Experimental Hematology & Oncology最新文献

{"title":"The clinical landscape of CAR NK cells.","authors":"Lasse Vedel Jørgensen, Emil Birch Christensen, Mike Bogetofte Barnkob, Torben Barington","doi":"10.1186/s40164-025-00633-8","DOIUrl":"10.1186/s40164-025-00633-8","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR) NK cell therapy has emerged as a promising alternative to CAR T cell therapy, offering significant advantages in terms of safety and versatility. Here we explore the current clinical landscape of CAR NK cells, and their application in hematologic malignancies and solid cancers, as well as their potential for treating autoimmune disorders. Our analysis draws from data collected from 120 clinical trials focused on CAR NK cells, and presents insights into the demographics and characteristics of these studies. We further outline the specific targets and diseases under investigation, along with the major cell sources, genetic modifications, combination strategies, preconditioning- and dosing regimens, and manufacturing strategies being utilized. Initial results from 16 of these clinical trials demonstrate promising efficacy of CAR NK cells, particularly in B cell malignancies, where response rates are comparable to those seen with CAR T cells but with lower rates of severe adverse effects, such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and graft-versus-host disease (GvHD). However, challenges remain in solid tumor applications, where only modest efficacy has been observed to date. Our analysis reveals that research is increasingly focused on enhancing CAR NK cell persistence, broadening their therapeutic targets, and refining manufacturing processes to improve accessibility and scalability. With recent advancements in NK cell engineering and their increased clinical applications, CAR NK cells are predicted to become an integral component of next-generation immunotherapies, not only for cancer but potentially for immune-mediated diseases as well.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"46"},"PeriodicalIF":9.4,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143729376","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":"Hepatitis B surface antigen: carcinogenesis mechanisms and clinical implications in hepatocellular carcinoma.","authors":"Bingyan Hao, Yachong Liu, Bohan Wang, Haofeng Wu, Yan Chen, Lei Zhang","doi":"10.1186/s40164-025-00642-7","DOIUrl":"10.1186/s40164-025-00642-7","url":null,"abstract":"<p><p>Liver cancer is the third leading cause of death globally, with hepatitis B virus (HBV) infection being identified as the primary risk factor for its development. The occurrence of HBV-related hepatocellular carcinoma (HCC) is attributed to various mechanisms, such as chronic inflammation and liver cell regeneration induced by the cytotoxic immune response triggered by the virus, abnormal activation of oncogenes arising from HBV DNA insertion mutations, and epigenetic alterations mediated by viral oncoproteins. The envelope protein of the HBV virus, known as hepatitis B surface antigen (HBsAg), is a key indicator of increased risk for developing HCC in HBsAg-positive individuals. The HBsAg seroclearance status is found to be associated with recurrence in HCC patients undergoing hepatectomy. Additional evidence indicates that HBsAg is essential to the entire process of tumor development, from initiation to advancement, and acts as an oncoprotein involved in accelerating tumor progression. This review comprehensively analyzes the extensive effects and internal mechanisms of HBsAg during the various stages of the initiation and progression of HCC. Furthermore, it highlights the importance and potential applications of HBsAg in the realms of HCC early diagnosis and personalized therapeutic interventions. An in-depth understanding of the molecular mechanism of HBsAg in the occurrence and development of HCC is provided, which is expected to develop more precise and efficient strategies for the prevention and management of HCC in the future.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"44"},"PeriodicalIF":9.4,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11938626/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718339","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}

{"title":"Mechanisms of resistance to CAR-T cell therapy in multiple myeloma: latest updates from the 2024 ASH annual meeting.","authors":"Yuhan Hu, Jiangxue Hou, Zhongxing Jiang, Quande Lin","doi":"10.1186/s40164-025-00643-6","DOIUrl":"10.1186/s40164-025-00643-6","url":null,"abstract":"<p><p>Chimeric Antigen Receptor T-Cell (CAR-T) therapy demonstrates significant potential in the treatment of multiple myeloma (MM). However, resistance to CAR-T therapy remains a critical challenge. Investigating the mechanisms underlying CAR-T resistance, including antigen escape, immunosuppression, and CAR-T cell exhaustion, is essential for enhancing the long-term efficacy of this therapeutic approach. This study provides an in-depth review of the latest findings presented at the 66th ASH Annual Meeting.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"45"},"PeriodicalIF":9.4,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11938694/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718342","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}

{"title":"MMP14 from BM-MSCs facilitates progression and Ara-C resistance in acute myeloid leukemia via the JAK/STAT pathway.","authors":"Jinxian Wu, Xinqi Li, Yin Liu, Guopeng Chen, Ruihang Li, Hongqiang Jiang, Wanyue Yin, Xiqin Tong, Rui Cao, Xianwang Wang, Xiaoyan Liu, Fuling Zhou","doi":"10.1186/s40164-025-00635-6","DOIUrl":"10.1186/s40164-025-00635-6","url":null,"abstract":"<p><p>Growing evidence underscores the pivotal impact of crosstalk between leukemic stem cells (LSCs) and mesenchymal stromal cells (MSCs) within their niche on leukemia initiation, progression, and therapy response. Although MMP14 plays an important role in inflammation and cancer, the regulation and role of MSC-derived MMP14 in acute myeloid leukemia (AML) are largely unknown. Here, we found that AML patient-derived MSCs (AML-MSCs) were more supportive of AML cell growth compared to healthy donor-derived MSCs (HD-MSCs). Moreover, AML-MSCs and HD-MSCs showed significant differences in gene expression and protein expression profiles. Knockdown of MMP14 in MSCs inhibited the CFU-F ability of MSC cells and increased the proportion of cells in the G0 phase, thereby inhibiting proliferation. Co-culture with MSCs inhibited the proliferation and cell cycle progression of leukemia cells, while increasing the apoptosis rate, thus impairing the leukemogenic potential of AML cells both in vitro and in vivo. Mechanistic studies revealed that MMP14-mediated alterations in the AML stromal microenvironment are driven by PGE2 secretion and activation of the JAK-STAT pathway, promoting leukemia progression. Notably, inhibition of MMP14 can attenuate the chemotherapy resistance of AML cells induced by MSCs to cytarabine (Ara-C). Together, our study, for the first time, demonstrates the critical role of MSC-derived MMP14 in promoting AML progression and chemoresistance. Targeting MMP14 signaling pathways may offer novel therapeutic options for AML.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"43"},"PeriodicalIF":9.4,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11929205/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691426","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}

{"title":"Dynamin2 mutations in newly diagnosed acute myeloid leukemia: clinical characteristics, and prognostic significance.","authors":"Kunpeng Luo, Jiayuan Chen, Wenting Wang, Yan Hui, Shaowei Qiu, Bingcheng Liu, Yingchang Mi, Jianxiang Wang, Hui Wei","doi":"10.1186/s40164-025-00628-5","DOIUrl":"10.1186/s40164-025-00628-5","url":null,"abstract":"<p><p>Acute myeloid leukemia (AML) is a highly heterogeneous myeloid malignancy which can be classified by genetic aberrations. To evaluate the impact of the dynamin 2 mutation in AML, we systematically assessed the characteristics and prognostic of DNM2 mutated patients in AML. In 912 AML patients, 20 somatic mutations in the DNM2 gene were identified among the 18 DNM2 mutated AML patients (2%). Of the mutation events, 60% (12/20) were in the dynamin central region of DNM2. DNM2mutations were preferentially occurred in AML with CEBPA mutation (11/18, 61.1%), or RUNX1::RUNX1T1 fusion gene (6/18, 33.3%). DNM2 mutations were associated with better overall survival (P = 0.028), event-free survival (P = 0.0093) and trends towards better relapse-free survival (P = 0.08), which seems potentially attribute to its coexisting with CEBPA mutation and RUNX1::RUNX1T1 fusion gene. Our study demonstrated the clinical characteristics and the role of DNM2 mutations in AML, which might facilitate understanding the pathogenesis of AML.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"42"},"PeriodicalIF":9.4,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11927327/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143676769","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}

{"title":"Antibody-drug conjugates in breast cancer: current evidence and future directions.","authors":"Ning Li, Lu Yang, Zixuan Zhao, Tian Du, Gehao Liang, Na Li, Jun Tang","doi":"10.1186/s40164-025-00632-9","DOIUrl":"10.1186/s40164-025-00632-9","url":null,"abstract":"<p><p>Antibody-drug conjugates (ADCs) are a rapidly evolving class of antitumor drugs and have already revolutionized the treatment strategy of many hematologic and solid cancers. So far, trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), sacituzumab govitecan (SG) and datopotamab deruxtecan (Dato-DXd) are the four ADCs that have been approved by US food and drug administration (FDA) in treatment of breast cancer, and SKB264 has been approved by Chinese national medical products administration (NMPA). Many ADCs for treatment of breast cancer are currently being tested in late-phase clinical trials, with several encouraging results achieved recently. However, major issues arise during the use of ADCs, including emergence of acquired resistance, occurrence of treated-related toxicities, and identification of biomarkers of response and resistance. ADCs are being increasingly tested in combination with other agents, and novel next-generation ADC development is progressing rapidly. A better understanding of the design and development of ADCs will promote ADC development for cancer treatment. In this review, we aim to provide a broad overview of the design and the recent advances of ADCs in breast cancer. We also propose several notable future directions of ADCs in treatment of breast cancer.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"41"},"PeriodicalIF":9.4,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11924693/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143669571","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}

{"title":"All-in-one CRISPR/Cas-engineered glucocorticoid-receptor knock-out EBV-gp350-CAR knock-in T cells are potent and resistant to dexamethasone.","authors":"Theresa Kaeuferle, Maximilian Zwermann, Nadine Stoll, Paulina Ferrada-Ernst, Lena Jablonowski, Reinhard Zeidler, Semjon Willier, Dana Stenger, Abdallah Yassin, Renata Stripecke, Tobias Feuchtinger","doi":"10.1186/s40164-025-00631-w","DOIUrl":"10.1186/s40164-025-00631-w","url":null,"abstract":"<p><strong>Background: </strong>Epstein-Barr virus (EBV) reactivation in immunocompromised patients and post-transplantation is associated with morbidity, mortality and with the onset of a variety of malignant diseases. Adoptive T-cell therapies have emerged as promising therapeutic options, but post-transplant immunosuppression jeopardizes the protective anti-EBV immune surveillance by adoptively transferred T cells.</p><p><strong>Methods: </strong>Using an all-in-one CRISPR/Cas-mediated approach, we inserted an anti-EBV (gp350) CAR into the T-cell receptor (TRAC) locus and simultaneously knocked-out the glucocorticoid receptor (GR) on a good manufacturing practice (GMP)-compatible platform.</p><p><strong>Results: </strong>CAR knock-in (CAR^KI) was confirmed in primary human T cells on genetic and on protein level with a mean efficiency of 41%. With 83%, additional GR knock-out was highly efficient in CAR^KI cells. On a functional level CAR^KIGR^KO T cells showed target-specific potency in terms of cytokine secretion patterns, proliferative capacity and cytotoxic activity against gp350-expressing target cells. Further, CAR^KIGR^KO T cells were insensitive to dexamethasone treatment and maintained T-cell functionality. In contrast, CAR^KIGR^KO T cells were sensitive to the GR-independent immunosuppressant cyclosporine A (CsA), thereby providing a rescue treatment for patients in case of safety issues.</p><p><strong>Conclusions: </strong>The study lays the proof-of-concept for virus-free all-in-one GMP-manufacturing of glucocorticoid-resistant CAR T-cell products. Further, the glucocorticoid-resistant gp350-CAR T cells can provide a future therapeutic option for high-risk post-transplant patients with EBV-reactivations or patients with EBV-associated pathologies requiring steroid treatment.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"40"},"PeriodicalIF":9.4,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11921674/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663113","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}

{"title":"Disparities in the incidence, mortality and disability-adjusted life years of 33 early-onset cancer groups globally, 2012-2021: a systematic analysis.","authors":"Wenxin Yan, Min Liu, Wenzhan Jing, Liangyu Kang, Ning Zhang, Haoran Sun, Jinyu He, Zhongdan Chen, Jue Liu, Wannian Liang, Jiahong Dong","doi":"10.1186/s40164-025-00634-7","DOIUrl":"10.1186/s40164-025-00634-7","url":null,"abstract":"<p><strong>Background: </strong>The global cancer burden is rising, with early-onset cancers becoming more prevalent. We aimed to investigate the burden, trend and population disparity in 33 early-onset cancers from 2012 to 2021.</p><p><strong>Methods: </strong>Annual incidence, death, and disability-adjusted life years (DALY) numbers and rates for early-onset (15-49 years) cancer groups were calculated from Global Burden of Diseases (GBD) 2021 dataset, covering 2012-2021 across global, five SDI groupings, and 204 countries and territories. Estimated annual percentage change (EAPC) in the incidence, mortality and DALY rates was calculated to quantify temporal trends, while spearman correlation analysis was used to examine the correlation between rates, EAPC and SDI.</p><p><strong>Results: </strong>In 2021, there were 2.65 million new early-onset cancer cases excluding non-melanoma skin cancer (NMSC), resulting in 0.99 million deaths and 50.7 million DALYs. Breast, tracheal, bronchus and lung (TBL), cervical, colon and stomach cancers were the leading causes of DALYs. The DALY rate for early-onset cancer excluding NMSC changed from 65.7 million in 2012 to 67.0 million in 2021, with an estimated annual percentage change (EAPC) of -0.49%. While the DALY rate plateaued for females, it decreased by -0.95% for males. Ten of 33 cancer groups exhibited an EAPC > 0. The high SDI quintile had 1,100 DALYs per 100,000 caused by early-onset cancers excluding NMSC, with the highest declining trend in DALY and mortality rates, while the high-middle SDI quintile had the highest early-onset mortality rates. Rising trends in cancer incidence and mortality were especially notable among females in the middle, low-middle, and low SDI quintiles.</p><p><strong>Conclusion: </strong>The global burden of early-onset cancer differs significantly by SDI quintile and gender. The increasing burden across multiple cancer groups poses a significant public health challenge. The rising burden of multiple cancer types is alarming, highlighting the need for increased policy support and targeted medical assistance to address the disparities in their impact.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"38"},"PeriodicalIF":9.4,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11912769/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143647661","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}

{"title":"New exploration of KRAS^G12D inhibitors and the mechanisms of resistance.","authors":"Ying Li, Junfeng Zhao, Yintao Li","doi":"10.1186/s40164-025-00637-4","DOIUrl":"10.1186/s40164-025-00637-4","url":null,"abstract":"<p><p>The development of Kirsten rat sarcoma viral oncogene homologue (KRAS) targeted therapies has been the focus of cancer treatment. The most common mutant subtypes of KRAS driver genes are G12C, G12V, and G12D, and are associated with poor prognosis. Up to now, inhibitors specifically targeting KRAS^G12D mutant proteins are all in the pre-clinical/early clinical research stage, and there is still a lack of effective clinical targeting strategies. In their recently published article, Zhou et al. developed a high-affinity, selective, long-acting, non-covalent KRAS^G12D-specific inhibitor and, further combined with the proteasome inhibitor carfilzomib, found that this protocol can achieve the purpose of killing mutant cell lines and inhibiting tumor growth in vitro and in vivo. Here, we aim to describe a potential novel therapy for patients with KRAS^G12D mutations and present the first KRAS^G12D-specific inhibitor to be proven as clinically effective. Different mutations of KRAS gene and mechanisms of KRAS drug resistance were also discussed.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"39"},"PeriodicalIF":9.4,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11912584/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143647717","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}

{"title":"Post-translational modifications of immune checkpoints: unlocking new potentials in cancer immunotherapy.","authors":"Qiongjie Hu, Yueli Shi, Huang Wang, Liuwen Bing, Zhiyong Xu","doi":"10.1186/s40164-025-00627-6","DOIUrl":"10.1186/s40164-025-00627-6","url":null,"abstract":"<p><p>Immunotherapy targeting immune checkpoints has gained traction across various cancer types in clinical settings due to its notable advantages. Despite this, the overall response rates among patients remain modest, alongside issues of drug resistance and adverse effects. Hence, there is a pressing need to enhance immune checkpoint blockade (ICB) therapies. Post-translational modifications (PTMs) are crucial for protein functionality. Recent research emphasizes their pivotal role in immune checkpoint regulation, directly impacting the expression and function of these key proteins. This review delves into the influence of significant PTMs-ubiquitination, phosphorylation, and glycosylation-on immune checkpoint signaling. By targeting these modifications, novel immunotherapeutic strategies have emerged, paving the way for advancements in optimizing immune checkpoint blockade therapies in the future.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"37"},"PeriodicalIF":9.4,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11907956/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143633610","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}