Experimental Hematology & Oncology最新文献

{"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}

{"title":"Engineered circular RNA-based DLL3-targeted CAR-T therapy for small cell lung cancer.","authors":"Jingsheng Cai, Zheng Liu, Shaoyi Chen, Jingwei Zhang, Haoran Li, Xun Wang, Feng Yang, Shaodong Wang, Xiao Li, Yun Li, Kezhong Chen, Jun Wang, Ming Sun, Mantang Qiu","doi":"10.1186/s40164-025-00625-8","DOIUrl":"10.1186/s40164-025-00625-8","url":null,"abstract":"<p><strong>Purpose: </strong>Circular RNA (circRNA) has emerged as a promising RNA therapeutic molecule due to its enhanced stability and prolonged protein expression compared to messenger RNA (mRNA). Using circRNA to construct transient Chimeric Antigen Receptor (CAR)-T cells can mitigate the limitations of conventional viral vector-based CAR-T approaches, such as complex process and long-term side effects.</p><p><strong>Methods: </strong>The study first reconfirmed the advantageous properties of circRNA, focusing on its stability and protein expression efficiency. Electroporation conditions were then optimized for the efficient delivery of circRNA into human primary T cells. Subsequently, a circRNA encoding the anti-Delta-like Ligand 3 (DLL3) CAR was constructed, and CAR-T cells were generated via electroporation. The efficacy of circRNA-based CAR-T cells was compared to mRNA-based CAR-T cells in both in vitro and in vivo models, including subcutaneous and orthotopic small cell lung cancer (SCLC) mouse models.</p><p><strong>Results: </strong>CircRNA-based CAR-T cells demonstrated superior efficacy against SCLC compared to mRNA-based CAR-T cells. In vitro experiments showed enhanced tumor-killing effects, while in vivo studies revealed complete elimination of human SCLC tumors in both subcutaneous and orthotopic mouse models. These results underscored the therapeutic advantages of circRNA in CAR-T cell therapy.</p><p><strong>Conclusions: </strong>This study validated the feasibility of the circRNA-electroporation strategy in CAR-T cell therapy and offered a potentially effective approach for treating SCLC, highlighting the potential of circRNA-based technologies in advancing cell therapies.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"35"},"PeriodicalIF":9.4,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905684/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143614082","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":"Exosomal PD-L1 and lactate versus tissue PD-L1 as biomarkers for clinical outcomes of PD-1 Blockade plus chemotherapy in metastatic esophagogastric signet ring cell carcinoma.","authors":"Yuanyuan Tian, Wei Shi, Jing Wang, Wenjie Zhang, Lingling Xia, Lijuan Gao, Hu Qiu, Zhenhua Yu, Yongfeng Zhang, Yongshun Chen","doi":"10.1186/s40164-025-00615-w","DOIUrl":"10.1186/s40164-025-00615-w","url":null,"abstract":"<p><p>In this investigator-initiated, prospective, exploratory study, biomarkers predictive of clinical outcomes of first-line immune checkpoint inhibitor (ICI, nivolumab or pembrolizumab) plus XELOX(oxaliplatin and capecitabine) were identified in human epidermal growth factor receptor 2 (HER2)-negative patients with metastatic esophagogastric signet ring cell carcinoma. The findings showed an objective response rate (ORR) of 51.5% and a disease control rate of 86.8%, the median progression-free survival (PFS) for the entire cohort was 6.63 months. PD-L1 expression level in tumor tissues could not identify a high PD-L1 group that significantly benefited from ICI plus XELOX in terms of the ORR and PFS. By contrast, the patients expressing low exosomal PD-L1 or lactate in peripheral blood plasma before treatment initiation demonstrated a significantly increased ORR and prolonged PFS compared to that with high exosomal PD-L1 or lactate, patients with combining predictor of exosomal PD-L1 and lactate lower than - 0.249 was associated with a better ORR (82.1% vs. 30.0%, P < 0.001) and a longer median PFS (13.83 vs. 5.50 months, P < 0.001) compared to those with combining predictor ≥-0.249. The results also revealed that exosomal PD-L1 levels in peripheral blood plasma before the treatment were significantly correlated with the frequency of CD8⁺ T cells (P = 0.007), and in patients after receiving ICI plus XELOX, high exosomal PD-L1 level was associated with more PD-1⁺ Treg cells, high exosomal lactate level was associated with less CD8⁺ T cells and more Treg cells. Thus, the levels of PD-L1 and lactate in exosomes may affect the balance between Treg cells and CD8⁺T cells, leading to treatment resistance to ICI plus XELOX. Compared to PD-L1 expression level in tumor tissues, exosomal PD-L1 and lactate levels could more accurately predict clinical outcomes of HER2-negative patients with metastatic esophagogastric signet ring cell carcinoma receiving first-line PD-1 blockade plus chemotherapy.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"34"},"PeriodicalIF":9.4,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905711/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143614085","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":"Efficacy and safety of immune checkpoint inhibitors in metastatic penile squamous cell carcinoma: a retrospective multicenter analysis.","authors":"Timothy Schieber, Kelly Brunk, Anna Clennon, Benjamin L Woolbright, Leonidas E Bantis, Dennis Grauer, Tiewei Cheng, Saqib Abbasi, Elizabeth Wulff-Burchfield, Rahul Parikh, Haoran Li","doi":"10.1186/s40164-025-00629-4","DOIUrl":"10.1186/s40164-025-00629-4","url":null,"abstract":"<p><p>Penile squamous cell carcinoma (PSCC) is a rare malignancy, and first-line therapy typically involves cisplatin-based chemotherapy. However, these regimens are often unsuitable for patients with poor performance status or advanced age due to their toxicity. This retrospective, multicenter study evaluated patients with metastatic PSCC who received immune checkpoint inhibitor (ICI) therapy between 2017 and 2024. A total of 10 patients met the inclusion criteria. The median age was 75 years, and 50% had an ECOG performance status of 2 or higher. The objective response rate (ORR) was 30%, and the disease control rate (DCR) was 40%. The duration of response and disease control was over 12 months and 8 months respectively in all patients with response or disease control. The median progression-free survival (PFS) was 2.82 months, and the median overall survival (OS) was 4.32 months. PD-L1 and HPV-positive patients had a 67% response rate (n = 2/3). No patients experienced severe immune-related adverse events (irAEs). This multicenter retrospective analysis suggests that ICI monotherapy may be a promising treatment option for patients with advanced PSCC who are either ineligible for first-line platinum-based chemotherapy or who have progressed after platinum-based chemotherapy, including those with poor performance status. Further studies are needed to confirm these findings and identify baseline patient characteristics that may optimize selection criteria.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"36"},"PeriodicalIF":9.4,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905584/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143614062","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":"Development of a bispecific antibody-drug conjugate targeting EpCAM and CLDN3 for the treatment of multiple solid tumors.","authors":"Meiying Luo, Xiaohuan Wang, Guoji Yu, Jing Ji, Long Li, Fan Song","doi":"10.1186/s40164-025-00624-9","DOIUrl":"10.1186/s40164-025-00624-9","url":null,"abstract":"<p><p>Epithelial cell adhesion molecule (EpCAM), a tumor antigen for antibody-drug conjugates (ADCs), is highly expressed in many epithelial cancers. However, the clinical progress of EpCAM ADCs has been challenging, primarily due to their toxicity in normal high-expression tissues such as the gastrointestinal tract. CLDN3 is highly co-expressed with EpCAM in various human malignancies, coupled with its minimal presence in normal tissues, rendering it an ideal target for developing potent therapeutic ADCs. Here, we developed a bispecific ADC (BsADC) targeting EpCAM and CLDN3, designed to avoid toxicity in normal tissues with high EpCAM expression. The parental monoclonal antibodies (mAbs) were screened for high binding and endocytosis activities on tumor cell lines. We then modified them into monovalent structures and selected clones with decreased binding and endocytosis activities. We combined these clones into bispecific antibodies (BsAbs) and finally chose the molecules with restored binding and endocytosis activities as lead molecules. The BsADCs were generated by conjugating the Drutecan (Dxd) to BsAbs via a cleavable linker. These conjugates exhibit potent binding and effectively inhibit the growth of tumor cells with high levels of both EpCAM and CLDN3, indicating their anti-tumor efficacy. Importantly, they show weak binding to cells with high EpCAM but low CLDN3, implying minimal toxicity to normal tissues with elevated EpCAM expression. Moreover, the BsADCs displayed advantageous pharmacokinetics and low toxicity in mice. These findings position the BsADCs targeting EpCAM and CLDN3 as promising candidates for treating multiple solid tumors.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"33"},"PeriodicalIF":9.4,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11889805/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585239","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":"Lactylation modification in cancer: mechanisms, functions, and therapeutic strategies.","authors":"Mengqi Lv, Yefei Huang, Yansu Chen, Kun Ding","doi":"10.1186/s40164-025-00622-x","DOIUrl":"10.1186/s40164-025-00622-x","url":null,"abstract":"<p><p>Cancer remains the leading cause of mortality worldwide, and the emergence of drug resistance has made the identification of new therapeutic targets imperative. Lactate, traditionally viewed as a byproduct of glycolysis with limited ATP-producing capacity, has recently gained recognition as a critical signaling molecule. It plays a key role not only in cancer cell metabolism but also in shaping the tumor microenvironment (TME). Histone lysine lactylation, a newly identified post-translational modification, has been shown to influence a range of cellular processes in cancer. Current research focuses on the mechanisms and functions of histone lactylation in cancer, including its role in gene expression regulation, signal transduction, and protein synthesis. However, despite these advancements, there are still plenty of barriers in the quest to unravel the mechanisms of lactylation modification. The emergence of single-cell and spatial transcriptomics may offer valuable insights for selecting targets. This review provides a comprehensive summary of the mechanisms and the applications of lactylation modification in clinical settings. Through a detailed analysis, we identify the key challenges and limitations that exist in the current research landscape. These insights lay the groundwork for future studies by highlighting promising research directions.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"32"},"PeriodicalIF":9.4,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11889934/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585223","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":"Bone marrow sympathetic neuropathy is a hallmark of hematopoietic malignancies and it involves severe ultrastructural damage.","authors":"Aurora Bernal, Vincent Cuminetti, Marc Serulla, Adrian Florit, Joanna Konieczny, Golnaz Golnarnik, Yimeng Chen, Marc Ferré, Samuel Geiseler, Anders Vik, Randi Olsen, Lorena Arranz","doi":"10.1186/s40164-025-00614-x","DOIUrl":"10.1186/s40164-025-00614-x","url":null,"abstract":"<p><p>The hematopoietic stem cell (HSC) niche in the bone marrow (BM) supports HSC function, fate and numbers [1]. Sympathetic fibres innervate the BM and are components of the hematopoietic stem and progenitor cell (HSPC) niche [2]. Neuropathy of the HSPC niche is present and essential for disease development in experimental models of JAK2^V617F+ myeloproliferative neoplasms (MPN) and MLL-AF9⁺ acute myeloid leukemia (AML), and it is present in the BM of human MPN and AML patients [3-6]. Neuropathy contributes to mutant HSC expansion and represents an effective therapeutic target to block disease progression in JAK2^V617F+ MPN mice [3]. The sympathomimetic agonist mirabegron restored nestin⁺ cells and reduced reticulin fibrosis in MPN patients [7]. Here, we show that neuropathy of the HSPC niche emerges in two additional experimental models of hematological disease including pre-leukemic myelopoiesis driven by NRAS^G12D and lymphoma/lymphoblastic leukemia driven by p53 deletion. Neuropathy involves severe ultrastructural damage in NRAS^G12D+ mice and AML patients as shown by electron microscopy. When further reinforced chemically, neuropathy has a profound impact on the experimental NRAS^G12D mouse model, promoting myeloid bias, reducing HSPC numbers and inducing changes in the stem cell microenvironment that include reduced numbers of mesenchymal stromal cells (MSC) and increased presence of morphologically abnormal blood vessels in BM. Together, BM neuropathy is a prevalent factor in hematopoietic malignancies that involves important degradation of sympathetic fibres and contributes to disease in a different manner depending on the driver mutation. This should be taken in consideration in the clinic, given that chemotherapy induces neuropathy of the HSC niche [8] and it is the most frequent first line treatment for AML, acute lymphoblastic leukemia and MPN patients.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"31"},"PeriodicalIF":9.4,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11884145/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566526","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":"Matching-adjusted indirect comparison of efficacy and safety of lisocabtagene maraleucel and mosunetuzumab for the treatment of third-line or later relapsed or refractory follicular lymphoma.","authors":"Loretta J Nastoupil, Ashley Bonner, Pearl Wang, Lamees Almuallem, Jigar Desai, Thalia Farazi, Jinender Kumar, Saurabh Dahiya","doi":"10.1186/s40164-025-00610-1","DOIUrl":"10.1186/s40164-025-00610-1","url":null,"abstract":"<p><strong>Background: </strong>The treatment landscape for relapsed or refractory (R/R) follicular lymphoma (FL) has changed with the introduction of anti-CD19 chimeric antigen receptor T-cell therapies, including lisocabtagene maraleucel (liso-cel) and CD20 × CD3 bispecific T-cell-engaging monoclonal antibodies such as mosunetuzumab. Liso-cel and mosunetuzumab have demonstrated positive benefit-risk profiles for third-line or later (3L+) treatment of patients with R/R FL and are approved treatments for these patients. In the absence of a prospective, randomized study, we conducted an unanchored matching-adjusted indirect comparison (MAIC) to assess the efficacy and safety of liso-cel and mosunetuzumab for 3L+ treatment in patients with R/R FL.</p><p><strong>Methods: </strong>Unanchored MAICs were performed to estimate relative treatment effects between TRANSCEND FL (NCT04245839) and GO29781 (NCT02500407). For TRANSCEND FL, the leukapheresis set (N = 114) was used for primary comparisons of the following efficacy endpoints: objective response rate (ORR), complete response (CR) rate, duration of response (DOR), and progression-free survival (PFS). The treated set (N = 107) was used for comparisons of the following safety endpoints: cytokine release syndrome (CRS), neurological events (NE), serious infections, and use of corticosteroids or tocilizumab for CRS. Sensitivity analyses were conducted for efficacy using the TRANSCEND FL treated efficacy set (N = 101).</p><p><strong>Results: </strong>After adjustment, liso-cel was associated with higher ORR (odds ratio [OR] = 3.78, 95% confidence interval [CI] 1.48‒9.67]) and CR rate (OR = 6.46, 95% CI 2.85‒14.65), and improved DOR (hazard ratio [HR] = 0.45, 95% CI 0.26‒0.77) and PFS (HR = 0.28, 95% CI 0.16‒0.49) compared with mosunetuzumab. Results remained consistent across sensitivity analyses. Liso-cel had a lower incidence of grade ≥ 3 CRS (OR = 0.45, 95% CI 0.04‒5.13), grade 3‒4 serious infections (OR = 0.35, 95% CI 0.12‒1.03), and corticosteroid use for CRS management (OR = 0.14, 95% CI 0.03‒0.65); however, liso-cel exhibited higher incidence of any-grade CRS (OR = 1.86, 95% CI 1.01‒3.43), any-grade NEs (OR = 2.16, 95% CI 0.72‒6.44), and tocilizumab use for CRS management (OR = 2.27, 95% CI 0.86‒5.99).</p><p><strong>Conclusions: </strong>Findings highlight a potential positive benefit-risk profile of liso-cel over mosunetuzumab as a 3L+ treatment for R/R FL.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"30"},"PeriodicalIF":9.4,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881270/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566531","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":"Ibrutinib and acalabrutinib use and risk of incident atrial fibrillation: a propensity-matched analysis.","authors":"Joachim Alexandre, Jonaz Font, Thibault Lenormand, Sylvain Chantepie, Hippolyte Bardet, Gandhi Damaj, Charles Dolladille, Damien Legallois, Angélique Da-Silva, Paul Milliez, Arnaud Bisson, Laurent Fauchier","doi":"10.1186/s40164-025-00619-6","DOIUrl":"10.1186/s40164-025-00619-6","url":null,"abstract":"<p><p>Ibrutinib and acalabrutinib are both associated with an increased risk of atrial fibrillation (AF); however, the comparative risk of AF between these 2 BTK inhibitors remains largely unknown. Our primary aim was to evaluate the risk of incident AF in patients exposed to ibrutinib compared to those exposed to acalabrutinib. Using the TriNetX research network database, we established a retrospective cohort of adult patients (≥ 18 years) previously diagnosed with a B-cell malignancy (using ICD-10-CM codes) in whom a first BTKi introduction occurred between January 1st, 2013 (first patient exposed to ibrutinib in TriNetX) and July 1st, 2024. Patients were divided into 2 groups based on their exposure to ibrutinib or acalabrutinib. After propensity score matching (PSM) across 37 covariates, Cox proportional hazard models were used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) to compare the 2 matched groups. The appropriateness of the proportional hazard assumption was examined and risk differences (RDs) were used if appropriate. Results were summarized with the use of Kaplan-Meier survival curves. Follow-up started from 1 day after first BTKi introduction and continued over a 6-year follow-up period. A cohort of 12,449 patients exposed to ibrutinib and 4,131 to acalabrutinib were included in the study. After PSM, 4,090 patients remained in each group (1:1). During a mean duration of BTKi exposure of 2.3 ± 1.8 years, we found a significantly higher risk of incident AF in the ibrutinib group compared to the acalabrutinib group (RD 0.09, 95% CI 0.07-0.10). This difference was consistent across subgroups (age ≤ or > 75 and lower or higher baseline cardiovascular risk of developing AF). In conclusion, among patients with B-cell malignancies, the risk of developing incident AF is increased when treated with ibrutinib compared to acalabrutinib.Trial registration ClinicalTrial registration number: NCT06561243.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"29"},"PeriodicalIF":9.4,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11877785/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143556426","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":"Mesothelin-targeted CAR-T cells secreting NKG2D-BiTEs exhibit potent efficacy against triple-negative breast cancer.","authors":"Muhammad Auwal Saliu, Qi Wang, Mansur Dabai Salisu, Yuanfeng Ren, Pengchao Zhang, Rabiatu Bako Suleiman, Bingbing Cao, Yiqiao Xu, Xudong Liu, Frederic Lluis, Maoxuan Liu, Xiaochun Wan","doi":"10.1186/s40164-025-00621-y","DOIUrl":"10.1186/s40164-025-00621-y","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) is an aggressive subtype with poor prognosis and limited treatment options. Chimeric antigen receptor (CAR)-T cell therapy holds promise, but its efficacy is hindered by tumor antigen escape and heterogeneity. To address these challenges, we developed a novel bispecific T cell engagers CAR-T (BiTEs CAR-T) targeting Mesothelin (MSLN) and secreting NKG2D-Bispecific T cell Engagers (BiTEs) to engage NKG2D ligands (NKG2DL). Analysis of TNBC tissues using The Cancer Genome Atlas and tumor microarrays revealed high but weakly correlated expression of MSLN and NKG2DL, making them ideal targets for dual engagement. To reduce immunogenicity and enhance stability, we used a nanobody and the natural receptor NKG2D as antigen-binding domains instead of traditional scFvs in the CAR construct. The secreted BiTEs could promote the cytotoxicity of untransduced T cells against NKG2DL + tumor cells. In vitro, BiTEs CAR-T cells exhibited superior cytotoxicity, T cell activation, and cytokines production against heterogeneous target cells compared to MSLN CAR-T. In vivo, BiTEs CAR-T cells demonstrated potent antitumor activity in zebrafish and murine TNBC models, significantly reducing tumor burden and prolonging survival without detectable toxicity. These findings suggest that BiTE CAR-T cells offer a highly promising therapeutic strategy for TNBC by addressing antigen heterogeneity and immune escape mechanisms, with promising translational potential for clinical application.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"27"},"PeriodicalIF":9.4,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11874698/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143540816","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}