Pub Date : 2024-10-05DOI: 10.1007/s00262-024-03803-5
Allison L Gradone, Vincent T Ma, Alexi Vasbinder, Leslie A Fecher, Sarah Yentz, Salim S Hayek, Christopher D Lao
Background: Immune checkpoint inhibitor (ICI)-mediated myocarditis results in significant morbidity and mortality. At our institution, we noted an increased incidence of ICI-mediated myocarditis cases, leading to further investigation in our database of advanced melanoma patients treated with ICI therapy.
Methods: A single-center, retrospective cohort analysis of patients with advanced melanoma identified cases of ICI-mediated myocarditis and myositis.
Results: 366 patients with advanced melanoma received a dose of ICI from September 2014 to October 2019. Of these patients, there were 0 cases of ICI-mediated myocarditis (0%, 95% CI 0%-1.0%) and 2 cases of ICI-mediated myositis (0.55%, 95% CI 0.07%-1.96%). From November 2019 to December 2021, an additional 246 patients with advanced melanoma were identified. Of these patients, 10 (4.1%, 95% CI 1.97%-7.35%) developed ICI-mediated myocarditis and 10 developed ICI-mediated myositis.
Conclusion: Our study suggests an increase in prevalence of ICI-mediated muscle damage including myositis and myocarditis in the COVID-19 era. Differentiation of these patients and further risk stratification may allow for development of guidelines for nuanced management of this serious complication.
背景:免疫检查点抑制剂(ICI)介导的心肌炎会导致严重的发病率和死亡率。在我们医院,我们注意到 ICI 介导的心肌炎病例的发病率有所上升,因此我们对接受 ICI 治疗的晚期黑色素瘤患者数据库进行了进一步调查:方法:对晚期黑色素瘤患者进行单中心回顾性队列分析,确定ICI介导的心肌炎和肌炎病例:从2014年9月至2019年10月,366名晚期黑色素瘤患者接受了ICI治疗。在这些患者中,ICI介导的心肌炎病例为0例(0%,95% CI 0%-1.0%),ICI介导的肌炎病例为2例(0.55%,95% CI 0.07%-1.96%)。从2019年11月到2021年12月,又发现了246例晚期黑色素瘤患者。在这些患者中,10人(4.1%,95% CI 1.97%-7.35%)发生了ICI介导的心肌炎,10人发生了ICI介导的肌炎:我们的研究表明,在 COVID-19 时代,ICI 介导的肌肉损伤(包括肌炎和心肌炎)的发病率有所上升。对这些患者进行区分并进一步进行风险分层,可为这一严重并发症的精细化管理制定指南。
{"title":"Increased myositis and possible myocarditis in melanoma patients treated with immune checkpoint inhibitors in the COVID-19 era.","authors":"Allison L Gradone, Vincent T Ma, Alexi Vasbinder, Leslie A Fecher, Sarah Yentz, Salim S Hayek, Christopher D Lao","doi":"10.1007/s00262-024-03803-5","DOIUrl":"10.1007/s00262-024-03803-5","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint inhibitor (ICI)-mediated myocarditis results in significant morbidity and mortality. At our institution, we noted an increased incidence of ICI-mediated myocarditis cases, leading to further investigation in our database of advanced melanoma patients treated with ICI therapy.</p><p><strong>Methods: </strong>A single-center, retrospective cohort analysis of patients with advanced melanoma identified cases of ICI-mediated myocarditis and myositis.</p><p><strong>Results: </strong>366 patients with advanced melanoma received a dose of ICI from September 2014 to October 2019. Of these patients, there were 0 cases of ICI-mediated myocarditis (0%, 95% CI 0%-1.0%) and 2 cases of ICI-mediated myositis (0.55%, 95% CI 0.07%-1.96%). From November 2019 to December 2021, an additional 246 patients with advanced melanoma were identified. Of these patients, 10 (4.1%, 95% CI 1.97%-7.35%) developed ICI-mediated myocarditis and 10 developed ICI-mediated myositis.</p><p><strong>Conclusion: </strong>Our study suggests an increase in prevalence of ICI-mediated muscle damage including myositis and myocarditis in the COVID-19 era. Differentiation of these patients and further risk stratification may allow for development of guidelines for nuanced management of this serious complication.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"73 12","pages":"259"},"PeriodicalIF":5.4,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11456101/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142379131","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}
Background: Glioblastoma multiforme (GBM) is the most lethal primary brain tumor for which novel therapies are needed. Recently, chimeric antigen receptor (CAR) T cell therapy has been shown to be effective against GBM, but it is a personalized medicine and requires high cost and long time for the cell production. CAR-transduced natural killer (NK) cells can be used for "off-the-shelf" cellular immunotherapy because they do not induce graft-versus-host disease. Therefore, we aimed to analyze the anti-GBM effect of CAR-T or NK cells targeting B7-H3, which is known to be highly expressed in GBM.
Methods: CAR-T cells targeting B7-H3 were generated using previously reported anti-B7-H3 scFv sequences. Cord blood (CB)-derived NK cells transduced with the B7-H3 CAR were also generated. Their anti-GBM effect was analyzed in vitro. The antitumor effect of intracranial injection of the B7-H3 CAR-T or NK cells was investigated in an in vivo xenograft model with patient-derived GBM cells.
Results: Both B7-H3 CAR-T cells and CAR-NK cells exhibited marked cytotoxicity against patient-derived GBM cells in vitro. Furthermore, intracranial injection of CAR-T cells and CAR-NK cells targeting B7-H3 resulted in a significant antitumor effect against patient-derived GBM xenografts.
Conclusion: Not only CAR-T cells but also CB-derived CAR-NK cells targeting B7-H3 may have the potential to eliminate GBM cells.
{"title":"Antitumor effects of intracranial injection of B7-H3-targeted Car-T and Car-Nk cells in a patient-derived glioblastoma xenograft model.","authors":"Tetsuro Tachi, Noriyuki Kijima, Hideki Kuroda, Syunya Ikeda, Koki Murakami, Tomoyoshi Nakagawa, Moto Yaga, Kanji Nakagawa, Reina Utsugi, Ryuichi Hirayama, Yoshiko Okita, Naoki Kagawa, Haruhiko Kishima, Chihaya Imai, Naoki Hosen","doi":"10.1007/s00262-024-03808-0","DOIUrl":"10.1007/s00262-024-03808-0","url":null,"abstract":"<p><strong>Background: </strong>Glioblastoma multiforme (GBM) is the most lethal primary brain tumor for which novel therapies are needed. Recently, chimeric antigen receptor (CAR) T cell therapy has been shown to be effective against GBM, but it is a personalized medicine and requires high cost and long time for the cell production. CAR-transduced natural killer (NK) cells can be used for \"off-the-shelf\" cellular immunotherapy because they do not induce graft-versus-host disease. Therefore, we aimed to analyze the anti-GBM effect of CAR-T or NK cells targeting B7-H3, which is known to be highly expressed in GBM.</p><p><strong>Methods: </strong>CAR-T cells targeting B7-H3 were generated using previously reported anti-B7-H3 scFv sequences. Cord blood (CB)-derived NK cells transduced with the B7-H3 CAR were also generated. Their anti-GBM effect was analyzed in vitro. The antitumor effect of intracranial injection of the B7-H3 CAR-T or NK cells was investigated in an in vivo xenograft model with patient-derived GBM cells.</p><p><strong>Results: </strong>Both B7-H3 CAR-T cells and CAR-NK cells exhibited marked cytotoxicity against patient-derived GBM cells in vitro. Furthermore, intracranial injection of CAR-T cells and CAR-NK cells targeting B7-H3 resulted in a significant antitumor effect against patient-derived GBM xenografts.</p><p><strong>Conclusion: </strong>Not only CAR-T cells but also CB-derived CAR-NK cells targeting B7-H3 may have the potential to eliminate GBM cells.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"73 12","pages":"256"},"PeriodicalIF":5.4,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11456075/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142379129","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}
Pub Date : 2024-10-05DOI: 10.1007/s00262-024-03848-6
Zhenyang Geng, Feng Li, Zhichang Yang, Bowen Li, Yifan Xu, Bin Wu, Yinliang Sheng, Ping Yuan, Lan Huang, Yu Qi
Neoadjuvant chemoimmunotherapy (NACI) has significant implications for the treatment of esophageal cancer. However, its clinical efficacy varies considerably among patients, necessitating further investigation into the underlying mechanisms. The rapid advancement of single-cell RNA sequencing (scRNA-seq) technology facilitates the analysis of patient heterogeneity at the cellular level, particularly regarding treatment outcomes. In this study, we first analyzed scRNA-seq data of esophageal squamous cell carcinoma (ESCC) following NACI, obtained from the Gene Expression Omnibus (GEO) database. After performing dimensionality reduction, clustering, and annotation on the scRNA-seq data, we employed CellChat to investigate differences in cell-cell communication among samples from distinct efficacy groups. The results indicated that macrophages in the non-responder exhibited stronger cell communication intensity compared to those in responders, with SPP1 and GALECTIN signals showing the most significant differences between the two groups. This finding underscores the crucial role of macrophages in the efficacy of NACI. Subsequently, reclustering of macrophages revealed that Mac-SPP1 may be primarily responsible for treatment resistance, while Mac-C1QC appears to promote T cell activation. Finally, we conducted transcriptome sequencing on ESCC tissues obtained from 32 patients who underwent surgery following NACI. Utilizing CIBERSORT, CIBERSORTx, and WGCNA, we analyzed the heterogeneity of tumor microenvironment among different efficacy groups and validated the correlation between SPP1+ macrophages and resistance to NACI in ESCC using publicly available transcriptome sequencing datasets. These findings suggest that SPP1+ macrophages may represent a key factor contributing to resistance against NACI in ESCC.
{"title":"Integrative analyses of bulk and single-cell RNA-seq reveals the correlation between SPP1<sup>+</sup> macrophages and resistance to neoadjuvant chemoimmunotherapy in esophageal squamous cell carcinoma.","authors":"Zhenyang Geng, Feng Li, Zhichang Yang, Bowen Li, Yifan Xu, Bin Wu, Yinliang Sheng, Ping Yuan, Lan Huang, Yu Qi","doi":"10.1007/s00262-024-03848-6","DOIUrl":"10.1007/s00262-024-03848-6","url":null,"abstract":"<p><p>Neoadjuvant chemoimmunotherapy (NACI) has significant implications for the treatment of esophageal cancer. However, its clinical efficacy varies considerably among patients, necessitating further investigation into the underlying mechanisms. The rapid advancement of single-cell RNA sequencing (scRNA-seq) technology facilitates the analysis of patient heterogeneity at the cellular level, particularly regarding treatment outcomes. In this study, we first analyzed scRNA-seq data of esophageal squamous cell carcinoma (ESCC) following NACI, obtained from the Gene Expression Omnibus (GEO) database. After performing dimensionality reduction, clustering, and annotation on the scRNA-seq data, we employed CellChat to investigate differences in cell-cell communication among samples from distinct efficacy groups. The results indicated that macrophages in the non-responder exhibited stronger cell communication intensity compared to those in responders, with SPP1 and GALECTIN signals showing the most significant differences between the two groups. This finding underscores the crucial role of macrophages in the efficacy of NACI. Subsequently, reclustering of macrophages revealed that Mac-SPP1 may be primarily responsible for treatment resistance, while Mac-C1QC appears to promote T cell activation. Finally, we conducted transcriptome sequencing on ESCC tissues obtained from 32 patients who underwent surgery following NACI. Utilizing CIBERSORT, CIBERSORTx, and WGCNA, we analyzed the heterogeneity of tumor microenvironment among different efficacy groups and validated the correlation between SPP1<sup>+</sup> macrophages and resistance to NACI in ESCC using publicly available transcriptome sequencing datasets. These findings suggest that SPP1<sup>+</sup> macrophages may represent a key factor contributing to resistance against NACI in ESCC.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"73 12","pages":"257"},"PeriodicalIF":5.4,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11455823/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142379132","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}
Pub Date : 2024-10-05DOI: 10.1007/s00262-024-03812-4
Shijin Yuan, Yan Xia, Lihong Shen, Liuqing Ye, Lisha Li, Lifen Chen, Xinyou Xie, Haizhou Lou, Jun Zhang
{"title":"Correction to: Development of nomograms to predict therapeutic response and prognosis of non-small cell lung cancer patients treated with anti-PD-1 antibody.","authors":"Shijin Yuan, Yan Xia, Lihong Shen, Liuqing Ye, Lisha Li, Lifen Chen, Xinyou Xie, Haizhou Lou, Jun Zhang","doi":"10.1007/s00262-024-03812-4","DOIUrl":"10.1007/s00262-024-03812-4","url":null,"abstract":"","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"73 12","pages":"258"},"PeriodicalIF":4.6,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11455839/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142379130","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}
Pub Date : 2024-10-03DOI: 10.1007/s00262-024-03838-8
Sanyuan Shi, Luchen Zhang, Anjie Zheng, Fang Xie, Samuel Kesse, Yang Yang, Jinliang Peng, Yuhong Xu
Background: Tumor-reactive T cells play a crucial role in anti-tumor responses, but T cells induced by DNA vaccination are time-consuming processes and exhibit limited anti-tumor efficacy. Therefore, we evaluated the anti-tumor effectiveness of reactive T cells elicited by electroporation (EP)-mediated DNA vaccine targeting epidermal growth factor receptor variant III (pEGFRvIII plasmid), in conjunction with adoptive cell therapy (ACT), involving the transfer of lymphocytes from a pEGFRvIII EP-vaccinated healthy donor.
Methods: The validation of the established pEGFRvIII plasmid and EGFRvIII-positive cell model was confirmed through immunofluorescence and western blot analysis. Flow cytometry and cytotoxicity assays were performed to evaluate the functionality of antigen-specific reactive T cells induced by EP-mediated pEGFRvIII vaccines, ACT, or their combination. The anti-tumor effectiveness of EP-mediated pEGFRvIII vaccines alone or combined with ACT was evaluated in the B16F10-EGFRvIII tumor model.
Results: EP-mediated pEGFRvIII vaccines elicited serum antibodies and a robust cellular immune response in both healthy and tumor-bearing mice. However, this response only marginally inhibited early-stage tumor growth in established tumor models. EP-mediated pEGFRvIII vaccination followed by adoptive transfer of lymphocytes from vaccinated healthy donors led to notable anti-tumor efficacy, attributed to the synergistic action of antigen-specific CD4+ Th1 cells supplemented by ACT and antigen-specific CD8+ T cells elicited by the EP-mediated DNA vaccination.
Conclusions: Our preclinical studies results demonstrate an enhanced anti-tumor efficacy of EP-mediated DNA vaccination boosted with adoptively transferred, vaccinated healthy donor-derived allogeneic lymphocytes.
背景:肿瘤反应性 T 细胞在抗肿瘤反应中起着至关重要的作用,但 DNA 疫苗接种诱导的 T 细胞需要耗费大量时间,且抗肿瘤效果有限。因此,我们评估了电穿孔(EP)介导的针对表皮生长因子受体变异体 III 的 DNA 疫苗(pEGFRvIII 质粒)诱导的反应性 T 细胞的抗肿瘤效果,同时还评估了采用细胞疗法(ACT),即从接种了 pEGFRvIII EP 疫苗的健康供体中转移淋巴细胞:方法:通过免疫荧光和 Western 印迹分析确认了已建立的 pEGFRvIII 质粒和 EGFRvIII 阳性细胞模型。流式细胞术和细胞毒性试验评估了 EP 介导的 pEGFRvIII 疫苗、ACT 或它们的组合诱导的抗原特异性反应 T 细胞的功能。在B16F10-EGFRvIII肿瘤模型中评估了EP介导的pEGFRvIII疫苗单独使用或与ACT联合使用的抗肿瘤效果:结果:EP介导的 pEGFRvIII 疫苗可在健康小鼠和肿瘤小鼠体内激发血清抗体和强大的细胞免疫反应。然而,在已建立的肿瘤模型中,这种反应只能在一定程度上抑制早期肿瘤的生长。EP介导的pEGFRvIII疫苗接种后,再采用接种过疫苗的健康供体的淋巴细胞进行转移,可获得显著的抗肿瘤疗效,这归功于ACT补充的抗原特异性CD4+ Th1细胞和EP介导的DNA疫苗接种激发的抗原特异性CD8+ T细胞的协同作用:我们的临床前研究结果表明,EP介导的DNA疫苗接种与被收养转移、接种健康供体来源的异体淋巴细胞协同作用,可增强抗肿瘤疗效。
{"title":"Enhanced anti-tumor efficacy of electroporation (EP)-mediated DNA vaccine boosted by allogeneic lymphocytes in pre-established tumor models.","authors":"Sanyuan Shi, Luchen Zhang, Anjie Zheng, Fang Xie, Samuel Kesse, Yang Yang, Jinliang Peng, Yuhong Xu","doi":"10.1007/s00262-024-03838-8","DOIUrl":"10.1007/s00262-024-03838-8","url":null,"abstract":"<p><strong>Background: </strong>Tumor-reactive T cells play a crucial role in anti-tumor responses, but T cells induced by DNA vaccination are time-consuming processes and exhibit limited anti-tumor efficacy. Therefore, we evaluated the anti-tumor effectiveness of reactive T cells elicited by electroporation (EP)-mediated DNA vaccine targeting epidermal growth factor receptor variant III (pEGFRvIII plasmid), in conjunction with adoptive cell therapy (ACT), involving the transfer of lymphocytes from a pEGFRvIII EP-vaccinated healthy donor.</p><p><strong>Methods: </strong>The validation of the established pEGFRvIII plasmid and EGFRvIII-positive cell model was confirmed through immunofluorescence and western blot analysis. Flow cytometry and cytotoxicity assays were performed to evaluate the functionality of antigen-specific reactive T cells induced by EP-mediated pEGFRvIII vaccines, ACT, or their combination. The anti-tumor effectiveness of EP-mediated pEGFRvIII vaccines alone or combined with ACT was evaluated in the B16F10-EGFRvIII tumor model.</p><p><strong>Results: </strong>EP-mediated pEGFRvIII vaccines elicited serum antibodies and a robust cellular immune response in both healthy and tumor-bearing mice. However, this response only marginally inhibited early-stage tumor growth in established tumor models. EP-mediated pEGFRvIII vaccination followed by adoptive transfer of lymphocytes from vaccinated healthy donors led to notable anti-tumor efficacy, attributed to the synergistic action of antigen-specific CD4<sup>+</sup> Th1 cells supplemented by ACT and antigen-specific CD8<sup>+</sup> T cells elicited by the EP-mediated DNA vaccination.</p><p><strong>Conclusions: </strong>Our preclinical studies results demonstrate an enhanced anti-tumor efficacy of EP-mediated DNA vaccination boosted with adoptively transferred, vaccinated healthy donor-derived allogeneic lymphocytes.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"73 12","pages":"248"},"PeriodicalIF":5.4,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447239/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364448","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}
Pub Date : 2024-10-03DOI: 10.1007/s00262-024-03842-y
Patrick Reimann, Ilektra-Antonia Mavroeidi, Jonathan Burghofer, Hossein Taghizadeh, Gerald Webersinke, Stefan Kasper, Georg Schreil, Darius Morariu, Andreas Reichinger, Hideo Andreas Baba, Patrick Kirchweger, Martin Schuler, Angela Djanani, Gerald W Prager, Holger Rumpold, Magdalena Benda, Eva-Maria Schneider, Sylvia Mink, Thomas Winder, Bernhard Doleschal
Introduction: This study assesses the effectiveness of durvalumab with platinum and gemcitabine for biliary tract cancers (BTC). It aims to confirm the TOPAZ-1 trial results in a real-world context and explore the link between BTC molecular profiles and patient outcomes.
Methods: A retrospective analysis was conducted on 102 BTC patients treated with durvalumab, platinum, and gemcitabine at five cancer centers in Austria and one in Germany from 2022 to 2024. Molecular profiling used targeted DNA and RNA assays. Clinical endpoints, including progression-free survival (PFS) and overall survival (OS), were assessed using log-rank tests and Cox regression, with correlations to second-line molecular-targeted therapies.
Results: Among 102 patients, 60.8% had intrahepatic cholangiocarcinoma. The treatment achieved a disease control rate of 71.57% and an overall response rate of 35.11%. Median PFS was 6.51 months, and OS was 13.61 months. Patients under 65 had significantly better OS. Alterations in chromatin remodeling or homologous recombination repair genes were not predictive of survival benefit (HR: 0.45; p = 0.851 and HR: 1.63; p = 0.26, respectively). Patients with molecular-informed second-line therapy showed a trend toward survival benefit (HR: 0.23; p = 0.052).
Conclusion: This study confirms the phase 3 trial results of durvalumab with platinum and gemcitabine, providing a substantial real-world dataset with detailed molecular characterization. No specific patient subgroup showed a markedly better response to durvalumab based on conventional NGS panels. Further research is needed to explore the link between immunotherapy responses and molecular subgroups.
{"title":"Exploring the impact of durvalumab on biliary tract cancer: insights from real-world clinical data.","authors":"Patrick Reimann, Ilektra-Antonia Mavroeidi, Jonathan Burghofer, Hossein Taghizadeh, Gerald Webersinke, Stefan Kasper, Georg Schreil, Darius Morariu, Andreas Reichinger, Hideo Andreas Baba, Patrick Kirchweger, Martin Schuler, Angela Djanani, Gerald W Prager, Holger Rumpold, Magdalena Benda, Eva-Maria Schneider, Sylvia Mink, Thomas Winder, Bernhard Doleschal","doi":"10.1007/s00262-024-03842-y","DOIUrl":"10.1007/s00262-024-03842-y","url":null,"abstract":"<p><strong>Introduction: </strong>This study assesses the effectiveness of durvalumab with platinum and gemcitabine for biliary tract cancers (BTC). It aims to confirm the TOPAZ-1 trial results in a real-world context and explore the link between BTC molecular profiles and patient outcomes.</p><p><strong>Methods: </strong>A retrospective analysis was conducted on 102 BTC patients treated with durvalumab, platinum, and gemcitabine at five cancer centers in Austria and one in Germany from 2022 to 2024. Molecular profiling used targeted DNA and RNA assays. Clinical endpoints, including progression-free survival (PFS) and overall survival (OS), were assessed using log-rank tests and Cox regression, with correlations to second-line molecular-targeted therapies.</p><p><strong>Results: </strong>Among 102 patients, 60.8% had intrahepatic cholangiocarcinoma. The treatment achieved a disease control rate of 71.57% and an overall response rate of 35.11%. Median PFS was 6.51 months, and OS was 13.61 months. Patients under 65 had significantly better OS. Alterations in chromatin remodeling or homologous recombination repair genes were not predictive of survival benefit (HR: 0.45; p = 0.851 and HR: 1.63; p = 0.26, respectively). Patients with molecular-informed second-line therapy showed a trend toward survival benefit (HR: 0.23; p = 0.052).</p><p><strong>Conclusion: </strong>This study confirms the phase 3 trial results of durvalumab with platinum and gemcitabine, providing a substantial real-world dataset with detailed molecular characterization. No specific patient subgroup showed a markedly better response to durvalumab based on conventional NGS panels. Further research is needed to explore the link between immunotherapy responses and molecular subgroups.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"73 12","pages":"251"},"PeriodicalIF":5.4,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447177/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364449","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}
The hemagglutinating virus of Japan envelope (HVJ-E) is an inactivated Sendai virus particle with antitumor effect and inducing antitumor immunity. However, its dosage and efficacy have not been verified. We conducted a phase I clinical study on chemotherapy-resistant malignant pleural mesothelioma (MPM) aiming to determine the recommended dosage for a phase II study through dose-limiting toxicity and evaluate HVJ-E's preliminary efficacy. HVJ-E was administered intratumorally and subcutaneously to the patients with chemotherapy-resistant MPM. While no serious adverse events occurred, known adverse events of HVJ-E were observed. In the preliminary antitumor efficacy using modified response evaluation criteria in solid tumors (RECIST) criteria, three low-dose patients exhibited progressive disease, while all high-dose patients achieved stable disease, yielding disease control rates (DCRs) of 0% and 100%, respectively. Furthermore, the dose-dependent effect of HVJ-E revealed on DCR modified by RECIST and the baseline changes in target lesion size (by CT and SUL-peak; p < 0.05). Comparing targeted lesions receiving intratumoral HVJ-E with non-injected ones, while no clear difference existed at the end of the study, follow-up cases suggested stronger antitumor effects with intratumoral administration. Our findings suggest that HVJ-E could be safely administered to patients with chemotherapy-resistant MPM at both study doses. HVJ-E exhibited some antitumor activity against chemotherapy-resistant MPM, and higher doses tended to have stronger antitumor effects than lower doses. Consequently, a phase II clinical trial with higher HVJ-E doses has been conducted for MPM treatment. Trial registration number: UMIN Clinical Trials Registry (#UMIN000019345).
日本血凝病毒包膜(HVJ-E)是一种灭活的仙台病毒颗粒,具有抗肿瘤作用,可诱导抗肿瘤免疫。然而,其剂量和疗效尚未得到验证。我们对化疗耐药的恶性胸膜间皮瘤(MPM)进行了 I 期临床研究,旨在通过剂量限制毒性确定 II 期研究的推荐剂量,并评估 HVJ-E 的初步疗效。HVJ-E 经瘤内和皮下给药给耐化疗 MPM 患者。虽然没有发生严重不良事件,但观察到了 HVJ-E 的已知不良事件。在采用改良的实体瘤反应评价标准(RECIST)进行的初步抗肿瘤疗效研究中,有三名低剂量患者的病情出现进展,而所有高剂量患者的病情均趋于稳定,疾病控制率(DCR)分别为0%和100%。此外,HVJ-E对RECIST标准修改后的DCR和靶病灶大小的基线变化(通过CT和SUL-peak;p
{"title":"Dose-escalation, tolerability, and efficacy of intratumoral and subcutaneous injection of hemagglutinating virus of Japan envelope (HVJ-E) against chemotherapy-resistant malignant pleural mesothelioma: a clinical trial.","authors":"Kazuma Sakura, Muneyoshi Kuroyama, Yasushi Shintani, Soichiro Funaki, Shinji Atagi, Yoshihisa Kadota, Kozo Kuribayashi, Takashi Kijima, Takashi Nakano, Toshihiro Nakajima, Masao Sasai, Meinoshin Okumura, Yasufumi Kaneda","doi":"10.1007/s00262-024-03815-1","DOIUrl":"10.1007/s00262-024-03815-1","url":null,"abstract":"<p><p>The hemagglutinating virus of Japan envelope (HVJ-E) is an inactivated Sendai virus particle with antitumor effect and inducing antitumor immunity. However, its dosage and efficacy have not been verified. We conducted a phase I clinical study on chemotherapy-resistant malignant pleural mesothelioma (MPM) aiming to determine the recommended dosage for a phase II study through dose-limiting toxicity and evaluate HVJ-E's preliminary efficacy. HVJ-E was administered intratumorally and subcutaneously to the patients with chemotherapy-resistant MPM. While no serious adverse events occurred, known adverse events of HVJ-E were observed. In the preliminary antitumor efficacy using modified response evaluation criteria in solid tumors (RECIST) criteria, three low-dose patients exhibited progressive disease, while all high-dose patients achieved stable disease, yielding disease control rates (DCRs) of 0% and 100%, respectively. Furthermore, the dose-dependent effect of HVJ-E revealed on DCR modified by RECIST and the baseline changes in target lesion size (by CT and SUL-peak; p < 0.05). Comparing targeted lesions receiving intratumoral HVJ-E with non-injected ones, while no clear difference existed at the end of the study, follow-up cases suggested stronger antitumor effects with intratumoral administration. Our findings suggest that HVJ-E could be safely administered to patients with chemotherapy-resistant MPM at both study doses. HVJ-E exhibited some antitumor activity against chemotherapy-resistant MPM, and higher doses tended to have stronger antitumor effects than lower doses. Consequently, a phase II clinical trial with higher HVJ-E doses has been conducted for MPM treatment. Trial registration number: UMIN Clinical Trials Registry (#UMIN000019345).</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"73 12","pages":"243"},"PeriodicalIF":5.4,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447170/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364445","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}
Pub Date : 2024-10-03DOI: 10.1007/s00262-024-03835-x
Melissa Maxwell, Dingxue Yan, Brianna Rivest, Andrew Boone, James Cardia, Elfriede Noessner
Natural killer (NK) cells are frontline defenders against cancer and are capable of recognizing and eliminating tumor cells without prior sensitization or antigen presentation. Due to their unique HLA mismatch tolerance, they are ideal for adoptive cell therapy (ACT) because of their ability to minimize graft-versus-host-disease risk. The therapeutic efficacy of NK cells is limited in part by inhibitory immune checkpoint receptors, which are upregulated upon interaction with cancer cells and the tumor microenvironment. Overexpression of inhibitory receptors reduces NK cell-mediated cytotoxicity by impairing the ability of NK cells to secrete effector cytokines and cytotoxic granules. T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT), a well-known checkpoint receptor involved in T-cell exhaustion, has recently been implicated in the exhaustion of NK cells. Overcoming TIGIT-mediated inhibition of NK cells may allow for a more potent antitumor response following ACT. Here, we describe a novel approach to TIGIT inhibition using self-delivering RNAi compounds (INTASYL™) that incorporates the features of RNAi and antisense technology. INTASYL compounds demonstrate potent activity and stability, are rapidly and efficiently taken up by cells, and can be easily incorporated into cell product manufacturing. INTASYL PH-804, which targets TIGIT, suppresses TIGIT mRNA and protein expression in NK cells, resulting in increased cytotoxic capacity and enhanced tumor cell killing in vitro. Delivering PH-804 to NK cells before ACT has emerged as a promising strategy to counter TIGIT inhibition, thereby improving the antitumor response. This approach offers the potential for more potent off-the-shelf products for adoptive cell therapy, particularly for hematological malignancies.
自然杀伤(NK)细胞是抗癌的前线卫士,能够识别并消灭肿瘤细胞,而无需事先进行致敏或抗原递呈。由于其独特的 HLA 错配耐受性,它们是采用细胞疗法 (ACT) 的理想选择,因为它们能够最大限度地降低移植物抗宿主疾病的风险。NK 细胞的疗效部分受到抑制性免疫检查点受体的限制,这些受体在与癌细胞和肿瘤微环境相互作用时会上调。抑制性受体的过度表达会损害 NK 细胞分泌效应细胞因子和细胞毒性颗粒的能力,从而降低 NK 细胞介导的细胞毒性。具有免疫球蛋白和 ITIM 结构域的 T 细胞免疫受体(TIGIT)是众所周知的参与 T 细胞衰竭的检查点受体,最近也被认为与 NK 细胞的衰竭有关。克服 TIGIT 介导的 NK 细胞抑制可能使 ACT 后的抗肿瘤反应更有效。在这里,我们介绍了一种利用自传递 RNAi 化合物(INTASYL™)抑制 TIGIT 的新方法,该方法结合了 RNAi 和反义技术的特点。INTASYL 化合物具有强大的活性和稳定性,能快速、高效地被细胞吸收,并能方便地融入细胞产品生产中。INTASYL PH-804 以 TIGIT 为靶标,可抑制 NK 细胞中 TIGIT mRNA 和蛋白的表达,从而提高细胞毒性能力,增强体外杀伤肿瘤细胞的能力。在 ACT 前向 NK 细胞释放 PH-804 已成为对抗 TIGIT 抑制从而改善抗肿瘤反应的一种有前途的策略。这种方法有望为采用细胞疗法,特别是血液恶性肿瘤的治疗提供更有效的现成产品。
{"title":"INTASYL self-delivering RNAi decreases TIGIT expression, enhancing NK cell cytotoxicity: a potential application to increase the efficacy of NK adoptive cell therapy against cancer.","authors":"Melissa Maxwell, Dingxue Yan, Brianna Rivest, Andrew Boone, James Cardia, Elfriede Noessner","doi":"10.1007/s00262-024-03835-x","DOIUrl":"10.1007/s00262-024-03835-x","url":null,"abstract":"<p><p>Natural killer (NK) cells are frontline defenders against cancer and are capable of recognizing and eliminating tumor cells without prior sensitization or antigen presentation. Due to their unique HLA mismatch tolerance, they are ideal for adoptive cell therapy (ACT) because of their ability to minimize graft-versus-host-disease risk. The therapeutic efficacy of NK cells is limited in part by inhibitory immune checkpoint receptors, which are upregulated upon interaction with cancer cells and the tumor microenvironment. Overexpression of inhibitory receptors reduces NK cell-mediated cytotoxicity by impairing the ability of NK cells to secrete effector cytokines and cytotoxic granules. T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT), a well-known checkpoint receptor involved in T-cell exhaustion, has recently been implicated in the exhaustion of NK cells. Overcoming TIGIT-mediated inhibition of NK cells may allow for a more potent antitumor response following ACT. Here, we describe a novel approach to TIGIT inhibition using self-delivering RNAi compounds (INTASYL™) that incorporates the features of RNAi and antisense technology. INTASYL compounds demonstrate potent activity and stability, are rapidly and efficiently taken up by cells, and can be easily incorporated into cell product manufacturing. INTASYL PH-804, which targets TIGIT, suppresses TIGIT mRNA and protein expression in NK cells, resulting in increased cytotoxic capacity and enhanced tumor cell killing in vitro. Delivering PH-804 to NK cells before ACT has emerged as a promising strategy to counter TIGIT inhibition, thereby improving the antitumor response. This approach offers the potential for more potent off-the-shelf products for adoptive cell therapy, particularly for hematological malignancies.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"73 12","pages":"239"},"PeriodicalIF":5.4,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447204/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364453","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}
Pub Date : 2024-10-03DOI: 10.1007/s00262-024-03840-0
Xinrui Chen, Yan Qin, Xuemin Xue, Zucheng Xie, Tongji Xie, Liling Huang, Haohua Zhu, Lina Gao, Jiangtao Li, Jianliang Yang, Lin Gui, Sheng Yang, Haizhu Chen, Xiaoli Feng, Yuankai Shi
Patients with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) show varied responses to PD-1 monoclonal antibody (mAb) containing regimens. The mechanisms and predictive biomarkers for the efficacy of this regimen are unclear. This study retrospectively collected r/r DLBCL patients who received PD-1 mAb and rituximab regimens as salvage therapy. Clinical and genomic features were collected, and mechanisms were explored by multiplex immunofluorescence and digital spatial profiling. An artificial neural network (ANN) model was constructed to predict the response. Between October 16th, 2018 and May 4th, 2023, 50 r/r DLBCL patients were collected, 29 were response patients and 21 were non-response patients. CREBBP (p = 0.029) and TP53 (p = 0.015) alterations were statistically higher in non-response patients. Patients with PD-L1 CPS ≥ 5 were correlated with a longer overall survival (OS) than those with PD-L1 CPS < 5 (median OS: not reached vs. 9.7 months, hazard ratio [HR]: 3.8, 95% confidence interval [CI] 0.64-22.44, p = 0.016). Immune-related pathways were activated in response patients. The proportion and spatial organization of tumor-infiltrating immune cells affect the response. PD-L1 CPS level, age, and alterations of TP53, MYD88, CREBBP, EP300, GNA13 were used to build an ANN predictive model that showed high prediction efficiency (training set area under curve [AUC] of 0.97 and test set AUC of 0.94). The proportion and spatial distribution of tumor-infiltrating immune cells may be related to the function of immune-related pathways, thereby influencing the efficacy of PD-1 mAb containing regimens. The ANN predictive model showed potential value in predicting the responses of r/r DLBCL patients received PD-1 mAb and rituximab regimens.
{"title":"Multi-omics analysis and response prediction of PD-1 monoclonal antibody containing regimens in patients with relapsed/refractory diffuse large B-cell lymphoma.","authors":"Xinrui Chen, Yan Qin, Xuemin Xue, Zucheng Xie, Tongji Xie, Liling Huang, Haohua Zhu, Lina Gao, Jiangtao Li, Jianliang Yang, Lin Gui, Sheng Yang, Haizhu Chen, Xiaoli Feng, Yuankai Shi","doi":"10.1007/s00262-024-03840-0","DOIUrl":"10.1007/s00262-024-03840-0","url":null,"abstract":"<p><p>Patients with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) show varied responses to PD-1 monoclonal antibody (mAb) containing regimens. The mechanisms and predictive biomarkers for the efficacy of this regimen are unclear. This study retrospectively collected r/r DLBCL patients who received PD-1 mAb and rituximab regimens as salvage therapy. Clinical and genomic features were collected, and mechanisms were explored by multiplex immunofluorescence and digital spatial profiling. An artificial neural network (ANN) model was constructed to predict the response. Between October 16th, 2018 and May 4th, 2023, 50 r/r DLBCL patients were collected, 29 were response patients and 21 were non-response patients. CREBBP (p = 0.029) and TP53 (p = 0.015) alterations were statistically higher in non-response patients. Patients with PD-L1 CPS ≥ 5 were correlated with a longer overall survival (OS) than those with PD-L1 CPS < 5 (median OS: not reached vs. 9.7 months, hazard ratio [HR]: 3.8, 95% confidence interval [CI] 0.64-22.44, p = 0.016). Immune-related pathways were activated in response patients. The proportion and spatial organization of tumor-infiltrating immune cells affect the response. PD-L1 CPS level, age, and alterations of TP53, MYD88, CREBBP, EP300, GNA13 were used to build an ANN predictive model that showed high prediction efficiency (training set area under curve [AUC] of 0.97 and test set AUC of 0.94). The proportion and spatial distribution of tumor-infiltrating immune cells may be related to the function of immune-related pathways, thereby influencing the efficacy of PD-1 mAb containing regimens. The ANN predictive model showed potential value in predicting the responses of r/r DLBCL patients received PD-1 mAb and rituximab regimens.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"73 12","pages":"250"},"PeriodicalIF":5.4,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11448501/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364521","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}
Pub Date : 2024-10-03DOI: 10.1007/s00262-024-03814-2
Karen Toledo-Stuardo, Carolina H Ribeiro, Fabiola González-Herrera, Douglas J Matthies, María Soledad Le Roy, Claudio Dietz-Vargas, Yesenia Latorre, Ivo Campos, Yuneisy Guerra, Samantha Tello, Valeria Vásquez-Sáez, Pedro Novoa, Nicolás Fehring, Mauricio González, Jose Rodríguez-Siza, Gonzalo Vásquez, Pamela Méndez, Claudia Altamirano, María Carmen Molina
The biotechnological development of monoclonal antibodies and their immunotherapeutic use in oncology have grown exponentially in the last decade, becoming the first-line therapy for some types of cancer. Their mechanism of action is based on the ability to regulate the immune system or by interacting with targets that are either overexpressed in tumor cells, released into the extracellular milieu or involved in processes that favor tumor growth. In addition, the intrinsic characteristics of each subclass of antibodies provide specific effector functions against the tumor by activating antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and antibody-dependent cellular phagocytosis, among other mechanisms. The rational design and engineering of monoclonal antibodies have improved their pharmacokinetic and pharmacodynamic features, thus optimizing the therapeutic regimens administered to cancer patients and improving their clinical outcomes. The selection of the immunoglobulin G subclass, modifications to its crystallizable region (Fc), and conjugation of radioactive substances or antineoplastic drugs may all improve the antitumor effects of therapeutic antibodies. This review aims to provide insights into the immunological and pharmacological aspects of therapeutic antibodies used in oncology, with a rational approach at molecular modifications that can be introduced into these biological tools, improving their efficacy in the treatment of cancer.
近十年来,单克隆抗体的生物技术发展及其在肿瘤学中的免疫治疗应用呈指数增长,已成为某些类型癌症的一线疗法。单克隆抗体的作用机制基于其调节免疫系统的能力,或与肿瘤细胞中过度表达、释放到细胞外环境中或参与肿瘤生长过程的靶点相互作用。此外,每个亚类抗体的固有特性都能通过激活抗体依赖性细胞毒性、补体依赖性细胞毒性和抗体依赖性细胞吞噬作用等机制,对肿瘤发挥特定的效应功能。单克隆抗体的合理设计和工程化改善了其药代动力学和药效学特征,从而优化了癌症患者的治疗方案,提高了临床疗效。免疫球蛋白 G 亚类的选择、对其可结晶区(Fc)的修饰以及与放射性物质或抗肿瘤药物的结合都可以提高治疗性抗体的抗肿瘤效果。本综述旨在深入探讨肿瘤学中使用的治疗性抗体的免疫学和药理学方面的问题,并通过合理的方法对这些生物工具进行分子修饰,从而提高它们在治疗癌症方面的疗效。
{"title":"Therapeutic antibodies in oncology: an immunopharmacological overview.","authors":"Karen Toledo-Stuardo, Carolina H Ribeiro, Fabiola González-Herrera, Douglas J Matthies, María Soledad Le Roy, Claudio Dietz-Vargas, Yesenia Latorre, Ivo Campos, Yuneisy Guerra, Samantha Tello, Valeria Vásquez-Sáez, Pedro Novoa, Nicolás Fehring, Mauricio González, Jose Rodríguez-Siza, Gonzalo Vásquez, Pamela Méndez, Claudia Altamirano, María Carmen Molina","doi":"10.1007/s00262-024-03814-2","DOIUrl":"10.1007/s00262-024-03814-2","url":null,"abstract":"<p><p>The biotechnological development of monoclonal antibodies and their immunotherapeutic use in oncology have grown exponentially in the last decade, becoming the first-line therapy for some types of cancer. Their mechanism of action is based on the ability to regulate the immune system or by interacting with targets that are either overexpressed in tumor cells, released into the extracellular milieu or involved in processes that favor tumor growth. In addition, the intrinsic characteristics of each subclass of antibodies provide specific effector functions against the tumor by activating antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and antibody-dependent cellular phagocytosis, among other mechanisms. The rational design and engineering of monoclonal antibodies have improved their pharmacokinetic and pharmacodynamic features, thus optimizing the therapeutic regimens administered to cancer patients and improving their clinical outcomes. The selection of the immunoglobulin G subclass, modifications to its crystallizable region (Fc), and conjugation of radioactive substances or antineoplastic drugs may all improve the antitumor effects of therapeutic antibodies. This review aims to provide insights into the immunological and pharmacological aspects of therapeutic antibodies used in oncology, with a rational approach at molecular modifications that can be introduced into these biological tools, improving their efficacy in the treatment of cancer.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"73 12","pages":"242"},"PeriodicalIF":4.6,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11448508/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364526","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}