Journal of Hematology & Oncology最新文献

{"title":"Anti-LAG-3 antibody LBL-007 plus anti-PD-1 antibody toripalimab in advanced nasopharyngeal carcinoma and other solid tumors: an open-label, multicenter, phase Ib/II trial","authors":"Gang Chen, Dong-Chen Sun, Yi Ba, Ya-Xiong Zhang, Ting Zhou, Yuan-Yuan Zhao, Hong-Yun Zhao, Wen-Feng Fang, Yan Huang, Zhen Wang, Chao Deng, De-Sheng Hu, Wei Wang, Jin-Guan Lin, Gui-Ling Li, Su-Xia Luo, Zhi-Chao Fu, Hai-Sheng Zhu, Hui-Li Wang, Sheng-Li Cai, Xiao-Qiang Kang, Li Zhang, Yun-Peng Yang","doi":"10.1186/s13045-025-01666-6","DOIUrl":"https://doi.org/10.1186/s13045-025-01666-6","url":null,"abstract":"Open-label phase Ib/II study to investigate the safety and efficacy of LBL-007, an anti-LAG-3 antibody, plus toripalimab, an anti-PD-1 antibody, in patients with previously treated advanced nasopharyngeal carcinoma (NPC) and other solid tumors. Patients with advanced tumors refractory to prior standard therapies were enrolled. In phase Ib, patients received LBL-007 200 mg or 400 mg and toripalimab 240 mg intravenously once every 3 weeks. In phase II, all patients received LBL-007 at the recommended phase II dose (RP2D) and toripalimab 240 mg intravenously once every 3 weeks. The primary end points were safety in phase Ib and objective response rate (ORR) in phase II. The exploratory end point was the predictive capability of LAG-3 and PD-L1 expression for efficacy. Between November 30, 2021, and December 1, 2023, 80 patients were enrolled, including 30 (37.5%) with NPC and 50 (62.5%) with other tumors. Median follow-up was 26.0 months. In Phase Ib, LBL-007 was administered at 200 mg to four patients and 400 mg to six patients, with no dose-limiting toxicities observed. Therefore, the 400 mg dose of LBL-007 was established as the RP2D and administered to 70 patients in phase II. Nine (11.3%) of 80 patients had grade 3 or 4 treatment-related adverse events, the most common of which included anemia (2.5%), hyponatremia (2.5%), increased alanine aminotransferase (2.5%), increased aspartate aminotransferase (1.3%), and fatigue (1.3%). Eight patients (10.0%) had treatment-related serious adverse events. No treatment-related deaths were reported. In immunotherapy-naive NPC patients (n = 12), ORR was 33.3%, disease control rate (DCR) was 75%, and median progression-free survival (PFS) was 10.8 months (95% CI, 1.3 to not estimated). In IO-treated NPC patients (n = 17), ORR was 11.8%, DCR was 64.7%, and median PFS was 2.7 months (95% CI, 1.4 to 4.9). For other tumors, ORRs were 15.8% in immunotherapy-naive patients and 3.7% in immunotherapy-treated patients. Patients with ≥ 2 + LAG-3 expression had a higher ORR of 28.0%, compared to 7.7% in those with < 2 + LAG-3 expression. LBL-007 plus toripalimab exhibited a manageable safety profile in patients with advanced solid tumors and demonstrated promising antitumor activity in NPC, especially in immunotherapy-naive patients. These findings warrant further validation in future studies.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"48 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143367430","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}

{"title":"Transcriptional regulatory network analysis identifies GRN as a key regulator bridging chemotherapy and immunotherapy response in small cell lung cancer","authors":"Seungyeul Yoo, Ayushi S. Patel, Sarah Karam, Yi Zhong, Li Wang, Feng Jiang, Ranran Kong, Sharon Bikvan, Wenhui Wang, Abhilasha Sinha, Charles A. Powell, Jun Zhu, Hideo Watanabe","doi":"10.1186/s13045-025-01667-5","DOIUrl":"https://doi.org/10.1186/s13045-025-01667-5","url":null,"abstract":"Small cell lung cancer (SCLC) is an aggressive and heterogeneous subtype, representing 15% of lung cancer cases. Although SCLC initially responds to etoposide and platinum (EP) chemotherapy, nearly all patients relapse with resistant tumors. While recent advances in immunotherapy have shown promise, only 10–20% of patients benefit, and effective stratification methods are lacking. The mechanisms of resistance to both therapeutics remain obscure. In this study, we aimed to gain insights into those leveraging a recent surge in the field of SCLC genomics. We constructed a regulatory network for SCLC and identified granulin precursor (GRN) as a hub of EP response associated genes. GRN-low patients showed improved survival with chemotherapy, while GRN-high patients exhibited resistance. GRN overexpression in SCLC cells conferred resistance to EP treatment and suppressed neuroendocrine features. GRN and its associated genes were linked to cancer cell intrinsic immunogenicity, and single-cell RNA-seq data revealed that GRN expression is particularly high in subsets of tumor-associated macrophages. In concordance with these findings, GRN-low tumors showed significantly better survival with chemo-immunotherapy, while GRN-high tumors did not benefit from additional immunotherapy. GRN-high tumors, associated with non-neuroendocrine (non-NE) subtypes, had a higher level of macrophage infiltration, potentially contributing to immunotherapy resistance. These results highlight GRN as a critical regulator of chemo-resistance and a potential biomarker for immunotherapy resistance in SCLC. Targeted therapeutic strategies for GRN-low patients could improve outcomes, while new approaches are needed for GRN-high patients. Overall, our findings implicate GRN as a bridge between chemotherapy and immunotherapy resistance through GRN-mediated mechanisms.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"28 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143125349","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}

{"title":"Correction: Prognostic impact of donor mitochondrial genomic variants in myelodysplastic neoplasms after stem-cell transplantation","authors":"Jing Dong, Shahram Arsang-Jang, Tao Zhang, Zhongyuan Chen, Yung-Tsi Bolon, Stephen Spellman, Raul Urrutia, Paul Auer, Wael Saber","doi":"10.1186/s13045-025-01662-w","DOIUrl":"https://doi.org/10.1186/s13045-025-01662-w","url":null,"abstract":"&lt;p&gt;&lt;b&gt;Correction: Journal of Hematology &amp; Oncology (2024) 17:104&lt;/b&gt; &lt;b&gt;https://doi.org/10.1186/s13045-024-01622-w&lt;/b&gt;&lt;/p&gt;&lt;p&gt;The authors wish to note the following amendments to the affiliations and the funding in the original article.&lt;/p&gt;&lt;br/&gt;&lt;p&gt;The affiliations should instead be as follows:&lt;/p&gt;&lt;p&gt;• Wael Saber:&lt;/p&gt;&lt;br/&gt;&lt;p&gt;CIBMTR® (Center for International Blood and Marrow Transplant Research), Medical College of Wisconsin, Milwaukee, WI&lt;/p&gt;&lt;p&gt;• Paul Auer:&lt;/p&gt;&lt;br/&gt;&lt;p&gt;Division of Biostatistics, Data Science Institute, Medical College of Wisconsin, Milwaukee, WI&lt;/p&gt;&lt;br/&gt;&lt;p&gt;CIBMTR® (Center for International Blood and Marrow Transplant Research), Medical College of Wisconsin, Milwaukee, WI&lt;/p&gt;&lt;br/&gt;&lt;p&gt;Cancer Center Biostatistics Shared Resource, Medical College of Wisconsin, Milwaukee, WI&lt;/p&gt;&lt;p&gt;• Zhongyuan Chen:&lt;/p&gt;&lt;br/&gt;&lt;p&gt;Division of Biostatistics, Data Science Institute, Medical College of Wisconsin, Milwaukee, WI&lt;/p&gt;&lt;br/&gt;&lt;p&gt;CIBMTR® (Center for International Blood and Marrow Transplant Research), Medical College of Wisconsin, Milwaukee, WI&lt;/p&gt;&lt;br/&gt;&lt;p&gt;The Funding should instead read as follows:&lt;/p&gt;&lt;p&gt;Jing Dong is supported by the NHLBI (K01 HL164972) and the Medical College of Wisconsin Cancer Center. N00014-17-1-2850 from the Office of Naval Research. CIBMTR is supported primarily by the Public Health Service U24CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases (NIAID); 75R60222C00011 from the Health Resources and Services Administration (HRSA); and N00014-23-1-2057 and N00014-24-1-2057 from the Office of Naval Research. Support is also provided by the Medical College of Wisconsin, NMDP, Gateway for Cancer Research, Pediatric Transplantation and Cellular Therapy Consortium and from the following commercial entities: AbbVie; Actinium Pharmaceuticals, Inc.; Adaptive Biotechnologies Corporation; ADC Therapeutics; Adienne SA; Alexion; AlloVir, Inc.; Amgen, Inc.; Astellas Pharma US; AstraZeneca; Atara Biotherapeutics; BeiGene; BioLineRX; Blue Spark Technologies; bluebird bio, inc.; Blueprint Medicines; Bristol Myers Squibb Co.; CareDx Inc.; CSL Behring; CytoSen Therapeutics, Inc.; DKMS; Elevance Health; Eurofins Viracor, DBA Eurofins Transplant Diagnostics; Gamida-Cell, Ltd.; Gift of Life Biologics; Gift of Life Marrow Registry; GlaxoSmithKline; HistoGenetics; Incyte Corporation; Iovance; Janssen Research &amp; Development, LLC; Janssen/Johnson &amp; Johnson; Jasper Therapeutics; Jazz Pharmaceuticals, Inc.; Karius; Kashi Clinical Laboratories; Kiadis Pharma; Kite, a Gilead Company; Kyowa Kirin; Labcorp; Legend Biotech; Mallinckrodt Pharmaceuticals; Med Learning Group; Medac GmbH; Merck &amp; Co.; Mesoblast; Millennium, the Takeda Oncology Co.; Miller Pharmacal Group, Inc.; Miltenyi Biotec, Inc.; MorphoSys; MSA-EDITLife; Neovii Pharmaceuticals AG; Novartis Pharmaceuticals Corporation; Omeros Corporation; OptumHealth; Orca Biosystems, In","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"61 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143077453","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}

{"title":"N7-methylguanosine modification in cancers: from mechanisms to therapeutic potential","authors":"Qihui Wu, Xiaodan Fu, Guoqian Liu, Xiaoyun He, Yimin Li, Chunlin Ou","doi":"10.1186/s13045-025-01665-7","DOIUrl":"https://doi.org/10.1186/s13045-025-01665-7","url":null,"abstract":"N7-methylguanosine (m7G) is an important RNA modification involved in epigenetic regulation that is commonly observed in both prokaryotic and eukaryotic organisms. Their influence on the synthesis and processing of messenger RNA, ribosomal RNA, and transfer RNA allows m7G modifications to affect diverse cellular, physiological, and pathological processes. m7G modifications are pivotal in human diseases, particularly cancer progression. On one hand, m7G modification-associated modulate tumour progression and affect malignant biological characteristics, including sustained proliferation signalling, resistance to cell death, activation of invasion and metastasis, reprogramming of energy metabolism, genome instability, and immune evasion. This suggests that they may be novel therapeutic targets for cancer treatment. On the other hand, the aberrant expression of m7G modification-associated molecules is linked to clinicopathological characteristics, including tumour staging, lymph node metastasis, and unfavourable prognoses in patients with cancer, indicating their potential as tumour biomarkers. This review consolidates the discovery, identification, detection methodologies, and functional roles of m7G modification, analysing the mechanisms by which m7G modification-associated molecules contribute to tumour development, and exploring their potential clinical applications in cancer diagnostics and therapy, thereby providing innovative strategies for tumour identification and targeted treatment.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"84 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143054936","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}

{"title":"Correction: Bortezomib-releasing silica-collagen xerogels for local treatment of osteolytic bone- and minimal residual disease in multiple myeloma","authors":"Dirk Hose, Seemun Ray, Sina Rößler, Ulrich Thormann, Reinhard Schnettler, Kim de Veirman, Thaqif El Khassawna, Christian Heiss, Anne Hild, Daniel Zahner, Francisca Alagboso, Anja Henss, Susanne Beck, Martina Emde-Rajaratnam, Jürgen Burhenne, Juliane Bamberger, Eline Menu, Elke de Bruyne, Michael Gelinsky, Marian Kampschulte, Marcus Rohnke, Sabine Wenisch, Karin Vanderkerken, Thomas Hanke, Anja Seckinger, Volker Alt","doi":"10.1186/s13045-025-01663-9","DOIUrl":"https://doi.org/10.1186/s13045-025-01663-9","url":null,"abstract":"&lt;p&gt;&lt;b&gt;Journal of Hematology &amp; Oncology (2024) 17:128&lt;/b&gt;&lt;/p&gt;&lt;p&gt;&lt;b&gt;https://doi.org/10.1186/s13045-024-01636-4&lt;/b&gt;&lt;/p&gt;&lt;p&gt;The original article mistakenly omitted last author, Volker Alt as a co-Corresponding Author due to an error mistakenly carried forward by the production team.&lt;/p&gt;&lt;p&gt;Dr. Alt has since been restored as co-Corresponding Author.&lt;/p&gt;&lt;span&gt;Author notes&lt;/span&gt;&lt;ol&gt;&lt;li&gt;&lt;p&gt;Dirk Hose, Seemun Ray, Sina Rößler, Ulrich Thormann, Thomas Hanke, Anja Seckinger and Volker Alt have contributed equally to this work.&lt;/p&gt;&lt;/li&gt;&lt;/ol&gt;&lt;h3&gt;Authors and Affiliations&lt;/h3&gt;&lt;ol&gt;&lt;li&gt;&lt;p&gt;Laboratory of Hematology and Immunology &amp; Labor für Myelomforschung, Vrije Universiteit Brussel, Laarbeeklaan 103, Jette, 1090, Belgium&lt;/p&gt;&lt;p&gt;Dirk Hose, Ulrich Thormann, Kim de Veirman, Susanne Beck, Martina Emde-Rajaratnam, Eline Menu, Elke de Bruyne, Karin Vanderkerken &amp; Anja Seckinger&lt;/p&gt;&lt;/li&gt;&lt;li&gt;&lt;p&gt;Experimentelle Unfallchirurgie (ForMED), Justus-Liebig-Universität Gießen, Aulweg 128, 35392, Gießen, Germany&lt;/p&gt;&lt;p&gt;Seemun Ray, Thaqif El Khassawna, Christian Heiss, Francisca Alagboso &amp; Volker Alt&lt;/p&gt;&lt;/li&gt;&lt;li&gt;&lt;p&gt;Institut für Werkstoffwissenschaft, Max-Bergmann-Zentrum für Biomaterialien, Technische Universität Dresden, Budapester Straße 27, 01069, Dresden, Germany&lt;/p&gt;&lt;p&gt;Sina Rößler &amp; Thomas Hanke&lt;/p&gt;&lt;/li&gt;&lt;li&gt;&lt;p&gt;Justus-Liebig-Universität Gießen, Ludwigstraße 23, 35392, Gießen, Germany&lt;/p&gt;&lt;p&gt;Reinhard Schnettler &amp; Daniel Zahner&lt;/p&gt;&lt;/li&gt;&lt;li&gt;&lt;p&gt;Klinische Anatomie und Experimentelle Chirurgie C/O Institut für Veterinär-Anatomie, -Histologie und - Embryologie, Justus-Liebig-Universität Gießen, Frankfurter Straße 98, 35392, Gießen, Germany&lt;/p&gt;&lt;p&gt;Anne Hild &amp; Sabine Wenisch&lt;/p&gt;&lt;/li&gt;&lt;li&gt;&lt;p&gt;I. Physikalisches Institut, Justus-Liebig-Universität Gießen, Heinrich-Buff-Ring 16, 35392, Gießen, Germany&lt;/p&gt;&lt;p&gt;Anja Henss&lt;/p&gt;&lt;/li&gt;&lt;li&gt;&lt;p&gt;Innere Medizin IX - Abteilung für Klinische Pharmakologie und Pharmakoepidemiologie, Medizinische Fakultät/Universitätsklinikum Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany&lt;/p&gt;&lt;p&gt;Jürgen Burhenne&lt;/p&gt;&lt;/li&gt;&lt;li&gt;&lt;p&gt;Labor Für Experimentelle Radiologie, Justus-Liebig-Universität Gießen, Carl-Maria-von-Weber-Straße 8, 35392, Gießen, Germany&lt;/p&gt;&lt;p&gt;Juliane Bamberger &amp; Marian Kampschulte&lt;/p&gt;&lt;/li&gt;&lt;li&gt;&lt;p&gt;Zentrum für Translationale Knochen-, Gelenk- und Weichgewebeforschung, Technische Universität Dresden, Fetscherstraße 74, 01307, Dresden, Germany&lt;/p&gt;&lt;p&gt;Michael Gelinsky&lt;/p&gt;&lt;/li&gt;&lt;li&gt;&lt;p&gt;Physikalisch-Chemisches Institut, Justus-Liebig-Universität Gießen, Heinrich-Buff-Ring 17, 35392, Gießen, Germany&lt;/p&gt;&lt;p&gt;Marcus Rohnke&lt;/p&gt;&lt;/li&gt;&lt;li&gt;&lt;p&gt;Klinik und Poliklinik für Unfallchirurgie, Universitätsklinikum Regensburg, Franz-Josef-Strauß-Allee 11, 93053, Regensburg, Germany&lt;/p&gt;&lt;p&gt;Volker Alt&lt;/p&gt;&lt;/li&gt;&lt;/ol&gt;&lt;span&gt;Authors&lt;/span&gt;&lt;ol&gt;&lt;li&gt;&lt;span&gt;Dirk Hose&lt;/span&gt;View author publications&lt;p&gt;You can also search for this author in &lt;span&gt;PubMed&lt;span&gt; &lt;/span&gt;Google Scholar&lt;/span&gt;&lt;/p&gt;&lt;/li&gt;&lt;li&gt;&lt;span&gt;Seemun Ray&lt;/span&gt;View author publications&lt;p&gt;You can also search f","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"13 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143027224","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}

{"title":"Helicobacter pylori and gastric cancer: mechanisms and new perspectives","authors":"Yantao Duan, Yonghu Xu, Yi Dou, Dazhi Xu","doi":"10.1186/s13045-024-01654-2","DOIUrl":"https://doi.org/10.1186/s13045-024-01654-2","url":null,"abstract":"Gastric cancer remains a significant global health challenge, with Helicobacter pylori (H. pylori) recognized as a major etiological agent, affecting an estimated 50% of the world’s population. There has been a rapidly expanding knowledge of the molecular and pathogenetic mechanisms of H. pylori over the decades. This review summarizes the latest research advances to elucidate the molecular mechanisms underlying the H. pylori infection in gastric carcinogenesis. Our investigation of the molecular mechanisms reveals a complex network involving STAT3, NF-κB, Hippo, and Wnt/β-catenin pathways, which are dysregulated in gastric cancer caused by H. pylori. Furthermore, we highlight the role of H. pylori in inducing oxidative stress, DNA damage, chronic inflammation, and cell apoptosis—key cellular events that pave the way for carcinogenesis. Emerging evidence also suggests the effect of H. pylori on the tumor microenvironment and its possible implications for cancer immunotherapy. This review synthesizes the current knowledge and identifies gaps that warrant further investigation. Despite the progress in our previous knowledge of the development in H. pylori-induced gastric cancer, a comprehensive investigation of H. pylori’s role in gastric cancer is crucial for the advancement of prevention and treatment strategies. By elucidating these mechanisms, we aim to provide a more in-depth insights for the study and prevention of H. pylori-related gastric cancer.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"17 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143020545","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}

{"title":"WT1-mRNA dendritic cell vaccination of patients with glioblastoma multiforme, malignant pleural mesothelioma, metastatic breast cancer, and other solid tumors: type 1 T-lymphocyte responses are associated with clinical outcome","authors":"Zwi N. Berneman, Maxime De Laere, Paul Germonpré, Manon T. Huizing, Yannick Willemen, Eva Lion, Hans De Reu, Jolien Van den Bossche, Jan Van den Brande, Pol Specenier, Sevilay Altintas, Peter A. van Dam, Nathalie Cools, Griet Nijs, Barbara Stein, Kim Caluwaerts, Annemiek Snoeckx, Bart Op de Beeck, Kirsten Saevels, Lynn Rutsaert, Irma Vandenbosch, Gizem Oner, Martin Lammens, Pierre Van Damme, Sian Llewellyn-Lacey, David A. Price, Yoshihiro Oka, Yusuke Oji, Haruo Sugiyama, Marie M. Couttenye, Ann L. Van de Velde, Viggo F. Van Tendeloo, Marc Peeters, Sébastien Anguille, Evelien L.J.M. Smits","doi":"10.1186/s13045-025-01661-x","DOIUrl":"https://doi.org/10.1186/s13045-025-01661-x","url":null,"abstract":"Cell therapies, including tumor antigen-loaded dendritic cells used as therapeutic cancer vaccines, offer treatment options for patients with malignancies. We evaluated the feasibility, safety, immunogenicity, and clinical activity of adjuvant vaccination with Wilms’ tumor protein (WT1) mRNA-electroporated autologous dendritic cells (WT1-mRNA/DC) in a single-arm phase I/II clinical study of patients with advanced solid tumors receiving standard therapy. Disease status and immune reactivity were evaluated after 8 weeks and 6 months. WT1-mRNA/DC vaccination was feasible in all patients, except one. Vaccination was well tolerated without evidence of systemic toxicity. The disease control rate and overall response rate among a total of 39 evaluable patients were 74.4% and 12.8%, respectively. Median overall survival (OS) was 43.7 months among 13 patients with glioblastoma multiforme, 41.9 months among 12 patients with metastatic breast cancer, and 48.8 months among 10 patients with malignant pleural mesothelioma, comparing favourably with historical controls reported in the literature. OS was longer in patients with stable disease at 8 weeks and disease control at 6 months versus patients without disease control at either time point. Disease control and higher OS were associated with antigen-specific type 1 CD4+ and/or CD8+ T-lymphocyte responses, mainly induced by WT1-mRNA/DC vaccination. Antigen-nonspecific type 2 CD8+ T-cell responses were common before WT1-mRNA/DC vaccination but did not show any association with clinical outcome. Collectively, these data indicate that WT1-mRNA/DC vaccination is feasible, safe, and immunogenic and shows clinical activity in patients with advanced solid tumors, suggesting that it has the potential to help improve their survival.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"45 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143020549","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}

{"title":"Proteasome inhibition enhances oncolytic reovirus therapy in multiple myeloma independently of its direct cytotoxic effects","authors":"Ada Alice Dona, Theophilus Tandoh, Lokesh Nigam, Mahmoud Singer, Enrico Caserta, Mariam Murtadha, Yinghui Zhu, Milad Moloudizargari, Preeti Sharma, Ottavio Napolitano, Janet Winchester, Arnab Chowdhury, Alex Pozhitkov, James F. Sanchez, Hawa Vahed, Guido Marcucci, Matt Coffey, Gerard Nuovo, Douglas W. Sborov, Flavia Pichiorri, Craig C Hofmeister","doi":"10.1186/s13045-024-01645-3","DOIUrl":"https://doi.org/10.1186/s13045-024-01645-3","url":null,"abstract":"Reovirus (RV) is an oncolytic virus with natural tropism for cancer cells. We previously showed that RV administration in multiple myeloma (MM) patients was safe, but disease control associated with viral replication in the cancer cells was not observed. The combination with proteasome inhibitors (PIs) has shown to enhance RV therapeutic activity, but the mechanisms of action have not been fully elucidated. Electron microscopy, q-RT-PCR, single-cell mass cytometry (CyTOF), flow cytometry, plaque assays, immunohistochemistry, and Western blot analysis were used to assess RV infection of both myeloma and immune cells. Immune fluorescence, flow cytometry, and luciferase reporter assays were used to assess NF-κB pathway activation upon RV treatments. Immune profiling changes, both ex vivo and in MM patients, were analyzed by flow cytometry and CyTOF analysis. T-cell receptor (TCR) sequencing was also conducted both in immune competent MM mice and in patients enrolled in a phase 1b trial per a standard 3 + 3 dose escalation schedule. Here we show ex vivo and in vivo that proteasome inhibitors (PIs) potentiate reovirus replication in circulating classical monocytes, increasing viral delivery to myeloma cells. We found that the anti-viral signals in monocytes primarily rely on NF-κB activation and that this effect is impaired by the addition of PIs. Conversely, the addition of PIs to RV therapy supports immune activation and killing of MM, independently of direct PI sensitivity. To validate the importance of PIs in enhancing oncolytic viral therapy independently of their killing activity on cancer cells, we then conducted a phase 1b trial of the reovirus Pelareorep together with the PI carfilzomib in 13 heavily pretreated PI-resistant MM patients. Objective responses, which were associated with active reovirus replication in MM cells, T cell activation, and monocytic expansion, were noted in 70% of patients. Although characterized as immunosuppressive drugs, PIs improved RV delivery to MM cells but also enhanced anti-MM efficacy through immune-mediated killing of myeloma cells, independently of their PI sensitivity. These results highlight a more generalizable use of PIs as therapeutic companions to support oncolytic-based therapies in cancers. clinicaltrials.gov, NCT 02101944.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"56 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142989829","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}

{"title":"Multinational retrospective analysis of bridging therapy prior to chimeric antigen receptor t cells for relapsed/refractory acute lymphoblastic leukemia in children and young adults","authors":"Maike Breidenbach, Peter Bader, Andishe Attarbaschi, Claudia Rossig, Roland Meisel, Markus Metzler, Marion Subklewe, Fabian Mueller, Paul-Gerhardt Schlegel, Irene Teichert von Lüttichau, Jean-Pierre Bourquin, Gabriele Escherich, Gunnar Cario, Peter Lang, Ramona Coffey, Arend von Stackelberg, Semjon Willier, Brigitte Strahm, Christina Peters, Tobias Feuchtinger","doi":"10.1186/s13045-024-01659-x","DOIUrl":"https://doi.org/10.1186/s13045-024-01659-x","url":null,"abstract":"Anti-CD19 chimeric antigen receptor T cells (CAR) are a well-established treatment option for children and young adults suffering from relapsed/refractory B-lineage acute lymphoblastic leukemia. Bridging therapy is used to control disease prior to start of lymphodepletion before CAR infusion and thereby improve efficacy of CAR therapy. However, the effect of different bridging strategies on outcome, side effects and response to CAR therapy is still poorly understood. In this retrospective, multinational study, real-world data were collected from 14 different sites in Germany, Austria and Switzerland on 88 patients receiving 93 2nd-generation CAR therapies. Bridging therapy was classified into the categories 1) no systemic therapy (15/93 treatments), 2) low-intensity therapy (38/93 treatments) and 3) high-intensity therapy (39/93 treatments). We analyzed the impact of bridging regimens on clinical outcome. Patients receiving a high-intensity bridging therapy had a significantly higher tumor burden at time of eligibility compared to patients treated with a low-intensity or no systemic bridging therapy. They suffered significantly more from bacterial adverse events and mucositis. Overall survival was significantly better for patients who did not receive any bridging therapy in comparison to patients who had been treated with a low- or high-intensity bridging regimen. In conclusion, in this retrospective cohort, high-intensity bridging therapy has not improved the outcome in terms of overall and progression-free survival in comparison to a low-intensity therapy. Yet, high-intensity bridging therapy was associated with more adverse events. Our study suggests that a low-intensity bridging regimen may be preferred whenever tumor burden and disease kinetics allow this treatment strategy.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"37 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142988654","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}

{"title":"Olutasidenib in combination with azacitidine induces durable complete remissions in patients with relapsed or refractory mIDH1 acute myeloid leukemia: a multicohort open-label phase 1/2 trial","authors":"Jorge E. Cortes, Gail J. Roboz, Maria R. Baer, Brian A. Jonas, Gary J. Schiller, Karen Yee, P. Brent Ferrell, Jay Yang, Eunice S. Wang, William G. Blum, Alice Mims, Hua Tian, Aaron Sheppard, Stéphane de Botton, Pau Montesinos, Antonio Curti, Justin M. Watts","doi":"10.1186/s13045-024-01657-z","DOIUrl":"https://doi.org/10.1186/s13045-024-01657-z","url":null,"abstract":"Olutasidenib is a potent, selective, oral, small molecule inhibitor of mutant IDH1 (mIDH1) which induced durable remissions in high-risk, relapsed/refractory (R/R) mIDH1 AML patients in a phase 1/2 trial. We present a pooled analysis from multiple cohorts of the phase 1/2 trial of patients with R/R AML who received combination olutasidenib and azacitidine therapy. Adult patients with mIDH1R132 AML received 150 mg olutasidenib twice daily plus standard-of-care azacitidine (OLU + AZA) and were evaluated for response and safety. Sixty-seven patients with R/R mIDH1R132 AML received combination OLU + AZA. Median age was 66 years (range 28–82) and 54% were male. Most patients (83%) had 2 + prior regimens, including a hypomethylating agent in 40%, IDH1 inhibitor therapy in 31% (olutasidenib in 24%), and hematopoietic stem cell transplant in 10%. Cytogenetic risk was intermediate in 72%, poor in 18% and unknown in 10%. CR/CRh was achieved in 21/67 (31%; 95% CI 21–44) patients, with a median duration of 14.7 months (95% CI 4.6-not reached). CR was achieved in 18/67 (27%; 95% CI 17–39) patients, with median duration of 20.3 months (95% CI 3.7-not reached). Overall response (partial remission or better) was achieved in 34/67 (51%; 95% CI 38–63) patients. Median overall survival was 12.9 months (95% CI 18.7–19.3). In a subset analysis excluding patients who had prior OLU exposure (N = 51), CR/CRh was achieved in 19/51 (37%; 95% CI 24–52) patients, CR was achieved in 16/51 (31%; 95% CI 19–46), and overall response was achieved in 30/51 (59%; 95% CI 44–72). In patients who achieved CR/CRh and were transfusion-dependent at baseline, transfusion independence (RBC and platelets) was achieved in 64% (7/11) and 57% (4/7) of patients, respectively. The most common Grade 3 or 4 adverse events (> 20% patients) were decreased platelet count (37%), red blood cell count (25%), and neutrophil count (24%). Six patients (9%) experienced differentiation syndrome. Four (6%) discontinued treatment due to an adverse event. Olutasidenib plus azacitidine induced high response rates and durable remissions with a tolerable side effect profile in patients with R/R AML with diverse treatment histories. The results represent another therapeutic option for patients with mIDH1 AML who may benefit from a targeted therapy. NCT02719574.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"24 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142986796","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}