瘤微环境中的活性,为提高疗效提供了潜在靶点。本研究旨在评估抗PD-1抗体对CAR T细胞治疗肺癌脑转移的影响:方法:我们利用小鼠免疫功能健全的同种异体正位脑转移模型进行重复脑内双光子激光扫描显微镜检查,从而在单细胞水平上对红色荧光肿瘤细胞和CAR T细胞随时间变化的情况进行体内表征。红色荧光 EpCAM 转化的 Lewis 肺癌细胞(EpCAM/tdtLL/2 细胞)被植入颅内。在脑转移形成后,将 EpCAM 引导的 CAR T 细胞注射到邻近的脑组织,动物接受抗 PD-1 或同型对照:结果:与接受缺乏CAR的T细胞的对照组相比,接受EpCAM定向CAR T细胞的小鼠在实质内注射后的初期表现出更高的瘤内CAR T细胞密度。这一发现伴随着肿瘤生长的减少,并转化为生存获益。然而,额外的抗PD-1治疗并没有影响瘤内CAR T细胞的持续性或肿瘤生长,因此也没有提供额外的治疗效果:结论:CAR T细胞疗法治疗脑部恶性肿瘤似乎很有前景。然而,额外的抗PD-1治疗并不能增强瘤内CAR T细胞的持久性或效应功能,这凸显出需要新的策略来改善CAR T细胞治疗实体瘤的效果。
{"title":"PD-1 blockade does not improve efficacy of EpCAM-directed CAR T-cell in lung cancer brain metastasis.","authors":"Jens Blobner, Laura Dengler, Constantin Eberle, Julika J Herold, Tao Xu, Alexander Beck, Anton Mühlbauer, Katharina J Müller, Nico Teske, Philipp Karschnia, Dominic van den Heuvel, Ferdinand Schallerer, Hellen Ishikawa-Ankerhold, Niklas Thon, Joerg-Christian Tonn, Marion Subklewe, Sebastian Kobold, Patrick N Harter, Veit R Buchholz, Louisa von Baumgarten","doi":"10.1007/s00262-024-03837-9","DOIUrl":"10.1007/s00262-024-03837-9","url":null,"abstract":"<p><strong>Background: </strong>Lung cancer brain metastasis has a devastating prognosis, necessitating innovative treatment strategies. While chimeric antigen receptor (CAR) T-cell show promise in hematologic malignancies, their efficacy in solid tumors, including brain metastasis, is limited by the immunosuppressive tumor environment. The PD-L1/PD-1 pathway inhibits CAR T-cell activity in the tumor microenvironment, presenting a potential target to enhance therapeutic efficacy. This study aims to evaluate the impact of anti-PD-1 antibodies on CAR T-cell in treating lung cancer brain metastasis.</p><p><strong>Methods: </strong>We utilized a murine immunocompetent, syngeneic orthotopic cerebral metastasis model for repetitive intracerebral two-photon laser scanning microscopy, enabling in vivo characterization of red fluorescent tumor cells and CAR T-cell at a single-cell level over time. Red fluorescent EpCAM-transduced Lewis lung carcinoma cells (<sup>EpCAM/tdt</sup>LL/2 cells) were implanted intracranially. Following the formation of brain metastasis, EpCAM-directed CAR T-cell were injected into adjacent brain tissue, and animals received either anti-PD-1 or an isotype control.</p><p><strong>Results: </strong>Compared to controls receiving T-cell lacking a CAR, mice receiving EpCAM-directed CAR T-cell showed higher intratumoral CAR T-cell densities in the beginning after intraparenchymal injection. This finding was accompanied with reduced tumor growth and translated into a survival benefit. Additional anti-PD-1 treatment, however, did not affect intratumoral CAR T-cell persistence nor tumor growth and thereby did not provide an additional therapeutic effect.</p><p><strong>Conclusion: </strong>CAR T-cell therapy for brain malignancies appears promising. However, additional anti-PD-1 treatment did not enhance intratumoral CAR T-cell persistence or effector function, highlighting the need for novel strategies to improve CAR T-cell therapy in solid tumors.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447167/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
HLA-G neo-expression modifies genetic programs governing tumor cell lines. HLA-G 的新表达改变了肿瘤细胞系的基因程序。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-10-03 DOI: 10.1007/s00262-024-03768-5
Diana Tronik-Le Roux, Marina Daouya, Isabelle Poras, François Desgrandchamps, Edgardo D Carosella

The development of immunotherapies has proved to be clinically encouraging to re-establish the immune function modified by the expression of immune inhibitory molecules in tumors. However, there are still patients with poor survival rates following treatment. The elucidation of molecular mechanisms triggered by the neo-expression of particular IC in tumors would constitute a major step toward better understanding tumor evolution and would help to design future clinical protocols. To this end, we investigate the modifications triggered by the neo-expression of the immune checkpoints HLA-G in ccRCC tumor cells. We demonstrate, for the first time, that HLA-G modifies key genes implicated mainly in tumor development, angiogenesis, calcium flow and mitochondria dynamics. The involvement of HLA-G on the expression of genes belonging to these pathways such as ADAM-12, NCAM1 and NRP1 was confirmed by the CRISPR/Cas9-mediated edition of HLA-G. The data reveal multifaceted roles of HLA-G in tumor cells which are far beyond the well-known function of HLA-G in the immune anti-tumor response. This warrants further investigation of HLA-G and these new partners in tumors of different origin so as to propose future new treatments to improve health patient's outcome.

免疫疗法的发展在临床上证明是令人鼓舞的,它可以重建因肿瘤中免疫抑制分子的表达而改变的免疫功能。然而,仍有一些患者在接受治疗后生存率很低。阐明特定 IC 在肿瘤中的新表达所引发的分子机制将是更好地理解肿瘤演变的重要一步,并有助于设计未来的临床方案。为此,我们研究了免疫检查点 HLA-G 在 ccRCC 肿瘤细胞中的新表达所引发的改变。我们首次证明,HLA-G 会改变主要与肿瘤发生、血管生成、钙流和线粒体动力学有关的关键基因。通过 CRISPR/Cas9 介导的 HLA-G 基因编辑,证实了 HLA-G 参与了 ADAM-12、NCAM1 和 NRP1 等这些通路基因的表达。这些数据揭示了 HLA-G 在肿瘤细胞中的多方面作用,远远超出了人们所熟知的 HLA-G 在免疫抗肿瘤反应中的功能。这就需要进一步研究 HLA-G 和这些新伙伴在不同来源肿瘤中的作用,以便提出未来的新疗法,改善患者的健康状况。
{"title":"HLA-G neo-expression modifies genetic programs governing tumor cell lines.","authors":"Diana Tronik-Le Roux, Marina Daouya, Isabelle Poras, François Desgrandchamps, Edgardo D Carosella","doi":"10.1007/s00262-024-03768-5","DOIUrl":"10.1007/s00262-024-03768-5","url":null,"abstract":"<p><p>The development of immunotherapies has proved to be clinically encouraging to re-establish the immune function modified by the expression of immune inhibitory molecules in tumors. However, there are still patients with poor survival rates following treatment. The elucidation of molecular mechanisms triggered by the neo-expression of particular IC in tumors would constitute a major step toward better understanding tumor evolution and would help to design future clinical protocols. To this end, we investigate the modifications triggered by the neo-expression of the immune checkpoints HLA-G in ccRCC tumor cells. We demonstrate, for the first time, that HLA-G modifies key genes implicated mainly in tumor development, angiogenesis, calcium flow and mitochondria dynamics. The involvement of HLA-G on the expression of genes belonging to these pathways such as ADAM-12, NCAM1 and NRP1 was confirmed by the CRISPR/Cas9-mediated edition of HLA-G. The data reveal multifaceted roles of HLA-G in tumor cells which are far beyond the well-known function of HLA-G in the immune anti-tumor response. This warrants further investigation of HLA-G and these new partners in tumors of different origin so as to propose future new treatments to improve health patient's outcome.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447172/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Immunotherapy may be more appropriate for ERBB2 low-expressing extramammary paget's disease patients: a prognosis analysis and exploration of targeted therapy and immunotherapy of extramammary paget's disease patients. 免疫疗法可能更适合ERBB2低表达的乳腺外乳头状瘤病患者:乳腺外乳头状瘤病患者的预后分析及靶向治疗和免疫疗法探索。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-10-03 DOI: 10.1007/s00262-024-03846-8
Jiawen Yang, Yurong Chen, Xiuyuan Zhang, Ziyan Tong, Shanshan Weng, Ning Zhu, Ying Yuan

Extramammary Paget's disease (EMPD) is a rare cutaneous malignancy characterized by its uncertain etiology and metastatic potential. Surgery remains the first-line clinical treatment for EMPD, but the efficacy of radiotherapy and chemotherapy remains to be fully evaluated, and new therapies for EMPD are urgently needed. In this study, we initially screened 815 EMPD patients in the Surveillance, Epidemiology, and End Results (SEER) database and analyzed their clinical features and prognostic factors. Using the dataset from the Genome Sequence Archive (GSA) database, we subsequently conducted weighted gene coexpression network analysis (WGCNA), gene set enrichment analysis (GSEA), gene set variation analysis (GSVA), and immune infiltration analyses, grouping the samples based on EMPD disease status and the levels of ERBB2 expression. The prognostic analysis based on the SEER database identified increased age at diagnosis, distant metastasis, and receipt of radiotherapy as independent risk factors for EMPD. Moreover, our results indicated that patients who received chemotherapy had worse prognoses than those who did not, highlighting the urgent need for novel treatment approaches for EMPD. Functional analysis of the GSA-derived dataset revealed that EMPD tissues were significantly enriched in immune-related pathways compared with normal skin tissues. Compared with those with high ERBB2 expression, tissues with low ERBB2 expression displayed greater immunogenicity and enrichment of immune pathways, particularly those related to B cells. These findings suggest that patients with low ERBB2 expression are likely to benefit from immunotherapy, especially B-cell-related immunotherapy.

乳腺外Paget病(EMPD)是一种罕见的皮肤恶性肿瘤,其特点是病因不明确且具有转移潜力。手术仍是 EMPD 的一线临床治疗方法,但放疗和化疗的疗效仍有待全面评估,EMPD 急需新疗法。在这项研究中,我们首先从监测、流行病学和最终结果(SEER)数据库中筛选了815名EMPD患者,并分析了他们的临床特征和预后因素。利用基因组序列档案(GSA)数据库中的数据集,我们随后进行了加权基因共表达网络分析(WGCNA)、基因组富集分析(GSEA)、基因组变异分析(GSVA)和免疫浸润分析,并根据EMPD疾病状态和ERBB2表达水平对样本进行了分组。基于SEER数据库的预后分析发现,诊断时年龄增大、远处转移和接受过放疗是EMPD的独立危险因素。此外,我们的研究结果表明,接受化疗的患者比未接受化疗的患者预后更差,这凸显了对新型 EMPD 治疗方法的迫切需求。GSA衍生数据集的功能分析显示,与正常皮肤组织相比,EMPD组织的免疫相关通路明显丰富。与ERBB2高表达的组织相比,ERBB2低表达的组织显示出更强的免疫原性和更丰富的免疫通路,尤其是与B细胞相关的通路。这些研究结果表明,ERBB2表达量低的患者有可能从免疫疗法中获益,尤其是与B细胞相关的免疫疗法。
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引用次数: 0
GPCRs: emerging targets for novel T cell immune checkpoint therapy. GPCR:新型 T 细胞免疫检查点疗法的新兴靶点。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-10-03 DOI: 10.1007/s00262-024-03801-7
Kaitlyn Dickinson, Elliott J Yee, Isaac Vigil, Richard D Schulick, Yuwen Zhu

Although immune checkpoint blockade (ICB) has become the mainstay of treatment for advanced solid organ malignancies, success in revitalizing the host anticancer immune response remains limited. G-protein coupled receptors (GPCRs) are a broad family of cell-surface proteins that have been regarded as main players in regulating the immune system, namely by mediating the activity of T lymphocytes. Among the most novel immunoregulatory GPCRs include GPR171, lysophosphatidic acid receptors (LPARs), GPR68, cannabinoid receptor 2 (CB2), and prostaglandin E receptors, many of which have shown promise in mediating antitumor response via activation of cytotoxic T cells, inhibiting immunosuppressive lymphocytes, and facilitating immune cell infiltration within the tumor microenvironment across multiple types of cancers. This paper reviews our current understanding of some of the most novel GPCRs-their expression patterns, evolving roles within the immune system and cancer, potential therapeutic applications, and perspective for future investigation.

尽管免疫检查点阻断疗法(ICB)已成为晚期实体器官恶性肿瘤的主要治疗方法,但在重振宿主抗癌免疫反应方面取得的成功仍然有限。G 蛋白偶联受体(GPCRs)是一个广泛的细胞表面蛋白家族,一直被认为是调节免疫系统的主要角色,即通过介导 T 淋巴细胞的活性。最新颖的免疫调节GPCR包括GPR171、溶血磷脂酸受体(LPARs)、GPR68、大麻素受体2(CB2)和前列腺素E受体,其中许多都有望通过激活细胞毒性T细胞、抑制免疫抑制淋巴细胞和促进免疫细胞在多种类型癌症的肿瘤微环境中浸润来介导抗肿瘤反应。本文回顾了我们目前对一些最新型 GPCRs 的了解--它们的表达模式、在免疫系统和癌症中不断演变的作用、潜在的治疗应用以及未来研究的前景。
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引用次数: 0
PD-L1+ neutrophils induced NETs in malignant ascites is a potential biomarker in HCC. 恶性腹水中PD-L1+中性粒细胞诱导的NET是HCC的潜在生物标志物。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-10-03 DOI: 10.1007/s00262-024-03833-z
Xiaoyu Sun, Yaoqi Gui, Tai Yang, Lingbing Chen, Yi Zhang, Ling Yan, Weixian Chen, Bo Wang

Background: Since differentiating malignant ascites from benign ascites has always been a clinical difficult, recognition of novel biomarkers in malignant ascites of hepatocellular carcinoma (HCC) patients could be helpful for establishing a diagnosis for HCC patients with ascitic fluids.

Methods: Thirty-five HCC patients with malignant ascites and chronic liver diseases patients with benign ascites were enrolled. Serum and ascites specimens were collected to determine TAN subpopulations and NETs concentration. Then, the correlation between ascitic NETs levels and clinical features were analyzed, and ROC curves were generated to evaluate the diagnostic value of NETs. For in vitro study, fresh neutrophils were employed to explore the underlying mechanism of TAN polarization and NETs formation using RNAseq analysis.

Results: Significantly increased pro-tumor PD-L1+ TANs and higher lactate levels were measured in HCC ascites. RNAseq data showed that lactate regulated genes expression involving PD-L1 expression and NETs formation, suggesting that ascitic lactate might be responsible for tumor progression in TME. Then, NETs-related markers including calprotectin, dsDNA, CitH3, MPO and MPO-DNA were found dramatically elevated in malignant ascites. Next, correlation analysis revealed that ascitic NETs levels positively correlated with LDH, a classic ascitic biochemical indicator. Furthermore, we identified the diagnostic values of NETs in discriminating malignant ascites from benign ascites.

Conclusions: Our findings highlighted that elevated ascitic NETs served as a biomarker in HCC patients with malignant ascites, which provided useful insights for both clinical and basic research for malignant ascites diagnosis and management.

背景:由于恶性腹水与良性腹水的鉴别一直是临床难题,因此识别肝细胞癌(HCC)患者恶性腹水中的新型生物标志物有助于对有腹水的 HCC 患者进行确诊:方法:研究人员招募了 35 名患有恶性腹水的 HCC 患者和患有良性腹水的慢性肝病患者。收集血清和腹水标本,测定 TAN 亚群和 NETs 浓度。然后,分析腹水 NETs 水平与临床特征之间的相关性,并生成 ROC 曲线以评估 NETs 的诊断价值。体外研究采用新鲜中性粒细胞,利用RNAseq分析探讨TAN极化和NETs形成的内在机制:结果:在 HCC 腹水中测得了显著增加的亲肿瘤 PD-L1+ TAN 和较高的乳酸盐水平。RNAseq数据显示,乳酸调节涉及PD-L1表达和NETs形成的基因表达,这表明腹水乳酸可能是TME中肿瘤进展的原因。恶性腹水中的钙蛋白、dsDNA、CitH3、MPO和MPO-DNA等NETs相关标记物显著升高。接着,相关分析表明,腹水 NETs 水平与腹水生化指标 LDH 呈正相关。此外,我们还发现了 NETs 在区分恶性腹水和良性腹水方面的诊断价值:我们的研究结果表明,腹腔 NETs 升高可作为 HCC 恶性腹水患者的生物标志物,这为恶性腹水诊断和管理的临床和基础研究提供了有益的启示。
{"title":"PD-L1<sup>+</sup> neutrophils induced NETs in malignant ascites is a potential biomarker in HCC.","authors":"Xiaoyu Sun, Yaoqi Gui, Tai Yang, Lingbing Chen, Yi Zhang, Ling Yan, Weixian Chen, Bo Wang","doi":"10.1007/s00262-024-03833-z","DOIUrl":"10.1007/s00262-024-03833-z","url":null,"abstract":"<p><strong>Background: </strong>Since differentiating malignant ascites from benign ascites has always been a clinical difficult, recognition of novel biomarkers in malignant ascites of hepatocellular carcinoma (HCC) patients could be helpful for establishing a diagnosis for HCC patients with ascitic fluids.</p><p><strong>Methods: </strong>Thirty-five HCC patients with malignant ascites and chronic liver diseases patients with benign ascites were enrolled. Serum and ascites specimens were collected to determine TAN subpopulations and NETs concentration. Then, the correlation between ascitic NETs levels and clinical features were analyzed, and ROC curves were generated to evaluate the diagnostic value of NETs. For in vitro study, fresh neutrophils were employed to explore the underlying mechanism of TAN polarization and NETs formation using RNAseq analysis.</p><p><strong>Results: </strong>Significantly increased pro-tumor PD-L1<sup>+</sup> TANs and higher lactate levels were measured in HCC ascites. RNAseq data showed that lactate regulated genes expression involving PD-L1 expression and NETs formation, suggesting that ascitic lactate might be responsible for tumor progression in TME. Then, NETs-related markers including calprotectin, dsDNA, CitH3, MPO and MPO-DNA were found dramatically elevated in malignant ascites. Next, correlation analysis revealed that ascitic NETs levels positively correlated with LDH, a classic ascitic biochemical indicator. Furthermore, we identified the diagnostic values of NETs in discriminating malignant ascites from benign ascites.</p><p><strong>Conclusions: </strong>Our findings highlighted that elevated ascitic NETs served as a biomarker in HCC patients with malignant ascites, which provided useful insights for both clinical and basic research for malignant ascites diagnosis and management.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447185/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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Cancer Immunology, Immunotherapy
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