Journal of Hematology & Oncology最新文献

{"title":"Immunosenescence and cancer: molecular hallmarks, tumor microenvironment remodeling, and age-specific immunotherapy challenges","authors":"Qianwen Liu, Jingfeng Li, Xiuqiao Sun, Jiayu Lin, Zhengwei Yu, Yue Xiao, Dan Li, Baofa Sun, Haili Bao, Yihao Liu","doi":"10.1186/s13045-025-01735-w","DOIUrl":"https://doi.org/10.1186/s13045-025-01735-w","url":null,"abstract":"Immunosenescence, the age-related decline in immune function, profoundly impacts cancer progression and therapeutic outcomes by fostering a tumor-promoting microenvironment and impairing immune surveillance. This review delineates eleven molecular hallmarks of immunosenescence, including genomic instability, telomere attrition, epigenetic dysregulation, mitochondrial dysfunction, and chronic inflammation, which collectively drive immune cell dysfunction and systemic immunosuppression. Aging reshapes the tumor microenvironment (TME) through recruitment of immunosuppressive cells, senescence-associated secretory phenotypes (SASP), and metabolic reprogramming, contributing to therapy resistance and poor prognosis in elderly patients. While immunotherapies such as immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T-cell immunotherapy (CAR-T) cells show promise, their efficacy in aging populations is limited by T cell exhaustion, myeloid bias, and altered intercellular communication. Emerging strategies—including senolytics, epigenetic modulators (e.g., histone deacetylase (HDAC) inhibitor), and metabolic interventions (e.g., spermidine, nicotinamide mononucleotide (NMN))—highlight potential avenues to rejuvenate aged immunity. Single-cell multi-omics (single cell RNA-seq, single cell ATAC-seq) further unravel immune cell heterogeneity, revealing tissue-specific chromatin accessibility dynamics and novel targets like interleukin-34 (IL-34) for microglia-mediated neuroinflammation. However, challenges persist in translating preclinical findings to clinical practice, necessitating age-tailored trials and biomarker-driven approaches. By integrating mechanistic insights with translational innovations, this review underscores the urgency of addressing immunosenescence to optimize cancer immunotherapy for aging populations, ultimately bridging the gap between aging biology and precision oncology.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"15 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144899266","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":"Target neutrophil heterogeneity and plasticity in cancer","authors":"Ye Feng, Guang Liu, Haiqing Li, Lin Cheng","doi":"10.1186/s13045-025-01731-0","DOIUrl":"https://doi.org/10.1186/s13045-025-01731-0","url":null,"abstract":"Neutrophils have long been regarded as cells of a limited lifespan, known to produce pro-inflammatory molecules, and primarily engaged in combating infections. However, recent advancements in single-cell analysis and molecular biology have revealed their remarkable heterogeneity and plasticity, particularly within the context of tumors. This review explores the development and diversity of neutrophils under both physiological and pathological conditions, with a particular focus on their roles in cancer. The discussion encompasses the emergence of distinct neutrophil subtypes, particularly senescent neutrophils, within tumors and their context-dependent functions in tumorigenesis, progression, metastasis, and recurrence. The plasticity of these cells, driven by intrinsic factors and the tumor microenvironment, allows them to be reprogrammed between pro-tumor and anti-tumor phenotypes. This process is influenced by cytokines, metabolic reprogramming, and interactions with other immune cells. The potential of targeting and engineering neutrophil as a therapeutic avenue for cancer treatment is further underscored, including the use of senolytic agents, metabolic inhibitors, and reprogramming strategies. Finally, future research directions are proposed to further elucidate the mechanisms underlying neutrophil heterogeneity and plasticity, with the aim of developing novel therapeutic approaches to modulate neutrophil function in cancer.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"3 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144819432","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":"Mitophagy’s impacts on cancer and neurodegenerative diseases: implications for future therapies","authors":"Jason Huang, Vincent Truong Pham, Shaozi Fu, Gang Huang, Ya-Guang Liu, Lei Zheng","doi":"10.1186/s13045-025-01727-w","DOIUrl":"https://doi.org/10.1186/s13045-025-01727-w","url":null,"abstract":"Substantial evidence supports an inverse relationship between cancer and neurodegenerative diseases (NDDs), but few studies investigate the biological mechanisms underlying this phenomenon. While previous explanations—such as inflammation, reactive oxygen species (ROS), genetic mutations, and cell death—remain significant, they ultimately converge on mitophagy. This review identifies mitophagy as a pivotal factor in the development of both cancer and NDDs, while also evaluating specific mechanisms and processes to clarify how mitophagy connects these opposing disease trajectories. By examining these factors, we aim to uncover the underlying mechanisms that explain the inverse relationship between cancer and NDDs, which will help develop therapeutic strategies that target common factors for both conditions.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"11 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144756579","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":"Necroptosis in cancer: insight from epigenetic, post-transcriptional and post-translational modifications","authors":"Jinxin Tang, Yan Zhuang, Yibo Zhang, Hongkun Hu, Hua Wang, Haodong Xu, Yintao Li, Chao Tu","doi":"10.1186/s13045-025-01726-x","DOIUrl":"https://doi.org/10.1186/s13045-025-01726-x","url":null,"abstract":"Necroptosis represents a distinct form of programmed cell death that exhibits characteristics of both necrosis and apoptosis. Due to its potential to activate anti-cancer immune responses, utilizing necroptosis to enhance immune activity within the tumor microenvironment has garnered significant attention. However, effectively regulating necroptosis in cancer remains a formidable challenge. Epigenetic, post-transcriptional and post-translational modifications are three primary mechanisms that alter molecular expression patterns without changing DNA sequence, playing crucial roles in cancer progression. While these modifications have been shown to significantly influence cancer development, their specific roles in regulating necroptosis in cancer have not been systematically elucidated. This review explores the role and mechanism of epigenetic, post-transcriptional and post-translational modification in the regulation of necroptosis in cancer, identifying potential regulatory targets and their therapeutic implications, thereby providing systematic theoretical support for necroptosis as an emerging target for cancer therapy.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"21 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144747294","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":"Targeting CD276 with Adapter-CAR T-cells provides a novel therapeutic strategy in small cell lung cancer and prevents CD276-dependent fratricide","authors":"Beate Kristmann, Niels Werchau, Lakshmi Suresh, Elisabeth L. Pezzuto, Sophia Scheuermann, Simon Krost, Karin Schilbach, Moustafa Moustafa-Oglou, Anna-Sophia Mast, Miriam Droste, André Felsberger, Lukas Kiefer, Pierre Abramowski, Lars Zender, Joerg Mittelstaet, Christian M. Seitz","doi":"10.1186/s13045-025-01729-8","DOIUrl":"https://doi.org/10.1186/s13045-025-01729-8","url":null,"abstract":"Survival rates in Small Cell Lung Cancer (SCLC) remain dismal, posing a huge medical need for novel therapies. T-cells, engineered to express chimeric antigen receptors (CAR-T) have demonstrated clinical activity against a variety of haematological malignancies. Yet, efficacy against solid tumour entities remains limited. In this study, we investigated the expression of CD276 (B7-H3), an immune checkpoint molecule and promising target antigen for CAR-T therapy in SCLC, at the RNA and protein level. We further developed novel Fab-based adapter molecules (AM) targeting CD276 and optimized our previously established modular Adapter CAR-T (AdCAR-T) platform as well as AM dosing schemes. CD276 is broadly expressed across SCLC subtypes, representing a promising target for CAR-T therapy. We describe that T-cell activation and CAR-signalling induces CD276-expression on CAR-T, resulting in CD276-dependent fratricide, limiting anti-CD276-CAR-T expansion and activity. The AdCAR-T platform allows CAR-T expansion in absence of CD276 targeting. Novel CD276 targeted AMs demonstrate potent in vitro and in vivo activity against SCLC. Intermittent AM-dosing allows functional persistence of AdCAR-T in vivo in contrast to CD276-targeted conventional CAR-T. AdCAR-T in vivo expansion and activity is further promoted by introducing activation-induced, AM remote controlled, IL-18 secretion into the AdCAR-T design. We identified CD276 as a promising target antigen, uniformly expressed in SCLC and demonstrate the therapeutic potential of novel anti-CD276 Fab-based AM in combination with optimized, IL-18 armoured AdCAR-T.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"215 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144719470","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":"Iparomlimab and tuvonralimab (QL1706) plus chemotherapy and bevacizumab for EGFR-mutant patients with advanced non-small cell lung cancer after failure of EGFR-tyrosine kinase inhibitors: updated results from cohort 5 in the DUBHE-L-201 study","authors":"Yaxiong Zhang, Yan Huang, Yunpeng Yang, Yuanyuan Zhao, Hongyun Zhao, Ningning Zhou, Likun Chen, Ting Zhou, Gang Chen, Shen Zhao, Huaqiang Zhou, Hui Li, Xiaoyan Kang, Li Zhang, Wenfeng Fang","doi":"10.1186/s13045-025-01728-9","DOIUrl":"https://doi.org/10.1186/s13045-025-01728-9","url":null,"abstract":"Iparomlimab and tuvonralimab (QL1706), a bifunctional anti-programmed death-1/cytotoxic T-lymphocyte antigen-4 antibody, in combination with bevacizumab and doublet chemotherapy was tolerable and showed preliminary antitumor activity in advanced non-small cell lung cancer (NSCLC) in DUBHE-L-201 study. Here, we report the updated data of long-term survival prognosis and safety from cohort 5. Epidermal growth factor receptor (EGFR)-mutant patients who progressed on EGFR-tyrosine kinase inhibitors (TKIs) were enrolled in cohort 5 and received QL1706 (5 mg/kg) combined with bevacizumab, pemetrexed and carboplatin in a three-week cycle for up to four cycles followed by maintenance therapy of QL1706, bevacizumab and pemetrexed. Survival outcomes and adverse events were followed up. As of July 5, 2024, the median duration of response, progression-free survival (PFS), and overall survival (OS) in the 31 patients in cohort 5 was 11.33 months (95% confidence interval [CI]: 4.17–19.91), 8.51 months (95% CI: 5.72–13.31), and 26.51 months (95% CI: 12.81-not reached), respectively. In 23 (74.2%) patients who received subsequent anticancer therapy after disease progression, the median PFS was 10.02 months. The median PFS (8.51 months vs. 5.95 months, P = 0.622) and median OS (30.19 months vs. 10.68 months, P = 0.177) appeared longer in patients with 21L858R mutation compared to those with 19Del, although the differences were not statistically significant. Grade ≥ 3 treatment-related adverse events occurred in 13 (41.9%) patients. Nineteen (61.3%) patients had immune-related adverse events, of whom one (3.2%) were grade ≥ 3. No new safety signal was observed. QL1706 combining pemetrexed, carboplatin, and bevacizumab showed long-term favorable prognosis and manageable safety profile for advanced EGFR-mutant patients with NSCLC after failure of EGFR-TKIs.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"118 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144710706","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":"Circular RNA signature of aggressive CLL with t(14;19)(q32;q13). An ERIC study","authors":"Eleonora Roncaglia, Enrico Gaffo, Giulia Calabretto, Moritz Fürstenau, Kerry A. Rogers, Panagiotis Baliakas, Chenghua Cui, Cecelia Miller, Claudia Haferlach, Karla Plevova, David Oscier, Zadie Davis, Florence Nguyen-Khac, Gian Matteo Rigolin, Anastasia Athanasiadou, Fanny Baran-Marszak, Alberto Valiente, Maria José Terol, Pau Abrisqueta, Blanca Espinet, Anna Puiggros, Annalisa Martines, Laura Bonaldi, Francesca Romana Mauro, Lydia Scarfò, Thomas Chatzikonstantinou, Eugen Tausch, Karl-Anton Kreuzer, Arnon Kater, Francesc Bosch, Michael Doubek, Panagiotis Panagiotidis, Olga Kalashnikova, Federica Frezzato, Valeria Ruocco, Silvia Orsi, Kimia Salek, Roberto Merlo, Alberto Caregari, Ilias Glogovitis, Alessandro Cellini, Francesco Angotzi, Andrea Serafin, Shuhua Yi, Barbara Eichhorst, Jennifer A. Woyach, Antonio Cuneo, Paolo Ghia, Kostas Stamatopoulos, Livio Trentin, Andrea Visentin, Stefania Bortoluzzi","doi":"10.1186/s13045-025-01725-y","DOIUrl":"https://doi.org/10.1186/s13045-025-01725-y","url":null,"abstract":"In Chronic Lymphocytic Leukemia (CLL), t(14;19)(q32;q13), leading to the overexpression of BCL3, is found in ∼1% of cases and is associated with an aggressive disease. In this study, leveraging a large CLL patient cohort collected thanks to an international collaboration, we investigate for the first time the circular transcriptome (circRNAome) associated with the rare t(14;19), in comparison with CLL without t(14;19) and B cells of age-matched healthy donors. We described the circRNAs commonly dysregulated in CLL, including circCSNK1G3 and circEXOC6B(3–5), which were depleted, and circZNF609 and circLPAR3, which were overexpressed in malignant cells. Of importance, we disclosed the circRNA signature of CLL with t(14;19), formed by circRNAs with expression significantly altered specifically in link with this lesion, ectopically expressed like circCDK14(3–4), circCORO1C, circCLEC2D, and circEMB, or downregulated like circCEP70(3–6). Several of these molecules were previously shown to be dysregulated or play a role in cancer, whereas most of the signature circRNAs deserve further investigation. CLL patients with high circCORO1C and circCLEC2D expression had significantly worse clinical outcomes, with shorter time to first treatment and overall survival. This study disclosed new molecular features of the aggressive CLL subtype with t(14;19).","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"27 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144678016","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":"Phase I first-in-human dose escalation study of the oral casein kinase 1α and cyclin dependent kinase 7/9 inhibitor BTX A51 in advanced MDS and AML","authors":"Brian J. Ball, Wenbin Xiao, Gautam Borthakur, Le Xuan Truong Nguyen, Melissa Valerio, Avanthika Venkatachalam, Guido Marcucci, Anthony S. Stein, Dung Luong Thai, David N. Cook, Kyle Chan, Sonali Persaud, Ross L. Levine, Omar Abdel-Wahab, Yinon Ben-Neriah, Eytan M. Stein","doi":"10.1186/s13045-025-01724-z","DOIUrl":"https://doi.org/10.1186/s13045-025-01724-z","url":null,"abstract":"BTX A51, a first-in-class oral small molecule inhibitor of casein kinase 1α (CK1α) and cyclin-dependent kinase (CDK) 7 and 9, induces apoptosis of leukemic cells by activating p53 and inhibiting expression of Mcl1. Here, we report on the results of the phase 1 clinical trial of BTX A51 in patients with relapsed or refractory AML and MDS. Adult patients with R/R AML and high-risk MDS were enrolled into eight potential doses ranging from 1 to 42 mg dosed orally three days/week for 21 or 28 days out of a 28-day cycle. The maximum tolerated dose, recommended phase 2 dose (RP2D), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of BTX A51 were investigated. Thirty-one patients were enrolled and received treatment with BTX A51. Median age was 75 (range 22- 84) and 55% were male. Most patients (97%) had received prior treatment with venetoclax and hypomethylating agents. The most common treatment-emergent adverse events of any grade were nausea (67%), emesis (63%), hypokalemia (53%), and diarrhea (40%). Two patients experienced hepatic toxicity as DLTs, which resolved upon holding treatment. No treatment-related deaths occurred. The recommended phase 2 dose was 21 mg dosed three days/week for 4 weeks of a 28-day cycle. BTX A51 increased the expression of p53 and reduced the expression of MCL1 and RNA polymerase II phosphorylation in pre- and post-treatment immunocytochemistry studies. Overall, 3 patients (10%) experienced complete remission with incomplete count recovery (CRi). All 3 responding patients had RUNX1 mutations and the CR/CRi rate for RUNX1-mutated patients receiving BTX A51 at efficacious doses (11 mg or higher) was 30%. Ex-vivo studies confirmed higher efficacy of BTX A51 on RUNX1-mutated myeloblasts and demonstrated synergy with azacitidine and venetoclax. Although the overall efficacy was modest, this study lays the groundwork for future studies with improved patient selection and combination approaches. NCT04872166.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"52 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144640353","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":"Development and validation of a prognostic staging system for primary plasma cell leukemia","authors":"Mengru Tian, Gang An, Weijun Fu, Wenqiang Yan, Lu Li, Chunyan Sun, Zhenyu Li, Lijuan Chen, Aijun Liao, Guangxun Gao, Xiaoqi Qin, Mengyao Li, Chunrui Li, Hua Xue, Li Gao, Yi Wang, Aili He, Fan Zhou, Dongmei Guo, Yujun Dong, Zhihong Fang, Xiaoxia Chu, Jianqing Mi, Chengcheng Fu, Hui Zeng, Shuling Hou, Xiaotao Wang, Hua Wang, Yongqiang Wei, Xinyue Liang, Xingcheng Yi, Yue Sun, Lugui Qiu, Yun Dai, Fengyan Jin","doi":"10.1186/s13045-025-01723-0","DOIUrl":"https://doi.org/10.1186/s13045-025-01723-0","url":null,"abstract":"The existing risk models for multiple myeloma (MM) are suboptimal for the stratification of patients with primary plasma cell leukemia (pPCL), a rare and peculiar MM. In this study, we aimed to develop a staging system for pPCL defined as the presence of ≥ 5% circulating plasma cells (CPC) according to the new diagnostic criteria, utilizing one of the largest series of patients with pPCL. This multicenter retrospective study included 340 patients with pPCL (the training cohort) from 25 centers nationwide in China. The prognostic impact of baseline characteristics and cytogenetic abnormalities was evaluated. Univariate and multivariate analyses were conducted to identify variables predicting overall survival (OS) to develop a staging system. Its performance was then validated in an independent cohort (n = 80). Genome-wide DNA and RNA sequencing were performed to explore the molecular basis for inter-stage clinical heterogeneity. Del(17p), t(4;14), and t(14;16), but not 1q+, were verified as high-risk cytogenetic abnormalities (HRCAs) of pPCL. HRCA, elevated LDH, and thrombocytopenia had the highest impact on OS and were used to create a simple algorithm, stratifying patients with pPCL into stages I, II, and III, with median OS of 54.1, 24.0, and 5.4 months (II vs. I: HR, 1.986; 95% CI, 1.034–3.814; P = 0.0394; III vs. II: HR, 3.206; 95% CI, 1.757–5.852; P = 0.0001) in the training cohort and 62.1, 31.6, and 21.8 months (II vs. I: HR, 2.013; 95% CI, 0.954–4.251; P = 0.0664; III vs. II: HR, 2.694; 95% CI, 1.136–6.392; P = 0.0245) in the independent validation cohort. The accuracy (c-index 0.711) was higher than other models. Moreover, patients with different stages had highly diverse genomic and transcriptomic aberrations. We propose a pPCL-specific staging system based on LDH, thrombocytopenia, and cytogenetic abnormalities, which warrants further validation, particularly in a prospective setting.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"9 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144629672","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":"Treatment-related adverse events of antibody drug-conjugates in clinical trials","authors":"Harold Nathan Tan, Marta Ascanio Morcillo, Juanita Lopez, Anna Minchom, Adam Sharp, Alec Paschalis, Georgina Silva-Fortes, Bindu Raobaikady, Udai Banerji","doi":"10.1186/s13045-025-01720-3","DOIUrl":"https://doi.org/10.1186/s13045-025-01720-3","url":null,"abstract":"Antibody–drug conjugates (ADCs) aim to enhance the therapeutic index of cytotoxic agents but can cause unexpected toxicities. This study evaluated adverse events (AEs) from phase 1 trials at The Royal Marsden Drug Development Unit (DDU) over a decade and pivotal phase 2 and 3 trials leading to FDA registration, correlating AEs with ADC components such as target, antibody, linker, payload, and Drug-to-Antibody Ratio (DAR). We performed a retrospective cohort analysis of patients treated with ADCs in phase 1 trials (January 2014 to January 2024) compared to published phase 2–3 trials of FDA-approved ADCs. Univariate and multivariate logistic regression analyzed ADC components and treatment toxicities. One hundred thirty one phase 1 trial patients and 2666 phase 2–3 trial participants were included. High incidences of any-grade treatment-related AEs were observed (89% in phase 1, 93% in phase 2–3), with 58% experiencing grade 3 or higher toxicities in phase 1 and 46% in later phases. Major AEs included fatigue, hematologic toxicities, nausea/vomiting, ocular toxicities, and peripheral neuropathy. Antibody targets were linked to neuropathy, non-cleavable linkers to ocular, pulmonary, and hematologic toxicities, and tubulin-binding payloads to peripheral neuropathy. ADCs with DAR > 4 were associated with higher pulmonary and hematologic AEs. Despite their design to minimize toxicity, ADCs were linked to significant AEs. Specific ADC components may contribute to distinct toxicities, necessitating more robust trial data to inform future ADC design. ","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"20 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144547381","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}