Experimental Hematology & Oncology最新文献

{"title":"Nuclear porcupine mediates XRCC6/Ku70 S-palmitoylation in the DNA damage response.","authors":"Yang Chen, Mingming Xiao, Yaqi Mo, Jinlu Ma, Yamei Han, Qing Li, Qinghua Zeng, Rebecca J Boohaker, Joshua Fried, Yonghe Li, Han Wang, Bo Xu","doi":"10.1186/s40164-024-00572-w","DOIUrl":"10.1186/s40164-024-00572-w","url":null,"abstract":"<p><strong>Background: </strong>The activation of the DNA damage response (DDR) heavily relies on post-translational modifications (PTMs) of proteins, which play a crucial role in the prevention of genetic instability and tumorigenesis. Among these PTMs, palmitoylation is a highly conserved process that is dysregulated in numerous cancer types. However, its direct involvement in the DDR and the underlying mechanisms remain unclear.</p><p><strong>Methods: </strong>CRISPR-Cas9 technology was used to generate the PORCN KO and PORCN NLS KO cell lines. The effects of PORCN NLS in the DDR were verified by colony formation assays, MTT assays, the DR/EJ5 homologous recombination/non-homologous end-joining reporter system, xenograft tumor growth and immunofluorescence. Mechanisms were explored by mass spectrometry, acyl-biotin exchange (ABE) palmitoylation assay, Click-iT assay, cell subcellular fractionation assay, Western blot analysis, and in vivo and in vitro co-immunoprecipitation.</p><p><strong>Results: </strong>In this study, we introduce evidence that Porcupine (PORCN) is an integral component of and plays a critical role in the DDR. PORCN deficiency hampers nonhomologous end joining (NHEJ) and highly sensitizes cells to ionizing radiation (IR) both in vitro and in vivo. We also provide evidence that PORCN possesses a nuclear fraction (nPORCN) with S-acyltransferase activity, unlike its membrane-bound O-acyltransferase in the endoplasmic reticulum. Furthermore, we show that nPORCN is necessary for the successful activation of NHEJ. Using mass spectrometry, we reveal the existence of an nPORCN complex and show that nPORCN mediates the S-palmitoylation of XRCC6/Ku70 at five specific cysteine sites in response to IR. Mutation of these sites causes a substantial increase in radiosensitivity and delays NHEJ. Additionally, we present evidence that nPORCN-dependent Ku70 palmitoylation is required for DNA-PKcs/Ku70/Ku80 complex formation.</p><p><strong>Conclusion: </strong>Our findings underscore the crucial role of nPORCN-dependent Ku70 S-palmitoylation in the DDR.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":null,"pages":null},"PeriodicalIF":9.4,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11536954/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142575574","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":"Crosstalk between O-GlcNAcylation and ubiquitination: a novel strategy for overcoming cancer therapeutic resistance.","authors":"Kai Sun, Yuan Zhi, Wenhao Ren, Shaoming Li, Jingjing Zheng, Ling Gao, Keqian Zhi","doi":"10.1186/s40164-024-00569-5","DOIUrl":"10.1186/s40164-024-00569-5","url":null,"abstract":"<p><p>Developing resistance to cancer treatments is a major challenge, often leading to disease recurrence and metastasis. Understanding the underlying mechanisms of therapeutic resistance is critical for developing effective strategies. O-GlcNAcylation, a post-translational modification that adds GlcNAc from the donor UDP-GlcNAc to serine and threonine residues of proteins, plays a crucial role in regulating protein function and cellular signaling, which are frequently dysregulated in cancer. Similarly, ubiquitination, which involves the attachment of ubiquitin to to proteins, is crucial for protein degradation, cell cycle control, and DNA repair. The interplay between O-GlcNAcylation and ubiquitination is associated with cancer progression and resistance to treatment. This review discusses recent discoveries regarding the roles of O-GlcNAcylation and ubiquitination in cancer resistance, their interactions, and potential mechanisms. It also explores how targeting these pathways may provide new opportunities to overcome cancer treatment resistance in cancer, offering fresh insights and directions for research and therapeutic development.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":null,"pages":null},"PeriodicalIF":9.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11529444/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564232","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":"Vertical targeting of the PI3K/AKT pathway at multiple points is synergistic and effective for non-Hodgkin lymphoma.","authors":"Kristyna Kupcova, Jana Senavova, Filip Jura, Vaclav Herman, Anezka Rajmonova, Mariana Pacheco-Blanco, Tereza Chrbolkova, Iva Hamova, R Eric Davis, Ondrej Havranek","doi":"10.1186/s40164-024-00568-6","DOIUrl":"10.1186/s40164-024-00568-6","url":null,"abstract":"<p><p>The phosphatidylinositol 3‑kinase/protein kinase B (PI3K/AKT) signaling pathway is critically active in many cell types, both normal and neoplastic. Many small-molecule inhibitors targeting different levels of the PI3K/AKT pathway have been developed for cancer therapy, but their efficacy is reduced by compensatory pathway re-activation mechanisms, and their tolerability by toxic side effects. We studied this problem using cell lines representing diffuse large B-cell lymphoma (SUDHL-4 and OCI-Ly7), a genetically-encoded live-cell reporter of AKT activity, and 3 small-molecule inhibitors targeting different levels of the pathway: idelalisib (PI3Kδ), GSK2334470 (PDPK1), and ipatasertib (AKT). Half-maximal (IC50) concentrations of these inhibitors for AKT activity inhibition at 1 h, when used individually, were much lower than their IC50 values for reduction of viable cell number after 4 days. Time-course studies explained this discrepancy: AKT activity in the continuous presence of the inhibitors returned to normal after 24 h, and was supranormal after inhibitor removal. Combining all 3 inhibitors produced sustained inhibition of AKT activity, was broadly synergistic at reducing viable cell number, enabled substantially lower doses of each inhibitor to be used, and was enhanced further by the mTOR inhibitor rapamycin. Moreover, combined PDPK1 and AKT inhibition showed synergy with multiple different PI3K inhibitors. In a syngeneic mouse cell line model of lymphoma (A20), the triple combination showed antitumor activity and no evidence of toxicity. Our findings provide proof of concept suggesting further study of the safety and efficacy of low-dose multilevel PI3K/AKT pathway inhibition, for lymphoma and perhaps other cancers.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":null,"pages":null},"PeriodicalIF":9.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11529427/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564233","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":"Spatial immunogenomic patterns associated with lymph node metastasis in lung adenocarcinoma.","authors":"Fanjie Meng, Hao Li, Ruoyi Jin, Airong Yang, Hao Luo, Xiao Li, Peiyu Wang, Yaxing Zhao, Olga Chervova, Kaicheng Tang, Sida Cheng, Bin Hu, Yun Li, Jianpeng Sheng, Fan Yang, David Carbone, Kezhong Chen, Jun Wang","doi":"10.1186/s40164-024-00574-8","DOIUrl":"10.1186/s40164-024-00574-8","url":null,"abstract":"<p><strong>Background: </strong>Lung adenocarcinoma (LUAD) with lymph node (LN) metastasis is linked to poor prognosis, yet the underlying mechanisms remain largely undefined. This study aimed to elucidate the immunogenomic landscape associated with LN metastasis in LUAD.</p><p><strong>Methods: </strong>We employed broad-panel next-generation sequencing (NGS) on a cohort of 257 surgically treated LUAD patients to delineate the molecular landscape of primary tumors and identify actionable driver-gene alterations. Additionally, we used multiplex immunohistochemistry (mIHC) on a propensity score-matched cohort, which enabled us to profile the immune microenvironment of primary tumors in detail while preserving cellular metaclusters, interactions, and neighborhood functional units. By integrating data from NGS and mIHC, we successfully identified spatial immunogenomic patterns and developed a predictive model for LN metastasis, which was subsequently validated independently.</p><p><strong>Results: </strong>Our analysis revealed distinct immunogenomic alteration patterns associated with LN metastasis stages. Specifically, we observed increased mutation frequencies in genes such as PIK3CG and ATM in LN metastatic primary tumors. Moreover, LN positive primary tumors exhibited a higher presence of macrophage and regulatory T cell metaclusters, along with their enriched neighborhood units (p < 0.05), compared to LN negative tumors. Furthermore, we developed a novel predictive model for LN metastasis likelihood, designed to inform non-surgical treatment strategies, optimize personalized therapy plans, and potentially improve outcomes for patients who are ineligible for surgery.</p><p><strong>Conclusions: </strong>This study offers a comprehensive analysis of the genetic and immune profiles in LUAD primary tumors with LN metastasis, identifying key immunogenomic patterns linked to metastatic progression. The predictive model derived from these insights marks a substantial advancement in personalized treatment, underscoring its potential to improve patient management.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":null,"pages":null},"PeriodicalIF":9.4,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11514955/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521480","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":"Advances in adoptive cellular immunotherapy and therapeutic breakthroughs in multiple myeloma.","authors":"Jingjing Pu, Ting Liu, Amit Sharma, Liping Jiang, Feng Wei, Xiubao Ren, Ingo G H Schmidt-Wolf, Jian Hou","doi":"10.1186/s40164-024-00576-6","DOIUrl":"10.1186/s40164-024-00576-6","url":null,"abstract":"<p><p>The basic idea of modulating the immune system to better recognize and fight tumor cells has led to the successful introduction of adoptive cellular immunotherapy (ACT). ACT-based treatment regimens, in which the patient's own immune cells are isolated and subsequently expanded (ex vivo) and reinfused, have also contributed significantly to the development of a personalized treatment strategy. Complementing this, the unprecedented advances in ACTs as chimeric antigen receptor (CAR)-T cell therapies and their derivatives such as CAR-NK, CAR-macrophages, CAR-γδT and CAR-NKT have further maximized the therapeutic outcomes. Herein, we provide a comprehensive overview of the development of ACTs in multiple myeloma (MM) and outline how they have evolved from an experimental form to a mainstay of standard clinical settings. Besides, we provide insights into cytokine-induced killer cell (CIK) therapy, an alternative form of ACT that (as CIK or CAR-CIK) has enormous potential in the clinical spectrum of MM. We also summarize the results of the major preclinical and clinical studies of adoptive cell therapy in MM and address the current challenges (such as cytokine release syndrome (CRS) and neurotoxicity) that limit its complete success in the cancer landscape.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":null,"pages":null},"PeriodicalIF":9.4,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11514856/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521479","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":"Targeting CD5 chimeric antigen receptor-engineered natural killer cells against T-cell malignancies.","authors":"Yingling Zu, Quan Ren, Jishuai Zhang, Hongchang Su, Qiumei Lu, Yongping Song, Jian Zhou","doi":"10.1186/s40164-024-00577-5","DOIUrl":"10.1186/s40164-024-00577-5","url":null,"abstract":"<p><strong>Background: </strong>Chimeric antigen receptor engineered T cells (CAR-T) have demonstrated promising clinical efficacy in B-cell malignancies, and the approach has been extended to T-cell malignancies. However, the use of allogeneic T cells in CAR therapy poses a challenge due to the risk of graft-versus-host disease. Recently, natural killer (NK) cells have exhibited \"off‑the‑shelf\" availability. The nanobody-based CAR structures have attracted much attention for their therapeutic potential owing to the advantages of nanobody, including small size, optimal stability, high affinity and manufacturing feasibility. CD5, a common surface marker of malignant T cells, has three scavenger receptor cysteine-rich domains (D1-D3) in the extracellular region. The present study aims to construct \"off‑the‑shelf\" CAR-NK cells targeting the membrane-proximal domain of CD5 derived from nanobody against T-cell malignancies.</p><p><strong>Methods: </strong>Anti-CD5-D3 nanobody was screened by phage display technology, followed by constructing fourth-generation CAR plasmids ectopically producing IL-15 to generate CD5 CAR-NK cells derived from peripheral blood. And the second-generation CD5 CAR-T cells based on nanobody were generated, referred to as 5D.b CAR-T and 12 C.b CAR-T. Furthermore, CAR-NK cells without IL-15 (IL-15^△ CAR-NK) were generated to assess the impact on cytotoxicity of CAR-NK cells. Cytotoxic activity against CD5⁺ hematologic malignant cell lines and normal T cells was exerted in vitro and NOD/ShiLtJGpt-Prkdcem26Cd52Il2rgem26Cd22/Gpt mouse model transplanted with Jurkat-Luc cells was used to evaluate the antitumor efficacy of CD5 CAR-NK cells in vivo.</p><p><strong>Results: </strong>Two nanobodies (5D and 12 C) competed for binding to the epitope of CD5-D3. 12 C CAR-NK cells were superior to 5D CAR-NK cells in antitumor potential and 12 C.b CAR-T cells exhibited superior cytotoxic activity than 5D CAR-T cells ex vivo. So, 12 C was regarded as the optimal nanobody. 12 C CAR-NK cells and IL-15^△ CAR-NK cells exhibited robust cytotoxicity against CD5⁺ malignant cell lines and controlled disease progression in xenograft mouse model. 12 C CAR-NK cells demonstrated greater antitumor activity compared to that of IL-15^△ CAR-NK cells in vitro and in vivo.</p><p><strong>Conclusions: </strong>Taken together, the fourth-generation nanobody-derived anti-CD5 CAR-NK cells may be a promising therapeutic against T-cell malignancies.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":null,"pages":null},"PeriodicalIF":9.4,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11515150/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497720","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":"Optimizing CD8⁺ T cell-based immunotherapy via metabolic interventions: a comprehensive review of intrinsic and extrinsic modulators.","authors":"Zihao Zhou, Jiarong Zheng, Ye Lu, Zizhao Mai, Yunfan Lin, Pei Lin, Yucheng Zheng, Xu Chen, Rongwei Xu, Xinyuan Zhao, Li Cui","doi":"10.1186/s40164-024-00575-7","DOIUrl":"https://doi.org/10.1186/s40164-024-00575-7","url":null,"abstract":"<p><p>CD8⁺ T cells are integral to the effective management of cancer and infectious diseases due to their cytotoxic functions. The efficacy of these cells is profoundly influenced by their metabolic state, which regulates their activation, differentiation, and longevity. Accordingly, the modulation of metabolic pathways within CD8⁺ T cells is crucial for enhancing the effectiveness of T cell-based immunotherapy. Precise metabolic control is paramount in optimizing therapeutic outcomes and minimizing potential toxicities associated with treatment. Importantly, the potential of exogenous metabolites to augment CD8⁺ T cell responses is critically evaluated, especially through in vivo evidence that underscores their therapeutic promise. This review also addresses current challenges, including the need for precise control of metabolic modulation to avoid adverse effects, the development of targeted delivery systems to ensure efficient metabolite delivery to CD8⁺ T cells, and the inherent variability of metabolic states among patients that may influence treatment outcomes. Addressing these hurdles will be crucial for the successful integration of metabolic interventions into established immunotherapeutic regimens.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":null,"pages":null},"PeriodicalIF":9.4,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11495118/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497719","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":"CRISPR/Cas9 technology for advancements in cancer immunotherapy: from uncovering regulatory mechanisms to therapeutic applications.","authors":"Xiaohang Feng, Zhengxing Li, Yuping Liu, Di Chen, Zhuolong Zhou","doi":"10.1186/s40164-024-00570-y","DOIUrl":"https://doi.org/10.1186/s40164-024-00570-y","url":null,"abstract":"<p><p>In recent years, immunotherapy has developed rapidly as a new field of tumour therapy. However, the efficacy of tumour immunotherapy is not satisfactory due to the immune evasion mechanism of tumour cells, induction of immunosuppressive tumour microenvironment (TME), and reduction of antigen delivery, etc. CRISPR/Cas9 gene editing technology can accurately modify immune and tumour cells in tumours, and improve the efficacy of immunotherapy by targeting immune checkpoint molecules and immune regulatory genes, which has led to the great development and application. In current clinical trials, there are still many obstacles to the application of CRISPR/Cas9 in tumour immunotherapy, such as ensuring the accuracy and safety of gene editing, overcoming overreactive immune responses, and solving the challenges of in vivo drug delivery. Here we provide a systematic review on the application of CRISPR/Cas9 in tumour therapy to address the above existing problems. We focus on CRISPR/Cas9 screening and identification of immunomodulatory genes, targeting of immune checkpoint molecules, manipulation of immunomodulators, enhancement of tumour-specific antigen presentation and modulation of immune cell function. Second, we also highlight preclinical studies of CRISPR/Cas9 in animal models and various delivery systems, and evaluate the efficacy and safety of CRISPR/Cas9 technology in tumour immunotherapy. Finally, potential synergistic approaches for combining CRISPR/Cas9 knockdown with other immunotherapies are presented. This study underscores the transformative potential of CRISPR/Cas9 to reshape the landscape of tumour immunotherapy and provide insights into novel therapeutic strategies for cancer patients.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":null,"pages":null},"PeriodicalIF":9.4,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11490091/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461427","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":"Natural killer cell-based cancer immunotherapy: from basics to clinical trials.","authors":"Yinghong Shi, Donglin Hao, Hui Qian, Zhimin Tao","doi":"10.1186/s40164-024-00561-z","DOIUrl":"https://doi.org/10.1186/s40164-024-00561-z","url":null,"abstract":"<p><p>Cellular immunotherapy exploits the capacity of the human immune system in self-protection and surveillance to achieve the anti-tumor effects. Natural killer (NK) cells are lymphocytes of innate immune system and they display a unique inherent ability to identify and eliminate tumor cells. In this review, we first introduce the basic characteristics of NK cells in the physiological and pathological milieus, followed by a discussion of their effector function and immunosuppression in the tumor microenvironment. Clinical strategies and reports regarding NK cellular therapy are analyzed in the context of tumor treatment, especially against solid tumors. Given the widely studied T-cell therapy in the recent years, particularly the chimeric antigen receptor (CAR) T-cell therapy, we compare the technical features of NK- and T-cell based tumor therapies at the clinical front. Finally, the technical challenges and potential solutions for both T and NK cell-based immunotherapies in treating tumor malignancies are delineated. By overviewing its clinical applications, we envision the NK-cell based immunotherapy as an up-and-comer in cancer therapeutics.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":null,"pages":null},"PeriodicalIF":9.4,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11484118/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461428","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":"CD19/CD22 CAR-T-cell cocktail therapy following autologous transplantation is an optimizing strategy for treating relapsed/refractory central nervous system lymphoma.","authors":"Xiaoxi Zhou, Qiuxia Yu, Zigang Dai, Jue Wang, Chunrui Li, Liang Huang, Yicheng Zhang, Yang Cao","doi":"10.1186/s40164-024-00538-y","DOIUrl":"https://doi.org/10.1186/s40164-024-00538-y","url":null,"abstract":"<p><p>Relapsed/refractory (R/R) primary and secondary central nervous system lymphomas (PCNSL, SCNSL) are associated with short survival and represent an unmet need, requiring novel effective strategies. We retrospectively compared the safety and efficacy of CD19/22 CAR-T-cell therapy following ASCT (ASCT + CAR-T group), CD19/22 CAR-T-cell cocktail therapy (CAR-T group) and chemoimmunotherapy (CIT group) in treating R/R CNSL patients. Analysis of the differences in clinical characteristics among the three groups revealed that the median age in the CIT group was older than that in the ASCT + CAR-T group and CAR-T group, and the median number of prior lines of therapy in the CIT group was less than that in the other groups. Patients in the two CAR-T-therapy groups exhibited comparable incidences and severities of CRS and ICANS. Grade 4-5 CRS and ICANS were not observed in either CAR-T-cell therapy group. The incidence of Grade 3/4 hematological toxicity in the ASCT + CAR-T and CAR-T groups was greater than that in the CIT group. The ORR was 82.75% in the ASCT + CAR-T group, 60.00% in the CAR-T group and 58.83% in the CIT group. As of December 31, 2022, the median follow-up after therapy was 16.73 months (range, 0.67-42.00 months). The median durations of PFS and OS were not reached in the ASCT + CAR-T group. The median PFS in the CAR-T group was 4.72 months, and OS was not reached. In the CIT group, the median PFS and OS were 6.63 months and 16.77 months, respectively. The 2-year PFS rate of patients in the ASCT + CAR-T group (65.52%) was significantly greater than that of patients in the CAR-T group (30.00%, P = 0.0321) and CIT group (23.53%, P = 0.0043). Our results support the development of CAR-T-cell therapy for R/R CNSL. With the durability of remission and low toxicity, ASCT combined with CAR-T-cell therapy appears to be a more effective and safer treatment option for primary and secondary R/R CNS lymphoma.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":null,"pages":null},"PeriodicalIF":9.4,"publicationDate":"2024-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11471030/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461426","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}