Experimental Hematology & Oncology最新文献

{"title":"Prominent efficacy and good safety of sequential CD19 and CD22 CAR-T therapy in relapsed/refractory adult B-cell acute lymphoblastic leukemia.","authors":"Tingting Yang, Yetian Dong, Mingming Zhang, Jingjing Feng, Shan Fu, Pingnan Xiao, Ruimin Hong, Huijun Xu, Jiazhen Cui, Simao Huang, Guoqing Wei, Delin Kong, Jia Geng, Alex H Chang, He Huang, Yongxian Hu","doi":"10.1186/s40164-024-00593-5","DOIUrl":"https://doi.org/10.1186/s40164-024-00593-5","url":null,"abstract":"<p><strong>Background: </strong>Sequential CD19 and CD22 chimeric antigen receptor (CAR)-T cell therapy offers a promising approach to antigen-loss relapse in relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL); however, research in adults remains limited.</p><p><strong>Methods: </strong>This study aimed to evaluate the efficacy and safety of sequential CD19 and CD22 CAR-T cell therapy in adult patients with R/R B-ALL between November 2020 and November 2023 (ChiCTR2100053871). Key endpoints included the adverse event incidence, overall survival (OS), and leukemia-free survival (LFS).</p><p><strong>Results: </strong>Twenty-three patients with a median age of 58.1 years (range 25.9-75.0) were enrolled. High-risk cytogenetic and genomic aberrations were identified in 43.5% of patients, and five patients had baseline extramedullary disease (EMD). The median interval between the two infusions was 3.8 months. Grade ≥ 3 hematological adverse events occurred at comparable rates after both infusions. Cytokine release syndrome was observed in 78.3% and 39.1% of patients after CD19 and CD22 CAR-T therapy, respectively. Two patients experienced grade 2 immune effector cell-associated neurotoxicity syndrome (ICANS) during CD19 CAR-T, and no ICANS was reported during CD22 CAR-T. The median OS was not reached with a median follow-up of 19.4 months (range 8.7-45.6), while the median LFS was 20.8 months. OS and LFS rates were 91.3% and 67.1% at 1 year and 58.6% and 47.0% at 2 years, respectively. Eight patients experienced relapse, with the cumulative incidence of relapse being 28.6% at 1 year and 42.5% at 2 years. Higher baseline leukemia burden (≥ 64% bone marrow blasts) and the presence of EMD were significant risk factors for inferior OS and LFS, respectively.</p><p><strong>Conclusions: </strong>Sequential CAR-T cell therapy demonstrated durable efficacy and a manageable safety profile in R/R B-ALL, providing a viable option to address antigen-loss relapse and improve long-term outcomes in high-risk adult patients.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"2"},"PeriodicalIF":9.4,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11697943/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926950","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":"Safety and efficacy of CD33-targeted CAR-NK cell therapy for relapsed/refractory AML: preclinical evaluation and phase I trial.","authors":"Ruihao Huang, Xiaoqi Wang, Hongju Yan, Xu Tan, Yingying Ma, Maihong Wang, Xiao Han, Jia Liu, Li Gao, Lei Gao, Guangjun Jing, Cheng Zhang, Qin Wen, Xi Zhang","doi":"10.1186/s40164-024-00592-6","DOIUrl":"10.1186/s40164-024-00592-6","url":null,"abstract":"<p><strong>Background: </strong>Due to the lack of effective treatment options, the prognosis of patients with relapsed/refractory acute myeloid leukemia (R/R AML) remains poor. Although chimeric antigen receptor (CAR)-T-cell therapy has shown promising effects in acute lymphoblastic leukemia (ALL) and lymphoma, its application in R/R AML is limited by \"off-target\" effects, which lead to severe bone marrow suppression and limit its clinical application. CAR-natural killer (NK) cells not only exhibit antitumor effects but also demonstrate increased safety and universality. We have developed a new CAR construct that targets CD33 and modified NK cells, specifically eliminating AML cells while reducing severe side effects on stem cells.</p><p><strong>Methods: </strong>The CD33-targeting domain was selected by CAR-T cells, and this optimized CAR construct was subsequently transduced into umbilical cord-derived NK cells via a retroviral vector. Preclinical efficacy and safety studies were conducted both in vitro and in vivo. Ten eligible patients with R/R AML aged 18-65 years who received one or more infusions of anti-CD33 CAR-NK cells following the preconditioning regimen were enrolled. We assessed the response rates and treatment-related side effects post-infusion, while also documenting the long-term efficacy of the therapy.</p><p><strong>Results: </strong>The CD33 sequence was selected on the basis of its antitumor efficacy and safety in CAR-T-cell studies conducted both in vitro and in vivo. CD33 CAR-NK cells demonstrated efficacy comparable to that of CD33 CAR-T cells but showed limited toxicity to hematopoietic stem cells (HSCs). Ten patients, with a median of five prior lines of treatment, completed the efficacy evaluation (range, 3-8). No grade 3-4 adverse events were observed, except bone marrow suppression, which was relieved within one month. No cases of immune effector cell-associated neurotoxicity syndrome (ICANS) or graft-versus-host disease (GVHD) were reported following CAR-NK cell infusion. Only one patient experienced grade 2 cytokine release syndrome (CRS) and presented with persistent fever. By day 28, six of ten patients had achieved minimal residual disease (MRD)-negative complete remission.</p><p><strong>Conclusions: </strong>Our preclinical and clinical data demonstrated the primary efficacy and safety of CD33 CAR-NK cells for patients with R/R AML. Expanded samples and longer follow-up periods are needed to provide further efficacy data.</p><p><strong>Trial registration: </strong>NCT05008575 ( https://clinicaltrials.gov/study/NCT05008575 ).</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"1"},"PeriodicalIF":9.4,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11694373/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921267","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":"AOH1996 targets mitochondrial dynamics and metabolism in leukemic stem cells via mitochondrial PCNA inhibition.","authors":"HyunJun Kang, Melissa Valerio, Jia Feng, Long Gu, Dinh Hoa Hoang, Amanda Blackmon, Shawn Sharkas, Khyatiben Pathak, Jennifer Jossart, Zhuo Li, Hongyu Zhang, Bin Zhang, Patrick Pirrotte, J Jefferson P Perry, Robert J Hickey, Linda Malkas, Guido Marcucci, Le Xuan Truong Nguyen","doi":"10.1186/s40164-024-00586-4","DOIUrl":"10.1186/s40164-024-00586-4","url":null,"abstract":"<p><p>Cytoplasmic proliferating cell nuclear antigen (PCNA) is highly expressed in acute myeloid leukemia (AML) cells, supporting oxidative metabolism and leukemia stem cell (LSC) growth. We report on AOH1996 (AOH), an oral compound targeting cancer-associated PCNA, which shows significant antileukemic activity. AOH inhibited growth in AML cell lines and primary CD34 + CD38 - blasts (LSC-enriched) in vitro while sparing normal hematopoietic stem cells (HSCs). In vivo, AOH-treated mice demonstrated prolonged survival compared to controls (50 vs. 35 days; p < 0.0001) with reduced LSC burden, as shown in secondary transplants (42 vs. 30 days, p < 0.0001). Mechanistically, AOH disrupted mitochondrial PCNA's binding to the OPA1 protein, enhancing OPA1's interaction with its E3 ligase, MARCH5, which led to OPA1 degradation. This process reduced mitochondrial length, fatty acid oxidation (FAO), and oxidative phosphorylation (OXPHOS), thereby inhibiting LSC expansion. The addition of venetoclax (VEN), an FDA-approved Bcl-2 inhibitor, further enhanced AOH's effects, reducing mitochondrial length, FAO, and OXPHOS while improving survival in AML models. While VEN is approved for AML, AOH is under clinical investigation for solid tumors, and our findings support its broader therapeutic potential.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"13 1","pages":"123"},"PeriodicalIF":9.4,"publicationDate":"2024-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11681632/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142893288","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":"Disrupting Notch signaling related HES1 in myeloid cells reinvigorates antitumor T cell responses.","authors":"Myung Sup Kim, Hyeokgu Kang, Jung-Hwan Baek, Moon-Gyu Cho, Eun Joo Chung, Seok-Jun Kim, Joon-Yong Chung, Kyung-Hee Chun","doi":"10.1186/s40164-024-00588-2","DOIUrl":"10.1186/s40164-024-00588-2","url":null,"abstract":"<p><strong>Background: </strong>Tumor-associated macrophages (TAMs) are immunosuppressive cells within the tumor microenvironment (TME) that hinder anti-tumor immunity. Notch signaling is a pathway crucial for TAM differentiation and function. Here, we investigate the role of HES1, a downstream target of Notch signaling, in TAM-mediated immunosuppression and explore its potential as a target for cancer immunotherapy.</p><p><strong>Methods: </strong>In this work, we constructed conditional Hes1 knockout mice to selectively delete Hes1 in TAMs. We further analyzed the TME composition, T cell infiltration and activation, and anti-tumor effects in these mice, both alone and in combination with PD-1 checkpoint blockade.</p><p><strong>Results: </strong>Our study showed that expression levels of Notch target Hes1 were increase in TAMs and mice with conditional knockout of Hes1 gene in TAMs exhibited decreased tumor growth, with increased infiltration and activation of cytotoxic T cells in tumors. Expression of tumor promoting factors was critically altered in Hes1-conditional KO TAMs, leading to the improved tumor microenvironment. Notably, arginase-1 expression was decreased in Hes1-conditional KO mice. Arg1 is known to deplete arginine and deactivate T cells in the TME. Administration of anti-PD-1 monoclonal antibody inhibited tumor growth to a greater extent in Hes1-conditional KO mice than in WT mice.</p><p><strong>Conclusions: </strong>We identified a pivotal role for the Notch signaling pathway in shaping TAM function, suggesting that T-cell dysfunction in the TME is caused when the Notch target, HES1, in TAMs is upregulated by tumor-associated factors (TAFs), which, in turn, increases the expression of arginase-1. Targeting HES1 in TAMs appears to be a promising strategy for cancer immunotherapy.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"13 1","pages":"122"},"PeriodicalIF":9.4,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11660887/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863890","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":"Identification of a novel subtype of SPP1 + macrophages expressing SIRPα: implications for tumor immune evasion and treatment response prediction.","authors":"Kun Chen, Yida Li, Jianjiao Ni, Xi Yang, Yue Zhou, Yechun Pang, Ruiting Ye, Hongru Chen, Silai Yu, Peng Wang, Zhengfei Zhu","doi":"10.1186/s40164-024-00587-3","DOIUrl":"10.1186/s40164-024-00587-3","url":null,"abstract":"<p><strong>Background: </strong>SPP1 + macrophages are among the major phagocytic cells, yet promoting tumor immune evasion and predicting unfavorable prognosis, in various cancer types. Meanwhile, the predictive value of the abundance of SPP1 + macrophages in patients receiving immunotherapy remains debatable, indicating the potential existence of subtypes of SPP1 + macrophages with diverse biological functions.</p><p><strong>Methods: </strong>The single cell RNA sequencing data of myeloid cells integrated from several cancers including esophageal squamous cell carcinoma was analyzed for characterizing the function and cellular interactions of SPP1 + macrophages expressing SIRPα. Multiplexed immunohistochemistry was used to quantify the quantity and spatial distribution of SPP1 + macrophages expressing SIRPα. Kaplan-Meier method was used for survival analysis. In vitro and in vivo studies investigating the function of SPP1 + macrophages were performed.</p><p><strong>Results: </strong>SPP1 + macrophages possessed a high phagocytic signature and could engulf more tumor cells in vitro and in vivo. SIRPα expression could represent the phagocytic activity of SPP1 + macrophages and delineated subsets of SPP1 + macrophages with different functions. SPP1 + SIRPα + macrophages showed close spatial distance to tumor cells and positively correlated with PD1 + CD8 + T cells. A high abundance of SPP1 + SIRPα + macrophages at baseline corresponded to patients' response to PD-1/PD-L1 inhibitors.</p><p><strong>Conclusion: </strong>A novel subtype of SPP1 + macrophages expressing SIRPα was identified and their abundance predicted patients' response to PD-1/PD-L1 inhibitors.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"13 1","pages":"119"},"PeriodicalIF":9.4,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11657677/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853532","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":"Chiglitazar diminishes the warburg effect through PPARγ/mTOR/PKM2 and increases the sensitivity of imatinib in chronic myeloid leukemia.","authors":"Hongpeng Duan, Qian Lai, Yuelong Jiang, Liuzhen Yang, Manman Deng, Zhijuan Lin, Weihang Shan, Mengya Zhong, Jingwei Yao, Li Zhang, Bing Xu, Jie Zha","doi":"10.1186/s40164-024-00589-1","DOIUrl":"10.1186/s40164-024-00589-1","url":null,"abstract":"<p><strong>Background: </strong>A tyrosine kinase inhibitor (TKI) such as Imatinib (IM) is the preferred treatment for Chronic Myeloid Leukemia (CML). However, the emergence of IM resistance presents a significant challenge to disease management. A characteristic of cancer cells, including IM-resistant CMLs, are characterized by heightened uptake of glucose and aberrant glycolysis in the cytosol, which is known as the Warburg effect. In addition to its potential to modulate the Warburg effect, Chiglitazar (Chi), a compound that regulates glucose metabolism, has also been investigated for its implication in cancer treatment. This suggests that combining Chi with IM may be a therapeutic strategy for overcoming IM resistance in CML.</p><p><strong>Methods: </strong>Sensitive and IM-resistance CML cells were treated with Chi in vitro, followed by detecting of extracellular acidification rate (ECAR) using a Seahorse XF Analyzer. CML cell proliferation, cell cycle distribution, and apoptosis were tested by CCK-8 assay and flow cytometry. RNA sequencing was utilized to investigate potential transcriptional changes induced by Chi usage. In vivo studies were conducted on immunodeficient mice implanted with CML cells and given Chi and/or IM later. Tumor growth was monitored, as well as tumor burden and survival rates between groups.</p><p><strong>Results: </strong>Our metabonomic, transcriptomic, and molecular biology studies demonstrated that Chi, in part, diminished the Warburg effect by reducing glucose and lactate production in imatinib-resistant CML cells through the PPARγ/mTOR/PKM2 pathway. This modulation of glucose metabolism resulted in reduced cell proliferation and enhanced sensitivity to IM in imatinib-resistant CML cells in vitro. Rescue assay by introducing shPPARγ or mTOR activator verified the underlying regulatory pathway. Also, the combination of Chi and IM synergistically increased the sensitivity of IM in vivo and prolonged the survival of imatinib-resistance CML transplanted mice.</p><p><strong>Conclusions: </strong>Our results demonstrated the potential of Chi to overcome IM resistance in vitro and in vivo. By inhibiting the Warburg effect through the PPARγ/mTOR/PKM2 pathway, Chi resensitizes CML cells towards imatinib treatment. Combining IM with Chi is an alternative therapeutic option for CML management, especially for IM-resistant CML patients.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"13 1","pages":"121"},"PeriodicalIF":9.4,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11657277/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853530","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":"Radiation-induced exosomal miR-21 enhances tumor proliferation and invasiveness in breast cancer: implications for poor prognosis in radiotherapy patients.","authors":"Kyungmin Kim, Kyung Oh Jung, Sera Oh, Young-Hwa Kim, Seok-Yong Lee, Seongje Hong, Su Han Cho, Hyejin Kim, Siyeon Rhee, Gi Jeong Cheon, Keon Wook Kang, June-Key Chung, Hyewon Youn","doi":"10.1186/s40164-024-00585-5","DOIUrl":"10.1186/s40164-024-00585-5","url":null,"abstract":"<p><p>Radiotherapy is widely used as an effective non-surgical strategy to control malignant tumors. However, recurrence is one of common causes of treatment failure even after the effective radiotherapy. In this study, we focused on the effects of radiation-induced exosomal miR-21 on the tumor microenvironment to investigate the causes of recurrence. Analysis of the TCGA database revealed that breast cancer patients with high levels of miR-21 have significantly reduced overall survival when treated with radiotherapy compared to those who did not receive radiotherapy, indicating a high hazard ratio for miR-21 in patients undergoing this treatment. Additionally, exosomal miR-21 is found to be highly expressed in the serum of breast adenocarcinoma patients. To explore how miR-21 induces poor prognosis in irradiated breast cancer, we irradiated 4T1 cell line with low or high doses of radiation, and examined the impact of secreted exosomal miR-21 on breast cancer cell and tumor microenvironment. After 10 Gy irradiation, 4T1 cells secreted 2.20 ± 0.10 times more exosomes and exhibited a 1.85 ± 0.01-fold increase in exosomal miR-21 levels. Treatment with exosomes from 10 Gy-irradiated cancer cells led to enhanced tumor cell proliferation, wound healing, and migration. The survival rate of 10 Gy-irradiated tumor cells incubated with 10 Gy-derived exosomes increased by 2.83-fold. Moreover, the growth of subcutaneous tumors treated with 10 Gy exosomes (n = 13) was significantly faster compared to tumors treated with 0 Gy exosomes (n = 10, P < 0.05). In summary, our study revealed high-dose irradiation-induced exosomes were found to enhance tumor proliferation and invasiveness via the transfer of exosomal miR-21. Based on these findings, we suggest that radiation-induced exosomal miR-21 may contribute to a poorer prognosis of breast cancer patients undergoing radiotherapy.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"13 1","pages":"120"},"PeriodicalIF":9.4,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11656813/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853533","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":"The development and application of chimeric antigen receptor natural killer (CAR-NK) cells for cancer therapy: current state, challenges and emerging therapeutic advances.","authors":"Pin Yao, Ya-Guang Liu, Gang Huang, Liangchun Hao, Runan Wang","doi":"10.1186/s40164-024-00583-7","DOIUrl":"10.1186/s40164-024-00583-7","url":null,"abstract":"<p><p>Immunotherapy has transformed the landscape of cancer treatment, with chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy emerging as a front runner in addressing some hematological malignancies. Despite its considerable efficacy, the occurrence of severe adverse effects associated with CAR-T cell therapy has limited their scope and prompted the exploration of alternative therapeutic strategies. Natural killer (NK) cells, characterized by both their innate cytotoxicity and ability to lyse target cells without the constraint of peptide specificity conferred by a major histocompatibility complex (MHC), have similarly garnered attention as a viable immunotherapy. As such, another therapeutic approach has recently emerged that seeks to combine the continued success of CAR-T cell therapy with the flexibility of NK cells. Clinical trials involving CAR-engineered NK (CAR-NK) cell therapy have exhibited promising efficacy with fewer deleterious side effects. This review aims to provide a concise overview of the cellular and molecular basis of NK cell biology, facilitating a better understanding of advancements in CAR design and manufacturing. The focus is on current approaches and strategies employed in CAR-NK cell development, exploring at both preclinical and clinical settings. We will reflect upon the achievements, advantages, and challenges intrinsic to CAR-NK cell therapy. Anticipating the maturation of CAR-NK cell therapy technology, we foresee its encouraging prospects for a broader range of cancer patients and other conditions. It is our belief that this CAR-NK progress will bring us closer to making significant strides in the treatment of refractory and recurrent cancers, as well as other immune-mediated disorders.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"13 1","pages":"118"},"PeriodicalIF":9.4,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11616395/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142779620","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":"Chimeric antigen receptor-T cell therapy for T cell-derived hematological malignancies.","authors":"Haiqiong Zheng, Houli Zhao, Shi Han, Delin Kong, Qiqi Zhang, Mingming Zhang, Yijin Chen, Meng Zhang, Yongxian Hu, He Huang","doi":"10.1186/s40164-024-00584-6","DOIUrl":"10.1186/s40164-024-00584-6","url":null,"abstract":"<p><p>Relapsed/refractory T cell-derived malignancies present with high heterogeneity and poor prognoses. Recently, chimeric antigen receptor (CAR)-T cell therapy has shown remarkable safety and efficacy in the treatment of B cell-derived malignancies. However, the treatment of CAR-T cells in T cell-derived malignancies has more limitations, such as fratricide, T cell aplasia, and tumor contamination, mainly because of the similarity between normal and malignant T cells. Pan-T antigen CAR-T cells (such as CD5 and CD7 targets), the most widely used CAR-T cells in clinical trials, can cover almost all T cell-derived malignant cells but can also induce severe killing of CAR-T cells and normal T cells. Compared to autologous sources of CAR-T cells, allogeneic CAR-T cells can prevent tumor contamination and become universal products by gene-editing. However, none of these CAR-T cells could completely prevent immune deficiency and disease relapse after T-targeted CAR-T cell therapy. In this review, we summarize the current challenges of CAR-T cell therapy for T cell-derived malignancies in clinical practice and potential strategies to address these limitations.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"13 1","pages":"117"},"PeriodicalIF":9.4,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11604015/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142750273","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":"CUL4A-DDB1-circRFWD2 E3 ligase complex mediates the ubiquitination of p27 to promote multiple myeloma proliferation.","authors":"Jie Min, Jialei Mao, Hui Shi, Yumeng Peng, Xiaoning Xu, Mengjie Guo, Xiaozhu Tang, Ye Yang, Chunyan Gu","doi":"10.1186/s40164-024-00582-8","DOIUrl":"10.1186/s40164-024-00582-8","url":null,"abstract":"<p><p>Multiple myeloma (MM) is an incurable disease characterized by the abnormal expansion of plasma cells in the bone marrow (BM). Numerous studies have shown that BM tumor cells can influence the tumor microenvironment (TME) through communication with extracellular vesicle circular RNAs (circRNAs), a type of noncoding RNA. Our study revealed that a circular RNA, circRFWD2 (hsa_circ_0015361), is expressed by MM cells and translated into a new protein, circRFWD2_369aa. We found that elevated levels of circRFWD2_369aa in MM peripheral blood samples were closely associated with poor outcomes in MM patients. Further investigation revealed that circRFWD2 promoted the degradation of p27 through the ubiquitination pathway, leading to increased proliferation of MM cells. We also confirmed the interaction between circRFWD2 and its downstream genes DDB1 and CUL4A, indicating that circRFWD2 could form an E3 ligase complex with other genes to mediate the ubiquitination of p27. Notably, the protein translated by a circular RNA of RFWD2 can also function as an E3 ligase. Our study highlights the potential of circRFWD2 as a biomarker for MM, which may improve the sensitivity and specificity of diagnosis and efficacy analyses.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"13 1","pages":"116"},"PeriodicalIF":9.4,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11583565/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142692851","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}