Pub Date : 2024-10-23DOI: 10.1186/s13045-024-01614-w
Jean Philippe Guegan, Nathan El Ghazzi, Julien Vibert, Christophe Rey, Lucile Vanhersecke, Jean Michel Coindre, Maud Toulmonde, Mariella Spalato Ceruso, Florent Peyraud, Alban Bessede, Antoine Italiano
Undifferentiated pleomorphic sarcomas (UPS) represent a prevalent and aggressive subtype of soft tissue sarcomas (STS) in adults. Despite advancements in loco regional treatments, many patients with high grade STS, including UPS, develop metastatic disease. Neoadjuvant chemotherapy is a standard approach to mitigate this risk, but response variability necessitates refined patient selection strategies. This study investigated the correlation between UPS microenvironment and neoadjuvant chemotherapy response in resectable UPS. The NEOSARCOMICS study (NCT02789384) enrolled patients with resectable STS from six sarcoma centers in France. Patients received anthracycline based chemotherapy, followed by surgery. Histological response, gene expression profiling, and multiplex immunohistofluorescence were performed on baseline and post treatment tumor samples. Plasma proteomics was analyzed to identify biomarkers. Good responders to neoadjuvant chemotherapy showed enrichment in genes related to stemness and cell cycle regulation, while poor responders exhibited immune related gene enrichment. Proteomic profiling revealed immune pathway activation and downregulation of cell cycle pathways in non responders. Despite being associated with a good prognosis, high immune infiltration, particularly of CD8 + T cells and CD20 + B cells, predicts a poor response to neoadjuvant chemotherapy in UPS, suggesting the need for alternative therapeutic strategies for patients with inflamed UPS.Ongoing clinical trials are exploring the efficacy of combining chemotherapy with immune checkpoint inhibitors to improve outcomes.
{"title":"Predictive value of tumor microenvironment on pathologic response to neoadjuvant chemotherapy in patients with undifferentiated pleomorphic sarcomas","authors":"Jean Philippe Guegan, Nathan El Ghazzi, Julien Vibert, Christophe Rey, Lucile Vanhersecke, Jean Michel Coindre, Maud Toulmonde, Mariella Spalato Ceruso, Florent Peyraud, Alban Bessede, Antoine Italiano","doi":"10.1186/s13045-024-01614-w","DOIUrl":"https://doi.org/10.1186/s13045-024-01614-w","url":null,"abstract":"Undifferentiated pleomorphic sarcomas (UPS) represent a prevalent and aggressive subtype of soft tissue sarcomas (STS) in adults. Despite advancements in loco regional treatments, many patients with high grade STS, including UPS, develop metastatic disease. Neoadjuvant chemotherapy is a standard approach to mitigate this risk, but response variability necessitates refined patient selection strategies. This study investigated the correlation between UPS microenvironment and neoadjuvant chemotherapy response in resectable UPS. The NEOSARCOMICS study (NCT02789384) enrolled patients with resectable STS from six sarcoma centers in France. Patients received anthracycline based chemotherapy, followed by surgery. Histological response, gene expression profiling, and multiplex immunohistofluorescence were performed on baseline and post treatment tumor samples. Plasma proteomics was analyzed to identify biomarkers. Good responders to neoadjuvant chemotherapy showed enrichment in genes related to stemness and cell cycle regulation, while poor responders exhibited immune related gene enrichment. Proteomic profiling revealed immune pathway activation and downregulation of cell cycle pathways in non responders. Despite being associated with a good prognosis, high immune infiltration, particularly of CD8 + T cells and CD20 + B cells, predicts a poor response to neoadjuvant chemotherapy in UPS, suggesting the need for alternative therapeutic strategies for patients with inflamed UPS.Ongoing clinical trials are exploring the efficacy of combining chemotherapy with immune checkpoint inhibitors to improve outcomes.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"4 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142488925","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}
Pub Date : 2024-10-21DOI: 10.1186/s13045-024-01623-9
Wangzhong Li, Hengrui Liang, Wei Wang, Jun Liu, Xiwen Liu, Shen Lao, Wenhua Liang, Jianxing He
Accurate and up-to-date estimates of the global cancer burden in adolescents and young adults (AYA) are scarce. This study aims to assess the global burden and trends of AYA cancer, with a focus on socioeconomic disparities, to inform global cancer control strategies. AYA cancer, defined as cancer occurring in individuals aged 15–39, was analyzed using data from the Global Burden of Disease (GBD) 2021 study and the Global Cancer Observatory (GLOBOCAN) 2022 project. We examined the global burden by age, sex, geographic location, and Human Development Index (HDI), as well as its temporal trends. Primary outcomes included age-standardized incidence and mortality rates (ASIR, ASMR) and the average annual percent change (AAPC). In 2022, an estimated 1,300,196 incidental cases and 377,621 cancer-related deaths occurred among AYAs worldwide, with an ASIR of 40.3 per 100,000 and an ASMR of 11.8 per 100,000. The most common cancers were breast, thyroid, and cervical, while the leading causes of death were breast, cervical, and leukemia. The incidence and mortality were disproportionately higher among females (ASIR: 52.9 for females vs. 28.3 for males; ASMR: 13.1 for females vs. 10.6 for males). Countries with higher HDI experienced a higher incidence of AYA cancers (ASIR: 32.0 [low HDI] vs. 54.8 [very high HDI]), while countries with lower HDI faced a disproportionately higher mortality burden (ASMR: 17.2 [low HDI] vs. 8.4 [very high HDI]) despite their relatively low incidence. Disproportionality and regression measures highlighted significant HDI-related inequalities. AYA cancer incidence was stable from 2000 to 2011 (AAPC: − 0.04) but increased from 2012 to 2021 (AAPC: 0.53), driven by growing gonadal and colorectal cancers. Mortality decreased substantially from 2000 to 2011 (AAPC: − 1.64), but the decline slowed from 2012 (AAPC: − 0.32) probably due to increased deaths from gonadal cancers. These trends varied by sex, cancer type, geography, and HDI. AYA cancers present a significant and growing global burden, with marked disparities across sex, geographic locations, and HDI levels. Policymakers should prioritize equitable resource allocation and implement targeted interventions to reduce these inequalities, particularly in low-HDI regions and with regard to gonadal cancers.
{"title":"Global cancer statistics for adolescents and young adults: population based study","authors":"Wangzhong Li, Hengrui Liang, Wei Wang, Jun Liu, Xiwen Liu, Shen Lao, Wenhua Liang, Jianxing He","doi":"10.1186/s13045-024-01623-9","DOIUrl":"https://doi.org/10.1186/s13045-024-01623-9","url":null,"abstract":"Accurate and up-to-date estimates of the global cancer burden in adolescents and young adults (AYA) are scarce. This study aims to assess the global burden and trends of AYA cancer, with a focus on socioeconomic disparities, to inform global cancer control strategies. AYA cancer, defined as cancer occurring in individuals aged 15–39, was analyzed using data from the Global Burden of Disease (GBD) 2021 study and the Global Cancer Observatory (GLOBOCAN) 2022 project. We examined the global burden by age, sex, geographic location, and Human Development Index (HDI), as well as its temporal trends. Primary outcomes included age-standardized incidence and mortality rates (ASIR, ASMR) and the average annual percent change (AAPC). In 2022, an estimated 1,300,196 incidental cases and 377,621 cancer-related deaths occurred among AYAs worldwide, with an ASIR of 40.3 per 100,000 and an ASMR of 11.8 per 100,000. The most common cancers were breast, thyroid, and cervical, while the leading causes of death were breast, cervical, and leukemia. The incidence and mortality were disproportionately higher among females (ASIR: 52.9 for females vs. 28.3 for males; ASMR: 13.1 for females vs. 10.6 for males). Countries with higher HDI experienced a higher incidence of AYA cancers (ASIR: 32.0 [low HDI] vs. 54.8 [very high HDI]), while countries with lower HDI faced a disproportionately higher mortality burden (ASMR: 17.2 [low HDI] vs. 8.4 [very high HDI]) despite their relatively low incidence. Disproportionality and regression measures highlighted significant HDI-related inequalities. AYA cancer incidence was stable from 2000 to 2011 (AAPC: − 0.04) but increased from 2012 to 2021 (AAPC: 0.53), driven by growing gonadal and colorectal cancers. Mortality decreased substantially from 2000 to 2011 (AAPC: − 1.64), but the decline slowed from 2012 (AAPC: − 0.32) probably due to increased deaths from gonadal cancers. These trends varied by sex, cancer type, geography, and HDI. AYA cancers present a significant and growing global burden, with marked disparities across sex, geographic locations, and HDI levels. Policymakers should prioritize equitable resource allocation and implement targeted interventions to reduce these inequalities, particularly in low-HDI regions and with regard to gonadal cancers.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"67 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142452124","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}
Pub Date : 2024-10-19DOI: 10.1186/s13045-024-01620-y
Marion Alcantara, Marion Chevrier, Fabrice Jardin, Anna Schmitt, Caroline Houillier, Lucie Oberic, Olivier Chinot, Franck Morschhauser, Frédéric Peyrade, Roch Houot, Khê Hoang-Xuan, Hervé Ghesquieres, Carole Soussain
<p><b>Correction: Journal of Hematology & Oncology (2024) 17:86</b></p><p><b>https://doi.org/10.1186/s13045-024-01606-w</b></p><p>The authors’ names in the authorship of the original article were mistakenly inverted and have since been amended.</p><h3>Authors and Affiliations</h3><ol><li><p>CellAction, Center for Cancer Immunotherapy, Institut Curie, Suresnes, France</p><p>Marion Alcantara</p></li><li><p>Clinical Hematology Unit, Institut Curie, Saint-Cloud, 92210, France</p><p>Marion Alcantara & Carole Soussain</p></li><li><p>Department of Biostatistics, Institut Curie, Saint-Cloud, 92210, France</p><p>Marion Chevrier</p></li><li><p>Department of Clinical Hematology and INSERM U1245, Centre Henri Becquerel, Rouen, France</p><p>Fabrice Jardin</p></li><li><p>Service d’Hématologie, Institut Bergonié, Bordeaux, France</p><p>Anna Schmitt</p></li><li><p>Neurooncology Department, Assistance Publique – Hôpitaux de Paris (APHP), Sorbonne Université, IHU, ICM, Groupe Hospitalier Pitié-Salpêtrière, Paris, France</p><p>Caroline Houillier & Khê Hoang-Xuan</p></li><li><p>Hematology, Institut Universitaire du Cancer de Toulouse Oncopôle, Toulouse, France</p><p>Lucie Oberic</p></li><li><p>AP-HM, Service de Neuro-Oncologie, CHU de la Timone, Aix-Marseille Université, CNRS, INP, Marseille Cedex, France</p><p>Olivier Chinot</p></li><li><p>Univ. Lille, CHU Lille, ULR 7365 - GRITA - Groupe de Recherche sur les formes Injectables et les Technologies Associées, Lille, F-59000, France</p><p>Franck Morschhauser</p></li><li><p>Service d’Onco-hématologie, Centre Hospitalier Simone Veil, Cannes, France</p><p>Frédéric Peyrade</p></li><li><p>Department of Hematology, University Hospital of Rennes, UMR U1236, INSERM, University of Rennes, French Blood Establishment, Rennes, France</p><p>Roch Houot</p></li><li><p>Department of Hematology, Hôpital Lyon Sud, Claude Bernard Lyon 1 University, Pierre- Bénite, France</p><p>Hervé Ghesquieres</p></li><li><p>Center for Cancer Immunotherapy, Institut Curie, PSL Research University, INSERM U932, Paris, 75005, France</p><p>Carole Soussain</p></li></ol><span>Authors</span><ol><li><span>Marion Alcantara</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Marion Chevrier</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Fabrice Jardin</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Anna Schmitt</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Caroline Houillier</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Lucie Oberic</span>View author publications<p>You can also search for this author in <s
更正：Journal of Hematology & Oncology (2024) 17:86https://doi.org/10.1186/s13045-024-01606-wThe 原文作者姓名被误颠倒，现已修改。作者和单位法国苏雷讷居里研究所癌症免疫治疗中心细胞行动Marion Alcantara法国圣克卢居里研究所临床血液学组Marion Alcantara &；Carole Soussain法国圣克卢居里研究所生物统计部Marion Chevrier法国鲁昂亨利贝克勒尔中心临床血液学部和 INSERM U1245Fabrice JardinService d'Hématologie、Anna SchmittNeurooncology Department, Assistance Publique - Hôpitaux de Paris (APHP), Sorbonne Université, IHU, ICM, Groupe Hospitalier Pitié-Salpêtrière, Paris, FranceCaroline Houillier &；Khê Hoang-Xuan Hematology, Institut Universitaire du Cancer de Toulouse Oncopôle, Toulouse, FranceLucie ObericAP-HM, Service de Neuro-Oncologie, CHU de la Timone, Aix-Marseille Université, CNRS, INP, Marseille Cedex, FranceOlivier ChinotUniv.Lille, CHU Lille, ULR 7365 - GRITA - Groupe de Recherche sur les formes Injectables et les Technologies Associées, Lille, F-59000, FranceFranck MorschhauserService d'Onco-hématologie, Centre Hospitalier Simone Veil, Cannes, FranceFrédéric PeyradeDepartment of Hematology, University Hospital of Rennes、UMR U1236、INSERM、雷恩大学、法国血液机构，法国雷恩Roch Houot里昂南方医院血液科、克劳德-贝尔纳-里昂第一大学，法国皮埃尔-贝尼特Hervé Ghesquieres癌症免疫治疗中心、居里研究所、PSL研究大学、INSERM U932，巴黎，75005、法国Carole Soussain作者Marion Alcantara查看作者发表的论文您也可以在PubMed Google Scholar中搜索该作者Marion Chevrier查看作者发表的论文您也可以在PubMed Google Scholar中搜索该作者Fabrice Jardin查看作者发表的论文您也可以在PubMed Google Scholar中搜索该作者Anna Schmitt查看作者发表的论文您也可以在PubMed Google Scholar中搜索该作者Caroline Houillier查看作者发表的论文您也可以在PubMed Google Scholar中搜索该作者ScholarLucie Oberic查看作者发表的作品您也可以在PubMed Google Scholar中搜索该作者Olivier Chinot查看作者发表的作品您也可以在PubMed Google Scholar中搜索该作者Franck Morschhauser查看作者发表的作品您也可以在PubMed Google Scholar中搜索该作者Frédéric Peyrade查看作者发表的作品您也可以在PubMed Google Scholar中搜索该作者Roch Houot查看作者发表的作品您也可以在PubMed Google Scholar中搜索该作者Khê Hoang-XuanView 作者发表作品您也可以在 PubMed Google Scholar中搜索该作者Hervé GhesquieresView 作者发表作品您也可以在 PubMed Google Scholar中搜索该作者Carole SoussainView 作者发表作品您也可以在 PubMed Google Scholar中搜索该作者通信作者Carole Soussain的通信。出版者注释Springer Nature对出版地图中的管辖权主张和机构隶属关系保持中立。原文的在线版本可在以下网址找到：https://doi.org/10.1186/s13045-024-01606-w.Open Access 本文采用知识共享署名-非商业性-禁止衍生 4.0 国际许可协议进行许可，该协议允许以任何媒介或格式进行任何非商业性使用、共享、分发和复制，只要您适当注明原作者和来源，提供知识共享许可协议的链接，并说明您是否修改了许可材料。根据本许可协议，您无权分享源自本文或本文部分内容的改编材料。本文中的图片或其他第三方材料均包含在文章的知识共享许可协议中，除非在材料的信用栏中另有说明。如果材料未包含在文章的知识共享许可协议中，且您打算使用的材料不符合法律规定或超出了许可使用范围，则您需要直接获得版权所有者的许可。如需查看该许可的副本，请访问 http://creativecommons.org/licenses/by-nc-nd/4.0/.Reprints and permissionsCite this articleAlcantara, M., Chevrier, M., Jardin, F. et al. Correction：LOC-R01的IB期部分，这是一项LOC网络非比较随机IB/II期研究，测试R-MPV联合来那度胺或伊布替尼治疗新诊断的原发性中枢神经系统淋巴瘤（PCNSL）患者。J Hematol Oncol 17, 98 (2024). https://doi.org/10.1186/s13045-024-01620-yDownload citationPublished: 19 October 2024DOI: https://doi.org/10. 1186/s13045-024-01620-y分享本文与您分享以下链接的任何人都可以阅读此内容：获取可分享链接很抱歉，本文目前不提供可分享链接，请复制到剪贴板由施普林格-自然SharedIt内容分享计划提供
{"title":"Correction: Phase IB part of LOC-R01, a LOC network non-comparative randomized phase IB/II study testing R-MPV in combination with escalating doses of lenalidomide or ibrutinib for newly diagnosed primary central nervous system lymphoma (PCNSL) patients","authors":"Marion Alcantara, Marion Chevrier, Fabrice Jardin, Anna Schmitt, Caroline Houillier, Lucie Oberic, Olivier Chinot, Franck Morschhauser, Frédéric Peyrade, Roch Houot, Khê Hoang-Xuan, Hervé Ghesquieres, Carole Soussain","doi":"10.1186/s13045-024-01620-y","DOIUrl":"https://doi.org/10.1186/s13045-024-01620-y","url":null,"abstract":"<p><b>Correction: Journal of Hematology & Oncology (2024) 17:86</b></p><p><b>https://doi.org/10.1186/s13045-024-01606-w</b></p><p>The authors’ names in the authorship of the original article were mistakenly inverted and have since been amended.</p><h3>Authors and Affiliations</h3><ol><li><p>CellAction, Center for Cancer Immunotherapy, Institut Curie, Suresnes, France</p><p>Marion Alcantara</p></li><li><p>Clinical Hematology Unit, Institut Curie, Saint-Cloud, 92210, France</p><p>Marion Alcantara & Carole Soussain</p></li><li><p>Department of Biostatistics, Institut Curie, Saint-Cloud, 92210, France</p><p>Marion Chevrier</p></li><li><p>Department of Clinical Hematology and INSERM U1245, Centre Henri Becquerel, Rouen, France</p><p>Fabrice Jardin</p></li><li><p>Service d’Hématologie, Institut Bergonié, Bordeaux, France</p><p>Anna Schmitt</p></li><li><p>Neurooncology Department, Assistance Publique – Hôpitaux de Paris (APHP), Sorbonne Université, IHU, ICM, Groupe Hospitalier Pitié-Salpêtrière, Paris, France</p><p>Caroline Houillier & Khê Hoang-Xuan</p></li><li><p>Hematology, Institut Universitaire du Cancer de Toulouse Oncopôle, Toulouse, France</p><p>Lucie Oberic</p></li><li><p>AP-HM, Service de Neuro-Oncologie, CHU de la Timone, Aix-Marseille Université, CNRS, INP, Marseille Cedex, France</p><p>Olivier Chinot</p></li><li><p>Univ. Lille, CHU Lille, ULR 7365 - GRITA - Groupe de Recherche sur les formes Injectables et les Technologies Associées, Lille, F-59000, France</p><p>Franck Morschhauser</p></li><li><p>Service d’Onco-hématologie, Centre Hospitalier Simone Veil, Cannes, France</p><p>Frédéric Peyrade</p></li><li><p>Department of Hematology, University Hospital of Rennes, UMR U1236, INSERM, University of Rennes, French Blood Establishment, Rennes, France</p><p>Roch Houot</p></li><li><p>Department of Hematology, Hôpital Lyon Sud, Claude Bernard Lyon 1 University, Pierre- Bénite, France</p><p>Hervé Ghesquieres</p></li><li><p>Center for Cancer Immunotherapy, Institut Curie, PSL Research University, INSERM U932, Paris, 75005, France</p><p>Carole Soussain</p></li></ol><span>Authors</span><ol><li><span>Marion Alcantara</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Marion Chevrier</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Fabrice Jardin</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Anna Schmitt</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Caroline Houillier</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Lucie Oberic</span>View author publications<p>You can also search for this author in <s","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"14 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142451419","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}
Pub Date : 2024-10-14DOI: 10.1186/s13045-024-01616-8
Xin Du, Xingxian Luo, Lanqiu Liu, Yanlin Cao, Yajuan Zhang, Yi Zhang
In recent years, cell therapy research and commercialization have significantly accelerated, especially after the US FDA approved CAR-T therapy. While cell therapy now leads immuno-oncology in clinical trials, challenges such as redundant R&D, target clustering, and unmet clinical need remain. Since 2017, China has established a dual-track regulatory framework, facilitating rapid growth in its cell therapy pipeline, making it the second largest in the world. Despite this progress, China faces similar global challenges. Our study covers 2,794 registered cell therapy clinical trials in China, including 2,045 for immune cell, 683 for stem cell, and 66 for other somatic cell. It compares cell therapy products approved in China, the US, EU, and Japan, analyzes the evolving clinical trials landscape, and highlights the characteristics of investigator-initiated trials (IITs) and industry-sponsored trials (ISTs) in China. Our findings indicate that despite the high disease burden and unmet clinical needs for solid tumors in China, over 38% of trials between 2021 and 2023 focused on hematologic malignancies with established targets like CD19 and BCMA. Over 90% of trials are IITs, which show notable clinical differences from ISTs. We recommend that Chinese regulators establish specific guidelines to promote clinical-value-driven research. Stricter regulatory standards should also be implemented to minimize redundant R&D. Additionally, a value-based reimbursement system for within-class targeted cell therapy products may further reduce duplicated R&D efforts. Given the prevalence of IITs, specifying requirements for IITs could create a new pathway to accelerate product development and better address unmet clinical needs in China.
{"title":"Mapping the cell therapy landscape: insights into clinical trials and regulatory advances in China","authors":"Xin Du, Xingxian Luo, Lanqiu Liu, Yanlin Cao, Yajuan Zhang, Yi Zhang","doi":"10.1186/s13045-024-01616-8","DOIUrl":"https://doi.org/10.1186/s13045-024-01616-8","url":null,"abstract":"In recent years, cell therapy research and commercialization have significantly accelerated, especially after the US FDA approved CAR-T therapy. While cell therapy now leads immuno-oncology in clinical trials, challenges such as redundant R&D, target clustering, and unmet clinical need remain. Since 2017, China has established a dual-track regulatory framework, facilitating rapid growth in its cell therapy pipeline, making it the second largest in the world. Despite this progress, China faces similar global challenges. Our study covers 2,794 registered cell therapy clinical trials in China, including 2,045 for immune cell, 683 for stem cell, and 66 for other somatic cell. It compares cell therapy products approved in China, the US, EU, and Japan, analyzes the evolving clinical trials landscape, and highlights the characteristics of investigator-initiated trials (IITs) and industry-sponsored trials (ISTs) in China. Our findings indicate that despite the high disease burden and unmet clinical needs for solid tumors in China, over 38% of trials between 2021 and 2023 focused on hematologic malignancies with established targets like CD19 and BCMA. Over 90% of trials are IITs, which show notable clinical differences from ISTs. We recommend that Chinese regulators establish specific guidelines to promote clinical-value-driven research. Stricter regulatory standards should also be implemented to minimize redundant R&D. Additionally, a value-based reimbursement system for within-class targeted cell therapy products may further reduce duplicated R&D efforts. Given the prevalence of IITs, specifying requirements for IITs could create a new pathway to accelerate product development and better address unmet clinical needs in China.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"229 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142431357","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}
Tumor cells develop multiple mechanisms to facilitate their immune evasion. Identifying tumor-intrinsic factors that support immune evasion may provide new strategies for cancer immunotherapy. We aimed to explore the function and the mechanism of the tumor-intrinsic factor NPM1, a multifunctional nucleolar phosphoprotein, in cancer immune evasion and progression. The roles of NPM1 in tumor progression and tumor microenvironment (TME) reprogramming were examined by subcutaneous inoculation of Npm1-deficient tumor cells into syngeneic mice, and then explored by CyTOF, flow cytometry, immunohistochemistry staining, and RNA-seq. The in-vitro T-cell killing of OVA-presenting tumor cells by OT-1 transgenic T cells was observed. The interaction of NPM1 and IRF1 was verified by Co-IP. The regulation of NPM1 in IRF1 DNA binding to Nlrc5, Ciita promoter was determined by dual-luciferase reporter assay and ChIP-qPCR. High levels of NPM1 expression predict low survival rates in various human tumors. Loss of NPM1 inhibited tumor progression and enhanced the survival of tumor-bearing mice. Npm1-deficient tumors showed increased CD8+ T cell infiltration and activation alongside the reduced presence of immunosuppressive cells. Npm1 deficiency increased MHC-I and MHC-II molecules and specific T-cell killing. Mechanistically, NPM1 associates with the transcription factor IRF1 and then sequesters IRF1 from binding to the Nlrc5 and Ciita promoters to suppress IRF1-mediated expression of MHC-I and MHC-II molecules in tumor cells. Tumor-intrinsic NPM1 promotes tumor immune evasion via suppressing IRF1-mediated antigen presentation to impair tumor immunogenicity and reprogram the immunosuppressive TME. Our study identifies NPM1 as a potential target for improving cancer immunotherapy.
{"title":"NPM1 inhibits tumoral antigen presentation to promote immune evasion and tumor progression","authors":"Xin Wang, Yangyang Chai, Yuan Quan, Jiaming Wang, Jiaying Song, Wenkai Zhou, Xiaoqing Xu, Henan Xu, Bingjing Wang, Xuetao Cao","doi":"10.1186/s13045-024-01618-6","DOIUrl":"https://doi.org/10.1186/s13045-024-01618-6","url":null,"abstract":"Tumor cells develop multiple mechanisms to facilitate their immune evasion. Identifying tumor-intrinsic factors that support immune evasion may provide new strategies for cancer immunotherapy. We aimed to explore the function and the mechanism of the tumor-intrinsic factor NPM1, a multifunctional nucleolar phosphoprotein, in cancer immune evasion and progression. The roles of NPM1 in tumor progression and tumor microenvironment (TME) reprogramming were examined by subcutaneous inoculation of Npm1-deficient tumor cells into syngeneic mice, and then explored by CyTOF, flow cytometry, immunohistochemistry staining, and RNA-seq. The in-vitro T-cell killing of OVA-presenting tumor cells by OT-1 transgenic T cells was observed. The interaction of NPM1 and IRF1 was verified by Co-IP. The regulation of NPM1 in IRF1 DNA binding to Nlrc5, Ciita promoter was determined by dual-luciferase reporter assay and ChIP-qPCR. High levels of NPM1 expression predict low survival rates in various human tumors. Loss of NPM1 inhibited tumor progression and enhanced the survival of tumor-bearing mice. Npm1-deficient tumors showed increased CD8+ T cell infiltration and activation alongside the reduced presence of immunosuppressive cells. Npm1 deficiency increased MHC-I and MHC-II molecules and specific T-cell killing. Mechanistically, NPM1 associates with the transcription factor IRF1 and then sequesters IRF1 from binding to the Nlrc5 and Ciita promoters to suppress IRF1-mediated expression of MHC-I and MHC-II molecules in tumor cells. Tumor-intrinsic NPM1 promotes tumor immune evasion via suppressing IRF1-mediated antigen presentation to impair tumor immunogenicity and reprogram the immunosuppressive TME. Our study identifies NPM1 as a potential target for improving cancer immunotherapy.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"78 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142431360","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}
Pub Date : 2024-10-12DOI: 10.1186/s13045-024-01615-9
Lianxuan Liu, Mi Shao, Yue Huang, Pengxu Qian, He Huang
Due to spatial and genomic independence, mitochondria possess a translational mechanism distinct from that of cytoplasmic translation. Several regulators participate in the modulation of mitochondrial translation. Mitochondrial translation is coordinated with cytoplasmic translation through stress responses. Importantly, the inhibition of mitochondrial translation leads to the inhibition of cytoplasmic translation and metabolic disruption. Therefore, defects in mitochondrial translation are closely related to the functions of hematopoietic cells and various immune cells. Finally, the inhibition of mitochondrial translation is a potential therapeutic target for treating multiple hematologic malignancies. Collectively, more in-depth insights into mitochondrial translation not only facilitate our understanding of its functions in hematopoiesis, but also provide a basis for the discovery of new treatments for hematological malignancies and the modulation of immune cell function.
{"title":"Unraveling the roles and mechanisms of mitochondrial translation in normal and malignant hematopoiesis","authors":"Lianxuan Liu, Mi Shao, Yue Huang, Pengxu Qian, He Huang","doi":"10.1186/s13045-024-01615-9","DOIUrl":"https://doi.org/10.1186/s13045-024-01615-9","url":null,"abstract":"Due to spatial and genomic independence, mitochondria possess a translational mechanism distinct from that of cytoplasmic translation. Several regulators participate in the modulation of mitochondrial translation. Mitochondrial translation is coordinated with cytoplasmic translation through stress responses. Importantly, the inhibition of mitochondrial translation leads to the inhibition of cytoplasmic translation and metabolic disruption. Therefore, defects in mitochondrial translation are closely related to the functions of hematopoietic cells and various immune cells. Finally, the inhibition of mitochondrial translation is a potential therapeutic target for treating multiple hematologic malignancies. Collectively, more in-depth insights into mitochondrial translation not only facilitate our understanding of its functions in hematopoiesis, but also provide a basis for the discovery of new treatments for hematological malignancies and the modulation of immune cell function.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"65 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142415681","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}
Letermovir (LTV) prophylaxis is effective in reducing the incidence of clinically significant cytomegalovirus (CMV) infection (cs CMVi) after allogeneic haematopoietic stem cell transplantation (allo-HSCT). Since our centre began administering LTV prophylaxis in June 2022, we have observed a certain increase in the incidence of Epstein–Barr virus (EBV) reactivation after haploidentical HSCT. We retrospectively analysed 230 consecutive patients who underwent haploidentical HSCT with rabbit anti-thymocyte globulin (ATG) from October 2022 to June 2023. The LTV group included 133 patients who received LTV prophylaxis, and the control group included 97 patients who did not receive LTV prophylaxis. At 1 year after HSCT, EBV reactivation was observed in 36 patients (27%) in the LTV group and 13 patients (13%) in the control group (p = 0.012). All patients with EBV reactivation had EBV-DNAemia, and one patient in each group developed EBV-associated posttransplantation lymphoproliferative disorder (PTLD). The proportion of patients with low EBV-DNA loads (> 5 × 102 to < 1 × 104 copies/mL) was greater in the LTV group than in the control group (23% vs. 10%, p = 0.01). The proportion of patients with CMV reactivation was lower in the LTV group than in the control group (35% vs. 56%, p = 0.002). There was no significant difference between the groups in terms of neutrophil and platelet count recovery, the cumulative incidence of acute/chronic graft-versus-host disease, overall survival, cumulative relapse rate or nonrelapse mortality. Our results show that the increased incidence of EBV reactivation may be associated with LTV prophylaxis for CMV after haploidentical HSCT.
{"title":"Increased Epstein‒Barr virus reactivation following prophylaxis for cytomegalovirus infection after haploidentical haematopoietic stem cell transplantation","authors":"Xin Kong, Ziyi Xu, Yanjun Wu, Xiaowen Tang, Shengli Xue, Miao Miao, Yue Han, Ying Wang, Suning Chen, Aining Sun, Huiying Qiu, Depei Wu, Ye Zhao, Feng Chen","doi":"10.1186/s13045-024-01612-y","DOIUrl":"https://doi.org/10.1186/s13045-024-01612-y","url":null,"abstract":"Letermovir (LTV) prophylaxis is effective in reducing the incidence of clinically significant cytomegalovirus (CMV) infection (cs CMVi) after allogeneic haematopoietic stem cell transplantation (allo-HSCT). Since our centre began administering LTV prophylaxis in June 2022, we have observed a certain increase in the incidence of Epstein–Barr virus (EBV) reactivation after haploidentical HSCT. We retrospectively analysed 230 consecutive patients who underwent haploidentical HSCT with rabbit anti-thymocyte globulin (ATG) from October 2022 to June 2023. The LTV group included 133 patients who received LTV prophylaxis, and the control group included 97 patients who did not receive LTV prophylaxis. At 1 year after HSCT, EBV reactivation was observed in 36 patients (27%) in the LTV group and 13 patients (13%) in the control group (p = 0.012). All patients with EBV reactivation had EBV-DNAemia, and one patient in each group developed EBV-associated posttransplantation lymphoproliferative disorder (PTLD). The proportion of patients with low EBV-DNA loads (> 5 × 102 to < 1 × 104 copies/mL) was greater in the LTV group than in the control group (23% vs. 10%, p = 0.01). The proportion of patients with CMV reactivation was lower in the LTV group than in the control group (35% vs. 56%, p = 0.002). There was no significant difference between the groups in terms of neutrophil and platelet count recovery, the cumulative incidence of acute/chronic graft-versus-host disease, overall survival, cumulative relapse rate or nonrelapse mortality. Our results show that the increased incidence of EBV reactivation may be associated with LTV prophylaxis for CMV after haploidentical HSCT.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"16 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142415682","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}
<p><b>Correction: Journal of Hematology & Oncology (2024) 17:71</b></p><p>https://doi.org/10.1186/s13045-024-01598-7</p><p>The datasets used are publicly available in GSE162454 and GSE15204855.</p><p> Our own data is available via the following links:</p><p> (1) https://github.com/zhengxj1/A-Single-Cell-and-Spatially-Resolved-Atlas-of-Human-Osteosarcomas; (2) https://codeocean.com/capsule/9535428/tree/v1.</p><h3>Authors and Affiliations</h3><ol><li><p>Departments of Orthopedics, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China</p><p>Xuejing Zheng, Xu Liu, Xinxin Zhang, Zhenguo Zhao & Shengji Yu</p></li><li><p>Department of Orthopedics, Peking University First Hospital, Beijing, 100021, China</p><p>Wence Wu</p></li></ol><span>Authors</span><ol><li><span>Xuejing Zheng</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Xu Liu</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Xinxin Zhang</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Zhenguo Zhao</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Wence Wu</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Shengji Yu</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li></ol><h3>Corresponding author</h3><p>Correspondence to Shengji Yu.</p><h3>Publisher’s note</h3><p>Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.</p><p>The online version of the original article can be found at https://doi.org/10.1186/s13045-024-01598-7</p><p><b>Open Access</b> This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need
更正：Journal of Hematology & Oncology (2024) 17:71https://doi.org/10.1186/s13045-024-01598-7The 所用数据集在 GSE162454 和 GSE15204855 中公开。我们自己的数据可通过以下链接获取：(1) https://github.com/zhengxj1/A-Single-Cell-and-Spatially-Resolved-Atlas-of-Human-Osteosarcomas; (2) https://codeocean.com/capsule/9535428/tree/v1。作者及工作单位中国医学科学院国家癌症中心/国家肿瘤临床研究中心/北京协和医院骨科，北京，100021 郑雪静，刘旭，张欣欣，赵振国 &；北京大学第一医院骨科，北京，100021、中国Wence Wu作者Xuejing Zheng查看作者发表的论文您也可以在PubMed Google Scholar中搜索该作者Xu Liu查看作者发表的论文您也可以在PubMed Google Scholar中搜索该作者Xinxin Zhang查看作者发表的论文您也可以在PubMed Google Scholar中搜索该作者Zhenguo Zhao查看作者发表的论文您也可以在PubMed Google Scholar中搜索该作者Zhenguo Zhao查看作者发表的论文作者发表的作品您也可以在 PubMed Google Scholar中搜索该作者Wence Wu查看作者发表的作品您也可以在 PubMed Google Scholar中搜索该作者Shengji Yu查看作者发表的作品您也可以在 PubMed Google Scholar中搜索该作者通讯作者：Shengji Yu。出版者注释施普林格-自然（Springer Nature）对出版地图中的管辖权主张和机构隶属关系保持中立。原文的在线版本可在 https://doi.org/10.1186/s13045-024-01598-7Open Access 找到。本文采用知识共享署名-非商业性-禁止衍生 4.0 国际许可协议进行许可，该协议允许以任何媒介或格式进行任何非商业性使用、共享、分发和复制，只要您适当注明原作者和来源，提供知识共享许可协议的链接，并说明您是否修改了许可材料。根据本许可协议，您无权分享源自本文或本文部分内容的改编材料。本文中的图片或其他第三方材料均包含在文章的知识共享许可协议中，除非在材料的信用栏中另有说明。如果材料未包含在文章的知识共享许可协议中，且您打算使用的材料不符合法律规定或超出了许可使用范围，则您需要直接获得版权所有者的许可。如需查看该许可的副本，请访问 http://creativecommons.org/licenses/by-nc-nd/4.0/.Reprints and permissionsCite this articleZheng, X., Liu, X., Zhang, X. et al. Correction：人类骨肉瘤的单细胞和空间分辨图谱。J Hematol Oncol 17, 93 (2024). https://doi.org/10.1186/s13045-024-01619-5Download citationPublished: 11 October 2024DOI: https://doi.org/10.1186/s13045-024-01619-5Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative
{"title":"Correction: A single-cell and spatially resolved atlas of human osteosarcomas","authors":"Xuejing Zheng, Xu Liu, Xinxin Zhang, Zhenguo Zhao, Wence Wu, Shengji Yu","doi":"10.1186/s13045-024-01619-5","DOIUrl":"https://doi.org/10.1186/s13045-024-01619-5","url":null,"abstract":"<p><b>Correction: Journal of Hematology & Oncology (2024) 17:71</b></p><p>https://doi.org/10.1186/s13045-024-01598-7</p><p>The datasets used are publicly available in GSE162454 and GSE15204855.</p><p> Our own data is available via the following links:</p><p> (1) https://github.com/zhengxj1/A-Single-Cell-and-Spatially-Resolved-Atlas-of-Human-Osteosarcomas; (2) https://codeocean.com/capsule/9535428/tree/v1.</p><h3>Authors and Affiliations</h3><ol><li><p>Departments of Orthopedics, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China</p><p>Xuejing Zheng, Xu Liu, Xinxin Zhang, Zhenguo Zhao & Shengji Yu</p></li><li><p>Department of Orthopedics, Peking University First Hospital, Beijing, 100021, China</p><p>Wence Wu</p></li></ol><span>Authors</span><ol><li><span>Xuejing Zheng</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Xu Liu</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Xinxin Zhang</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Zhenguo Zhao</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Wence Wu</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Shengji Yu</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li></ol><h3>Corresponding author</h3><p>Correspondence to Shengji Yu.</p><h3>Publisher’s note</h3><p>Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.</p><p>The online version of the original article can be found at https://doi.org/10.1186/s13045-024-01598-7</p><p><b>Open Access</b> This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need ","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"78 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142405258","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}
Pub Date : 2024-10-10DOI: 10.1186/s13045-024-01613-x
Junke Wang, Jie Yang, Amol Narang, Jin He, Christopher Wolfgang, Keyu Li, Lei Zheng
Pancreatic cancer remains one of the most aggressive solid tumors. As a systemic disease, despite the improvement of multi-modality treatment strategies, the prognosis of pancreatic cancer was not improved dramatically. For resectable or borderline resectable patients, the surgical strategy centered on improving R0 resection rate is consensus; however, the role of neoadjuvant therapy in resectable patients and the optimal neoadjuvant therapy of chemotherapy with or without radiotherapy in borderline resectable patients were debated. Postoperative adjuvant chemotherapy of gemcitabine/capecitabine or mFOLFIRINOX is recommended regardless of the margin status. Chemotherapy as the first-line treatment strategy for advanced or metastatic patients included FOLFIRINOX, gemcitabine/nab-paclitaxel, or NALIRIFOX regimens whereas 5-FU plus liposomal irinotecan was the only standard of care second-line therapy. Immunotherapy is an innovative therapy although anti-PD-1 antibody is currently the only agent approved by for MSI-H, dMMR, or TMB-high solid tumors, which represent a very small subset of pancreatic cancers. Combination strategies to increase the immunogenicity and to overcome the immunosuppressive tumor microenvironment may sensitize pancreatic cancer to immunotherapy. Targeted therapies represented by PARP and KRAS inhibitors are also under investigation, showing benefits in improving progression-free survival and objective response rate. This review discusses the current treatment modalities and highlights innovative therapies for pancreatic cancer.
{"title":"Consensus, debate, and prospective on pancreatic cancer treatments.","authors":"Junke Wang, Jie Yang, Amol Narang, Jin He, Christopher Wolfgang, Keyu Li, Lei Zheng","doi":"10.1186/s13045-024-01613-x","DOIUrl":"10.1186/s13045-024-01613-x","url":null,"abstract":"<p><p>Pancreatic cancer remains one of the most aggressive solid tumors. As a systemic disease, despite the improvement of multi-modality treatment strategies, the prognosis of pancreatic cancer was not improved dramatically. For resectable or borderline resectable patients, the surgical strategy centered on improving R0 resection rate is consensus; however, the role of neoadjuvant therapy in resectable patients and the optimal neoadjuvant therapy of chemotherapy with or without radiotherapy in borderline resectable patients were debated. Postoperative adjuvant chemotherapy of gemcitabine/capecitabine or mFOLFIRINOX is recommended regardless of the margin status. Chemotherapy as the first-line treatment strategy for advanced or metastatic patients included FOLFIRINOX, gemcitabine/nab-paclitaxel, or NALIRIFOX regimens whereas 5-FU plus liposomal irinotecan was the only standard of care second-line therapy. Immunotherapy is an innovative therapy although anti-PD-1 antibody is currently the only agent approved by for MSI-H, dMMR, or TMB-high solid tumors, which represent a very small subset of pancreatic cancers. Combination strategies to increase the immunogenicity and to overcome the immunosuppressive tumor microenvironment may sensitize pancreatic cancer to immunotherapy. Targeted therapies represented by PARP and KRAS inhibitors are also under investigation, showing benefits in improving progression-free survival and objective response rate. This review discusses the current treatment modalities and highlights innovative therapies for pancreatic cancer.</p>","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"17 1","pages":"92"},"PeriodicalIF":29.5,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11468220/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142400503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-08DOI: 10.1186/s13045-024-01610-0
Mathew Sheridan, Muhammad Ahmad Maqbool, Anne Largeot, Liam Clayfield, Jingru Xu, Natalia Moncaut, Robert Sellers, Jessica Whittle, Jerome Paggetti, Mudassar Iqbal, Romain Aucagne, Laurent Delva, Syed Murtuza Baker, Michael Lie-a-Ling, Valerie Kouskoff, Georges Lacaud
The epigenetic factors KAT6A (MOZ/MYST3) and KMT2A (MLL/MLL1) interact in normal hematopoiesis to regulate progenitors’ self-renewal. Both proteins are recurrently translocated in AML, leading to impairment of critical differentiation pathways in these malignant cells. We evaluated the potential of different KAT6A therapeutic targeting strategies to alter the growth of KAT6A and KMT2A rearranged AMLs. We investigated the action and potential mechanisms of the first-in-class KAT6A inhibitor, WM-1119 in KAT6A and KMT2A rearranged (KAT6Ar and KMT2Ar) AML using cellular (flow cytometry, colony assays, cell growth) and molecular (shRNA knock-down, CRISPR knock-out, bulk and single-cell RNA-seq, ChIP-seq) assays. We also used two novel genetic murine KAT6A models combined with the most common KMT2Ar AML, KMT2A::MLLT3 AML. In these murine models, the catalytic activity of KAT6A, or the whole protein, can be conditionally abrogated or deleted. These models allowed us to compare the effects of specific KAT6A KAT activity inhibition with the complete deletion of the whole protein. Finally, we also tested these therapeutic approaches on human AML cell lines and primary patient AMLs. We found that WM-1119 completely abrogated the proliferative and clonogenic potential of KAT6Ar cells in vitro. WM-1119 treatment was associated with a dramatic increase in myeloid differentiation program. The treatment also decreased stemness and leukemia pathways at the transcriptome level and led to loss of binding of the fusion protein at critical regulators of these pathways. In contrast, our pharmacologic and genetic results indicate that the catalytic activity of KAT6A plays a more limited role in KMT2Ar leukemogenicity, while targeting the whole KAT6A protein dramatically affects leukemic potential in murine KMT2A::MLLT3 AML. Our study indicates that inhibiting KAT6A KAT activity holds compelling promise for KAT6Ar AML patients. In contrast, targeted degradation of KAT6A, and not just its catalytic activity, may represent a more appropriate therapeutic approach for KMT2Ar AMLs.
{"title":"The small inhibitor WM-1119 effectively targets KAT6A-rearranged AML, but not KMT2A-rearranged AML, despite shared KAT6 genetic dependency","authors":"Mathew Sheridan, Muhammad Ahmad Maqbool, Anne Largeot, Liam Clayfield, Jingru Xu, Natalia Moncaut, Robert Sellers, Jessica Whittle, Jerome Paggetti, Mudassar Iqbal, Romain Aucagne, Laurent Delva, Syed Murtuza Baker, Michael Lie-a-Ling, Valerie Kouskoff, Georges Lacaud","doi":"10.1186/s13045-024-01610-0","DOIUrl":"https://doi.org/10.1186/s13045-024-01610-0","url":null,"abstract":"The epigenetic factors KAT6A (MOZ/MYST3) and KMT2A (MLL/MLL1) interact in normal hematopoiesis to regulate progenitors’ self-renewal. Both proteins are recurrently translocated in AML, leading to impairment of critical differentiation pathways in these malignant cells. We evaluated the potential of different KAT6A therapeutic targeting strategies to alter the growth of KAT6A and KMT2A rearranged AMLs. We investigated the action and potential mechanisms of the first-in-class KAT6A inhibitor, WM-1119 in KAT6A and KMT2A rearranged (KAT6Ar and KMT2Ar) AML using cellular (flow cytometry, colony assays, cell growth) and molecular (shRNA knock-down, CRISPR knock-out, bulk and single-cell RNA-seq, ChIP-seq) assays. We also used two novel genetic murine KAT6A models combined with the most common KMT2Ar AML, KMT2A::MLLT3 AML. In these murine models, the catalytic activity of KAT6A, or the whole protein, can be conditionally abrogated or deleted. These models allowed us to compare the effects of specific KAT6A KAT activity inhibition with the complete deletion of the whole protein. Finally, we also tested these therapeutic approaches on human AML cell lines and primary patient AMLs. We found that WM-1119 completely abrogated the proliferative and clonogenic potential of KAT6Ar cells in vitro. WM-1119 treatment was associated with a dramatic increase in myeloid differentiation program. The treatment also decreased stemness and leukemia pathways at the transcriptome level and led to loss of binding of the fusion protein at critical regulators of these pathways. In contrast, our pharmacologic and genetic results indicate that the catalytic activity of KAT6A plays a more limited role in KMT2Ar leukemogenicity, while targeting the whole KAT6A protein dramatically affects leukemic potential in murine KMT2A::MLLT3 AML. Our study indicates that inhibiting KAT6A KAT activity holds compelling promise for KAT6Ar AML patients. In contrast, targeted degradation of KAT6A, and not just its catalytic activity, may represent a more appropriate therapeutic approach for KMT2Ar AMLs.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"1 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142385533","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}
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