Jane Sun, Melissa Elliott, Fernando Souza-Fonseca-Guimaraes
Natural killer (NK) cells are increasingly recognised as potent tumoricidal agents that can be utilised for cancer immunotherapy. Their innate cytotoxicity against tumor cells, and reduced risk of causing transplantation or toxicity issues in patients, makes them a valuable option for exploration in allogeneic adoptive cell immunotherapies. However, sourcing NK cells from peripheral blood poses challenges in terms of scalability, consistency and variability. Induced pluripotent stem cells (iPSCs) are emerging as a platform to create specific cells with highly controlled processes, allowing for a common cell source for cell therapies and offering a promising inexhaustible source of genetically modifiable NK cells. This review highlights recent developments in the field of generating iPSC-derived NK cells in defined culture systems, and advancements in genetic modification to improve iPSC-NK cell therapy. We further discuss the development of iPSC banks and examine the potential of these cells in next-generation immunotherapies. Finally, we summarise the improvements in cancer targeting, expansion, persistence and cytotoxic functionality of iPSC-derived NK (iNK) cells both in vitro and in vivo, achieved through genetic modification of iPSCs, as well as recent related clinical trials.
{"title":"Engineered iPSC-derived natural killer cells: recent innovations in translational innate anti-cancer immunotherapy","authors":"Jane Sun, Melissa Elliott, Fernando Souza-Fonseca-Guimaraes","doi":"10.1002/cti2.70045","DOIUrl":"https://doi.org/10.1002/cti2.70045","url":null,"abstract":"<p>Natural killer (NK) cells are increasingly recognised as potent tumoricidal agents that can be utilised for cancer immunotherapy. Their innate cytotoxicity against tumor cells, and reduced risk of causing transplantation or toxicity issues in patients, makes them a valuable option for exploration in allogeneic adoptive cell immunotherapies. However, sourcing NK cells from peripheral blood poses challenges in terms of scalability, consistency and variability. Induced pluripotent stem cells (iPSCs) are emerging as a platform to create specific cells with highly controlled processes, allowing for a common cell source for cell therapies and offering a promising inexhaustible source of genetically modifiable NK cells. This review highlights recent developments in the field of generating iPSC-derived NK cells in defined culture systems, and advancements in genetic modification to improve iPSC-NK cell therapy. We further discuss the development of iPSC banks and examine the potential of these cells in next-generation immunotherapies. Finally, we summarise the improvements in cancer targeting, expansion, persistence and cytotoxic functionality of iPSC-derived NK (iNK) cells both <i>in vitro</i> and <i>in vivo</i>, achieved through genetic modification of iPSCs, as well as recent related clinical trials.</p>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"14 7","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70045","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144598754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xiaohan Xu, John Saxon, Megan Sioe Fei Soon, Colin YC Lee & Zewen Kelvin Tuong
Correction to: Clin Transl Immunol 2025; 14: e70033. https://doi.org/10.1002/cti2.70033
There is an error within a sentence within the first paragraph of the ‘Lack of important annotations’ section, as follows:
Moreover, a striking 83% of data sets did not provide adequate clinical features of each patient sample (e.g. sex, age, disease stage and treatment history) (Figure 3d).
This should have read:
Moreover, 17% of data sets did not provide adequate clinical features of each patient sample (e.g. sex, age, disease stage and treatment history) (Figure 3d).
The authors apologise for this error.
许晓涵，John Saxon, Megan Sioe Fei Soon, Colin YC Lee &；纠正：临床Transl Immunol 2025；14: e70033。https://doi.org/10.1002/cti2.70033There是“缺乏重要注释”部分第一段中的一个句子中的错误，如下所示：此外，惊人的83%的数据集没有提供每个患者样本的足够临床特征（例如性别、年龄、疾病分期和治疗史）（图3d）。此外，17%的数据集没有提供每个患者样本的足够临床特征（如性别、年龄、疾病分期和治疗史）（图3d）。作者为这个错误道歉。
{"title":"Data standards for single-cell RNA-sequencing of paediatric cancer","authors":"","doi":"10.1002/cti2.70044","DOIUrl":"https://doi.org/10.1002/cti2.70044","url":null,"abstract":"<p>Xiaohan Xu, John Saxon, Megan Sioe Fei Soon, Colin YC Lee & Zewen Kelvin Tuong</p><p><b>Correction to:</b> Clin Transl Immunol 2025; 14: e70033. https://doi.org/10.1002/cti2.70033</p><p>There is an error within a sentence within the first paragraph of the ‘Lack of important annotations’ section, as follows:</p><p>Moreover, a striking 83% of data sets did not provide adequate clinical features of each patient sample (e.g. sex, age, disease stage and treatment history) (Figure <b>3d</b>).</p><p>This should have read:</p><p>Moreover, 17% of data sets did not provide adequate clinical features of each patient sample (e.g. sex, age, disease stage and treatment history) (Figure <b>3d</b>).</p><p>The authors apologise for this error.</p>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"14 7","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70044","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144598753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Metastatic nasopharyngeal carcinoma (mNPC) following palliative chemotherapy has high incidence and mortality rates. While maintenance therapy shows promising potential, the optimal strategy remains undefined. This study aimed to evaluate the therapeutic efficacy of immunochemotherapy maintenance in patients with mNPC.
Methods
This cohort study evaluated the therapeutic efficacy of combined maintenance therapy with capecitabine and anti-PD-1 antibodies in mNPC patients, using a prospectively maintained database. The primary endpoint was progression-free survival (PFS), and secondary endpoints included overall survival and safety profile. Furthermore, stratification analysis and sensitivity analysis were performed.
Results
The study included 300 mNPC patients treated at Sun Yat-sen University Cancer Center from 2018 to 2023. Two hundred and thirty-four patients (78.0%) were male, and the median age was 45 years [interquartile range (IQR): 36–54]. At median follow-up of 43.6 months (IQR: 31.8–57.8), combination maintenance significantly improved PFS compared to single-drug maintenance [weighted hazard ratio (HR) 0.580, 95% confidence interval (95% CI) 0.387–0.872, P = 0.009; E-value, 2.27]. Stratification analysis revealed enhanced efficacy of immunochemotherapy maintenance in patients without prior local treatment (HR 0.414, 95% CI 0.224–0.767, P = 0.005) or with elevated premaintenance Epstein–Barr virus (EBV) DNA levels (HR 0.063, 95% CI 0.007–0.548, P = 0.012). No significant difference in PFS was observed between the capecitabine and anti-PD-1 single-agent groups. Notably, combination therapy yielded significantly longer PFS than either single-drug regimen. The safety profile was similar between combination maintenance and single-drug groups.
Conclusions
Combined maintenance therapy with anti-PD-1 antibodies and capecitabine may be a feasible treatment strategy for mNPC patients.
目的姑息性化疗后转移性鼻咽癌（mNPC）的发病率和死亡率较高。虽然维持治疗显示出良好的潜力，但最佳策略仍未确定。本研究旨在评价免疫化疗维持治疗mNPC患者的疗效。方法本队列研究使用前瞻性维护的数据库，评估卡培他滨和抗pd -1抗体联合维持治疗mNPC患者的疗效。主要终点是无进展生存期（PFS），次要终点包括总生存期和安全性。并进行分层分析和敏感性分析。该研究纳入了2018年至2023年在中山大学癌症中心接受治疗的300例mNPC患者。男性234例（78.0%），中位年龄45岁[四分位间距（IQR）： 36-54岁]。中位随访43.6个月（IQR: 31.8 ~ 57.8），联合维持较单药维持显著改善PFS[加权风险比（HR） 0.580, 95%可信区间（95% CI） 0.387 ~ 0.872, P = 0.009；创造价值,2.27]。分层分析显示，未接受过局部治疗的患者（HR 0.414, 95% CI 0.244 - 0.767, P = 0.005）或维持前eb病毒（EBV） DNA水平升高的患者（HR 0.063, 95% CI 0.007-0.548, P = 0.012）维持免疫化疗的疗效增强。卡培他滨与抗pd -1单药组间PFS无显著差异。值得注意的是，联合治疗的PFS明显长于单药治疗。联合维持组和单药组的安全性相似。结论抗pd -1抗体联合卡培他滨维持治疗可能是mNPC患者的一种可行的治疗策略。
{"title":"The role of immunochemotherapy maintenance in metastatic nasopharyngeal carcinoma: insights from a cohort study in an endemic region","authors":"Zhuoying Luo, Yue Xia, Yuping Zhao, Haoyang Huang, Ying Deng, Zejiang Zhan, Yingying Huang, Xun Cao, Xi Chen, Jiayu Zhou, Chixiong Liang, Weixiong Xia, Liangru Ke, Xuehua Wei, Jinling Duan, Xing Lv, Hu Liang","doi":"10.1002/cti2.70043","DOIUrl":"https://doi.org/10.1002/cti2.70043","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Metastatic nasopharyngeal carcinoma (mNPC) following palliative chemotherapy has high incidence and mortality rates. While maintenance therapy shows promising potential, the optimal strategy remains undefined. This study aimed to evaluate the therapeutic efficacy of immunochemotherapy maintenance in patients with mNPC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This cohort study evaluated the therapeutic efficacy of combined maintenance therapy with capecitabine and anti-PD-1 antibodies in mNPC patients, using a prospectively maintained database. The primary endpoint was progression-free survival (PFS), and secondary endpoints included overall survival and safety profile. Furthermore, stratification analysis and sensitivity analysis were performed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The study included 300 mNPC patients treated at Sun Yat-sen University Cancer Center from 2018 to 2023. Two hundred and thirty-four patients (78.0%) were male, and the median age was 45 years [interquartile range (IQR): 36–54]. At median follow-up of 43.6 months (IQR: 31.8–57.8), combination maintenance significantly improved PFS compared to single-drug maintenance [weighted hazard ratio (HR) 0.580, 95% confidence interval (95% CI) 0.387–0.872, <i>P</i> = 0.009; E-value, 2.27]. Stratification analysis revealed enhanced efficacy of immunochemotherapy maintenance in patients without prior local treatment (HR 0.414, 95% CI 0.224–0.767, <i>P</i> = 0.005) or with elevated premaintenance Epstein–Barr virus (EBV) DNA levels (HR 0.063, 95% CI 0.007–0.548, <i>P</i> = 0.012). No significant difference in PFS was observed between the capecitabine and anti-PD-1 single-agent groups. Notably, combination therapy yielded significantly longer PFS than either single-drug regimen. The safety profile was similar between combination maintenance and single-drug groups.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Combined maintenance therapy with anti-PD-1 antibodies and capecitabine may be a feasible treatment strategy for mNPC patients.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"14 7","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70043","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144537071","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yibo Wu, Xiaolin Yuan, Xiaoyu Lai, Lizhen Liu, Yue Liang, Lihong Ni, Luxin Yang, Shanshan Hu, Jimin Shi, Jian Yu, Yanmin Zhao, Weiyan Zheng, Jie Sun, Yuanyuan Zhu, Wenjun Wu, Zhen Cai, He Huang, Shanshan Pei, Yi Luo
Objectives
Differentiation hierarchies in myeloid malignancies influence therapeutic response and prognosis. Acute myeloid leukaemia (AML) with t(8;21) is one of the most recurrent genetic subtypes of AML and is considered a distinct entity with shared characteristics. However, clinical outcomes remain markedly heterogeneous. This study aimed to investigate the relationship between leukaemic arrest at specific differentiation stages, genomic profiles and clinical outcomes in t(8;21) AML.
Methods
We conducted a retrospective study involving 338 patients with t(8;21) AML from three clinical centres in China. Patients received either chemotherapy alone (49.11%, n = 166) or chemotherapy followed by allogeneic haematopoietic stem cell transplantation (allo-HSCT; 41.72%, n = 141). Immunophenotypic profiling classified patients into progenitor subgroups: MPP (20.12%, n = 68), lymphoid-primed multi-potent progenitor (14.50%, n = 49), CMP (12.72%, n = 43), GMP (24.85%, n = 84) and GP/MP (10.36%, n = 35). Based on differentiation stage, patients were categorised as primitive (Immuno-Prim; 47.34%, n = 160) or monocytic (Immuno-Mono; 35.21%, n = 119).
Results
The Immuno-Mono group was associated with lower 2-year overall survival (OS) and a higher 2-year cumulative incidence of relapse (CIR) compared to the Immuno-Prim group. Patients with a KIT mutation had poorer 2-year OS and higher 2-year CIR than those without the mutation. In the allo-HSCT cohort, the Immuno-Mono group continued to show lower 2-year OS and higher 2-year CIR relative to the Immuno-Prim group. Neither gene mutations (aside from KIT) nor chromosomal losses significantly affected OS or CIR.
Conclusions
Leukaemic differentiation stage independently predicts post-treatment outcomes in t(8;21) AML. Arrest at specific myeloid stages correlates significantly with genetic aberrations, clinical presentation, therapeutic response and survival.
目的髓系恶性肿瘤的分化等级影响治疗效果和预后。急性髓性白血病（AML）伴t（8;21）是AML最常复发的遗传亚型之一，被认为是具有共同特征的独特实体。然而，临床结果仍然存在明显的异质性。本研究旨在探讨t(8;21) AML在特定分化阶段白血病骤停、基因组谱和临床结局之间的关系。方法我们对来自中国三个临床中心的338例t(8;21) AML患者进行了回顾性研究。患者接受单独化疗（49.11%,n = 166）或化疗后异体造血干细胞移植(alloo - hsct；41.72%, n = 141)。免疫表型分析将患者分为祖细胞亚组：MPP （20.12%, n = 68）、淋巴细胞引发的多能祖细胞（14.50%,n = 49）、CMP （12.72%, n = 43）、GMP （24.85%, n = 84）和GP/MP （10.36%, n = 35）。根据分化阶段，将患者分为原始（immune - prim）；47.34%, n = 160)或单核细胞(immune - mono；35.21%, n = 119)。结果与免疫- prim组相比，免疫- mono组的2年总生存期（OS）较低，2年累积复发发生率（CIR）较高。与没有突变的患者相比，KIT突变患者的2年OS较差，2年CIR较高。在同种hsct队列中，相对于免疫- prim组，免疫- mono组继续显示较低的2年OS和较高的2年CIR。基因突变（KIT除外）和染色体缺失均未显著影响OS或CIR。结论白血病分化阶段独立预测t(8;21) AML治疗后预后。在特定的髓细胞阶段的阻滞与基因畸变、临床表现、治疗反应和生存显著相关。
{"title":"Cellular hierarchy for understanding heterogeneity of acute myeloid leukaemia with t(8;21)/RUNX1-RUNX1T1","authors":"Yibo Wu, Xiaolin Yuan, Xiaoyu Lai, Lizhen Liu, Yue Liang, Lihong Ni, Luxin Yang, Shanshan Hu, Jimin Shi, Jian Yu, Yanmin Zhao, Weiyan Zheng, Jie Sun, Yuanyuan Zhu, Wenjun Wu, Zhen Cai, He Huang, Shanshan Pei, Yi Luo","doi":"10.1002/cti2.70042","DOIUrl":"https://doi.org/10.1002/cti2.70042","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Differentiation hierarchies in myeloid malignancies influence therapeutic response and prognosis. Acute myeloid leukaemia (AML) with t(8;21) is one of the most recurrent genetic subtypes of AML and is considered a distinct entity with shared characteristics. However, clinical outcomes remain markedly heterogeneous. This study aimed to investigate the relationship between leukaemic arrest at specific differentiation stages, genomic profiles and clinical outcomes in t(8;21) AML.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We conducted a retrospective study involving 338 patients with t(8;21) AML from three clinical centres in China. Patients received either chemotherapy alone (49.11%, <i>n</i> = 166) or chemotherapy followed by allogeneic haematopoietic stem cell transplantation (allo-HSCT; 41.72%, <i>n</i> = 141). Immunophenotypic profiling classified patients into progenitor subgroups: MPP (20.12%, <i>n</i> = 68), lymphoid-primed multi-potent progenitor (14.50%, <i>n</i> = 49), CMP (12.72%, <i>n</i> = 43), GMP (24.85%, <i>n</i> = 84) and GP/MP (10.36%, <i>n</i> = 35). Based on differentiation stage, patients were categorised as primitive (Immuno-Prim; 47.34%, <i>n</i> = 160) or monocytic (Immuno-Mono; 35.21%, <i>n</i> = 119).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The Immuno-Mono group was associated with lower 2-year overall survival (OS) and a higher 2-year cumulative incidence of relapse (CIR) compared to the Immuno-Prim group. Patients with a KIT mutation had poorer 2-year OS and higher 2-year CIR than those without the mutation. In the allo-HSCT cohort, the Immuno-Mono group continued to show lower 2-year OS and higher 2-year CIR relative to the Immuno-Prim group. Neither gene mutations (aside from KIT) nor chromosomal losses significantly affected OS or CIR.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Leukaemic differentiation stage independently predicts post-treatment outcomes in t(8;21) AML. Arrest at specific myeloid stages correlates significantly with genetic aberrations, clinical presentation, therapeutic response and survival.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"14 7","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70042","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144537072","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kamila Bendíčková, Ioanna Papatheodorou, Gabriela Blažková, Martin Helán, Michaela Haláková, Petr Bednář, Erin Spearing, Lucie Obermannová, Julie Štíchová, Monika Dvořáková Heroldová, Tomáš Tomáš, Roman Panovský, Vladimír Šrámek, Marco De Zuani, Marcela Vlková, Daniel Růžek, Marcela Hortová-Kohoutková, Jan Frič
Objectives
Several years after the COVID-19 pandemic, the impact of SARS-CoV-2 on immunity and the potential protective role of Bacillus Calmette–Guérin (BCG) vaccination through trained immunity remain a subject of investigation. This study aimed to determine the long-term impact of SARS-CoV-2 on immune cells and the association between BCG vaccination, latent infections and COVID-19 severity and sepsis progression.
Methods
We conducted a prospective analysis of patients who recovered from mild/severe/critical COVID-19 (n = 97, 3–17 months after COVID-19) and sepsis patients (n = 64). First, we assessed the impact of COVID-19 and its severity on immune cell frequencies and expression of functional markers. Further, we analysed plasma titres of anti-Toxoplasma gondii/cytomegalovirus/BCG antibodies and their association with COVID-19 severity and sepsis outcome. To examine monocyte responses to secondary challenge, monocytes isolated from COVID-19 convalescent patients, BCG vaccinated and unvaccinated volunteers were stimulated with SARS-CoV-2 and LPS.
Results
Post-COVID-19 patients showed immune dysregulation regardless of disease severity characterised by altered expression of activation and functional markers in myeloid (CD39, CD64, CD85d, CD11b) and lymphoid cells (CD39, CD57, TIGIT). Strikingly, post-critical COVID-19 patients showed elevated expression of CD57 in CD8+ T cells compared to other severity groups. A trend toward improved outcomes in BCG-seropositive COVID-19/sepsis patients was observed, although this may be confounded by age differences between groups. In contrast, the monocyte response to stimulation appeared unaffected by COVID-19 severity.
Conclusion
These findings highlight the long-term alterations of immune cells in post-COVID-19 patients, emphasising the substantial impact of COVID-19 on immune function.
{"title":"Long-term immune changes after COVID-19 and the effect of BCG vaccination and latent infections on disease severity","authors":"Kamila Bendíčková, Ioanna Papatheodorou, Gabriela Blažková, Martin Helán, Michaela Haláková, Petr Bednář, Erin Spearing, Lucie Obermannová, Julie Štíchová, Monika Dvořáková Heroldová, Tomáš Tomáš, Roman Panovský, Vladimír Šrámek, Marco De Zuani, Marcela Vlková, Daniel Růžek, Marcela Hortová-Kohoutková, Jan Frič","doi":"10.1002/cti2.70041","DOIUrl":"https://doi.org/10.1002/cti2.70041","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Several years after the COVID-19 pandemic, the impact of SARS-CoV-2 on immunity and the potential protective role of Bacillus Calmette–Guérin (BCG) vaccination through trained immunity remain a subject of investigation. This study aimed to determine the long-term impact of SARS-CoV-2 on immune cells and the association between BCG vaccination, latent infections and COVID-19 severity and sepsis progression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We conducted a prospective analysis of patients who recovered from mild/severe/critical COVID-19 (<i>n</i> = 97, 3–17 months after COVID-19) and sepsis patients (<i>n</i> = 64). First, we assessed the impact of COVID-19 and its severity on immune cell frequencies and expression of functional markers. Further, we analysed plasma titres of anti-<i>Toxoplasma gondii</i>/cytomegalovirus/BCG antibodies and their association with COVID-19 severity and sepsis outcome. To examine monocyte responses to secondary challenge, monocytes isolated from COVID-19 convalescent patients, BCG vaccinated and unvaccinated volunteers were stimulated with SARS-CoV-2 and LPS.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Post-COVID-19 patients showed immune dysregulation regardless of disease severity characterised by altered expression of activation and functional markers in myeloid (CD39, CD64, CD85d, CD11b) and lymphoid cells (CD39, CD57, TIGIT). Strikingly, post-critical COVID-19 patients showed elevated expression of CD57 in CD8<sup>+</sup> T cells compared to other severity groups. A trend toward improved outcomes in BCG-seropositive COVID-19/sepsis patients was observed, although this may be confounded by age differences between groups. In contrast, the monocyte response to stimulation appeared unaffected by COVID-19 severity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These findings highlight the long-term alterations of immune cells in post-COVID-19 patients, emphasising the substantial impact of COVID-19 on immune function.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"14 7","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70041","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144492723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Anna Strömberg, Mirko Mandić, Brennan J Wadsworth, Sebastian Proschinger, Seher Alam, Lisa MJ Eriksson, Laura Barbieri, Eric Rullman, Helene Rundqvist
Objectives
The beneficial influence of exercise on outcomes such as infection control and cancer prevention has been attributed partly to the immune system response during physical exertion. CD8+ T cells play a crucial role in immune surveillance, and in this study, we performed an in-depth analysis of the impact of supramaximal high-intensity exercise (HIIT) on CD8+ T-cell dynamics and function, which are currently lacking in the literature.
Methods
CD8+ T cells obtained from healthy human subjects before and after 3 × 30 s of HIIT were analysed ex vivo for viability and expansion properties, metabolic function using SeaHorse, IFN-gamma release using EliSpot, phenotype using RNA-seq and flow cytometry, and cytotoxic capacity by co-culture with HEK293T cells.
Results
Exercise led to a threefold increase in CD8+ T-cell count, and CD8+ T cells obtained after exercise had a more cytotoxic profile. Post-exercise CD8+ T cells had a lower glycolytic capacity than pre-exercise cells, and incubation of pre-exercise CD8+ T cells with post-exercise serum replicated this metabolic shift, suggesting a systemic effect of exercise on CD8+ T-cell metabolism. Importantly, CD8+ T cells maintained their viability and expansion properties despite the metabolic challenges induced by exercise. Functionally, post-exercise CD8+ T cells showed increased release of IFN-gamma and an enhanced unspecific cell killing capacity as demonstrated by co-culture with the immortalised cell line HEK293T.
Conclusion
The pronounced increase in the total number of circulating CD8+ T-cells with an increased cytotoxic capacity suggests a potential improvement in immune surveillance after acute HIIT.
{"title":"Functional characterisation of CD8+ T cells mobilised with acute supramaximal high-intensity interval exercise: implications for immune surveillance","authors":"Anna Strömberg, Mirko Mandić, Brennan J Wadsworth, Sebastian Proschinger, Seher Alam, Lisa MJ Eriksson, Laura Barbieri, Eric Rullman, Helene Rundqvist","doi":"10.1002/cti2.70037","DOIUrl":"https://doi.org/10.1002/cti2.70037","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>The beneficial influence of exercise on outcomes such as infection control and cancer prevention has been attributed partly to the immune system response during physical exertion. CD8<sup>+</sup> T cells play a crucial role in immune surveillance, and in this study, we performed an in-depth analysis of the impact of supramaximal high-intensity exercise (HIIT) on CD8<sup>+</sup> T-cell dynamics and function, which are currently lacking in the literature.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>CD8<sup>+</sup> T cells obtained from healthy human subjects before and after 3 × 30 s of HIIT were analysed <i>ex vivo</i> for viability and expansion properties, metabolic function using SeaHorse, IFN-gamma release using EliSpot, phenotype using RNA-seq and flow cytometry, and cytotoxic capacity by co-culture with HEK293T cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Exercise led to a threefold increase in CD8<sup>+</sup> T-cell count, and CD8<sup>+</sup> T cells obtained after exercise had a more cytotoxic profile. Post-exercise CD8<sup>+</sup> T cells had a lower glycolytic capacity than pre-exercise cells, and incubation of pre-exercise CD8<sup>+</sup> T cells with post-exercise serum replicated this metabolic shift, suggesting a systemic effect of exercise on CD8<sup>+</sup> T-cell metabolism. Importantly, CD8<sup>+</sup> T cells maintained their viability and expansion properties despite the metabolic challenges induced by exercise. Functionally, post-exercise CD8<sup>+</sup> T cells showed increased release of IFN-gamma and an enhanced unspecific cell killing capacity as demonstrated by co-culture with the immortalised cell line HEK293T.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The pronounced increase in the total number of circulating CD8<sup>+</sup> T-cells with an increased cytotoxic capacity suggests a potential improvement in immune surveillance after acute HIIT.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"14 6","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70037","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144323674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Leyu Zheng, Carolin Fuchs, Christian Kleber, Georg Osterhoff, Gabriela Aust
Objectives
Traumatic injury triggers the rapid release of damage-associated patterns (DAMPs). Dendritic cells (DCs) and monocytes play key roles in sensing, processing, and presenting DAMPs to naïve T cells. These heterogeneous immune cells express the adhesion GPCR EMR2/ADGRE2, which is likely regulated by DAMPs.
Methods
We analysed the various blood DC and monocyte subsets in trauma patients and uninjured volunteers using flow cytometry. EMR2 and its closest relatives, CD97/ADGRE5 and EMR3/ADGRE3, were quantified on these subsets to gain insights into their (patho)physiological regulation.
Results
Following trauma, conventional and plasmocytoid DCs nearly disappeared from the circulation, which is inversely correlated with injury severity and adverse clinical parameters 120–240 h post injury. Alterations in EMR2 and CD97 on DCs were relatively minor. Classical monocytes increased, while non-classical monocytes showed a sustained decline in both absolute number and percentage, in a manner dependent on injury severity after trauma. EMR2 expression increased across all monocyte subsets, whereas CD97 showed little change. EMR3 expression decreased and remained low in classical monocytes, while it markedly increased in non-classical monocytes. These temporal patterns in adhesion GPRC expression were largely independent of injury severity and were observed in all injured patients.
Conclusion
Circulating DC and monocyte subsets underwent significant compositional changes after trauma, often correlating with injury severity and other clinical parameters. Despite structural similarities, EMR2, CD97, and EMR3 showed distinct regulatory patterns on monocyte subsets, suggesting different functional roles in the immune response to injury.
{"title":"Long-lasting changes in circulating dendritic cell and monocyte subsets, and altered expression of EMR2, CD97 and EMR3 on these cells in the posttraumatic course","authors":"Leyu Zheng, Carolin Fuchs, Christian Kleber, Georg Osterhoff, Gabriela Aust","doi":"10.1002/cti2.70040","DOIUrl":"https://doi.org/10.1002/cti2.70040","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Traumatic injury triggers the rapid release of damage-associated patterns (DAMPs). Dendritic cells (DCs) and monocytes play key roles in sensing, processing, and presenting DAMPs to naïve T cells. These heterogeneous immune cells express the adhesion GPCR EMR2/<i>ADGRE2</i>, which is likely regulated by DAMPs.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We analysed the various blood DC and monocyte subsets in trauma patients and uninjured volunteers using flow cytometry. EMR2 and its closest relatives, CD97/<i>ADGRE5</i> and EMR3/<i>ADGRE3</i>, were quantified on these subsets to gain insights into their (patho)physiological regulation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Following trauma, conventional and plasmocytoid DCs nearly disappeared from the circulation, which is inversely correlated with injury severity and adverse clinical parameters 120–240 h post injury. Alterations in EMR2 and CD97 on DCs were relatively minor. Classical monocytes increased, while non-classical monocytes showed a sustained decline in both absolute number and percentage, in a manner dependent on injury severity after trauma. EMR2 expression increased across all monocyte subsets, whereas CD97 showed little change. EMR3 expression decreased and remained low in classical monocytes, while it markedly increased in non-classical monocytes. These temporal patterns in adhesion GPRC expression were largely independent of injury severity and were observed in all injured patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Circulating DC and monocyte subsets underwent significant compositional changes after trauma, often correlating with injury severity and other clinical parameters. Despite structural similarities, EMR2, CD97, and EMR3 showed distinct regulatory patterns on monocyte subsets, suggesting different functional roles in the immune response to injury.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"14 6","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70040","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144300458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Andrea S Henden, Katie E Lineburg, Archana Panikkar, Arushi Mahajan, Ricky Nelles, Emma Wright, Pauline Crooks, Jyothy Raju, Laetitia Le Texier, Srividhya Swaminathan, Leone Beagley, Shannon Best, Matthew Solomon, Hilary Reddiex, Glen Kennedy, Siok-Keen Tey, Michelle A Neller, Rajiv Khanna, Corey Smith
Objectives
Despite the effective roll-out of COVID-19 vaccines, immunocompromised patients have a higher risk of morbidity and mortality following SARS-CoV-2 infection. Allogeneic adoptive T-cell immunotherapy is now established as an effective approach to treat viral diseases in immunocompromised patients. The objective of this study was to assess the safety of allogeneic virus-specific T-cell therapy in patients with COVID-19.
Methods
Using a repository of SARS-CoV-2-specific T cells generated from healthy exposed volunteers, we conducted an open-label phase I trial to assess the feasibility and safety of allogeneic SARS-CoV-2-specific T cells in immune-compromised cancer patients with COVID-19.
Results
Six participants at risk of severe COVID-19 were enrolled and received SARS-CoV-2-specific T-cell therapy within 4 days of recruitment. The first five participants who received two infusions of allogeneic SARS-CoV-2-specific T-cell therapy experienced no adverse events following treatment. Four of the six participants showed improvement in viral load following treatment and were alive at 12-week follow-up. One participant died 6 days after their second infusion, because of established pulmonary parenchymal damage following prolonged COVID infection. Another, who had underlying lupus nephritis, developed cytokine release syndrome and diffuse alveolar haemorrhage following a single infusion and was withdrawn from the study. They subsequently recovered from this serious adverse event.
Conclusion
Allogeneic SARS-CoV-2-specific T-cell therapy provides a platform to rapidly administer T cells to high-risk COVID-19 patients. It was associated with a reduced viral load and increased SARS-CoV-2-specific T-cell responses in the majority of treated patients.
{"title":"Allogeneic ‘off-the-shelf’ SARS-CoV-2-specific adoptive T-cell therapy for refractory viral infection and end organ disease","authors":"Andrea S Henden, Katie E Lineburg, Archana Panikkar, Arushi Mahajan, Ricky Nelles, Emma Wright, Pauline Crooks, Jyothy Raju, Laetitia Le Texier, Srividhya Swaminathan, Leone Beagley, Shannon Best, Matthew Solomon, Hilary Reddiex, Glen Kennedy, Siok-Keen Tey, Michelle A Neller, Rajiv Khanna, Corey Smith","doi":"10.1002/cti2.70038","DOIUrl":"https://doi.org/10.1002/cti2.70038","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Despite the effective roll-out of COVID-19 vaccines, immunocompromised patients have a higher risk of morbidity and mortality following SARS-CoV-2 infection. Allogeneic adoptive T-cell immunotherapy is now established as an effective approach to treat viral diseases in immunocompromised patients. The objective of this study was to assess the safety of allogeneic virus-specific T-cell therapy in patients with COVID-19.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Using a repository of SARS-CoV-2-specific T cells generated from healthy exposed volunteers, we conducted an open-label phase I trial to assess the feasibility and safety of allogeneic SARS-CoV-2-specific T cells in immune-compromised cancer patients with COVID-19.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Six participants at risk of severe COVID-19 were enrolled and received SARS-CoV-2-specific T-cell therapy within 4 days of recruitment. The first five participants who received two infusions of allogeneic SARS-CoV-2-specific T-cell therapy experienced no adverse events following treatment. Four of the six participants showed improvement in viral load following treatment and were alive at 12-week follow-up. One participant died 6 days after their second infusion, because of established pulmonary parenchymal damage following prolonged COVID infection. Another, who had underlying lupus nephritis, developed cytokine release syndrome and diffuse alveolar haemorrhage following a single infusion and was withdrawn from the study. They subsequently recovered from this serious adverse event.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Allogeneic SARS-CoV-2-specific T-cell therapy provides a platform to rapidly administer T cells to high-risk COVID-19 patients. It was associated with a reduced viral load and increased SARS-CoV-2-specific T-cell responses in the majority of treated patients.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"14 6","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70038","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144256081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yuwei Hao, Anthea Anantharajah, Jane M Wells, Lyndell L Lim, Anthony JH Hall, Gary YJ Chew, Matthew C Cook
Objectives
Sarcoidosis is the exemplar sterile granulomatous disease and can affect any organ system. Tattoo uveitis (TU) resembles sarcoidosis clinically and histologically but is distinguished by the absence of systemic lymphadenopathy, with inflammation restricted to skin and eyes. In this study, our objectives were, first, to resolve whether TU is a subset of sarcoidosis or a different antigen-driven condition and, second, by comparing TU and sarcoidosis, to identify blood-borne signatures of active and quiescent sterile granulomatous diseases.
Methods
We recruited patients with active and inactive TU, sarcoidosis and healthy controls on whom we performed blood cell phenotyping and transcriptomics.
Results
Unlike sarcoidosis, active TU is characterised by marked CXCR5 down-regulation on B cells and CD4+ T cells that normalises on remission. TCR-VDJ sequencing reveals an antigen-driven response in sarcoidosis, but not in TU, with clonally expanded cytotoxic and terminally differentiated CD8+ effectors. Both active TU and sarcoidosis exhibit gene signatures of epithelial-to-mesenchymal transition (EMT) in circulating monocytes, whereas epithelioid macrophages are a hallmark of active granulomas.
Conclusion
We have identified both shared and specific phenotypes in TU and sarcoidosis. Marked CXCR5 down-regulation occurs in active TU and could explain the unique absence of lymphadenopathy. Both TU and sarcoidosis are characterised by inflammatory monocyte phenotypes and transcriptional signatures of EMT.
{"title":"Loss of CXCR5 expression and monocyte epithelial–mesenchymal transition are blood-borne signatures of sterile granulomatous diseases","authors":"Yuwei Hao, Anthea Anantharajah, Jane M Wells, Lyndell L Lim, Anthony JH Hall, Gary YJ Chew, Matthew C Cook","doi":"10.1002/cti2.70039","DOIUrl":"https://doi.org/10.1002/cti2.70039","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Sarcoidosis is the exemplar sterile granulomatous disease and can affect any organ system. Tattoo uveitis (TU) resembles sarcoidosis clinically and histologically but is distinguished by the absence of systemic lymphadenopathy, with inflammation restricted to skin and eyes. In this study, our objectives were, first, to resolve whether TU is a subset of sarcoidosis or a different antigen-driven condition and, second, by comparing TU and sarcoidosis, to identify blood-borne signatures of active and quiescent sterile granulomatous diseases.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We recruited patients with active and inactive TU, sarcoidosis and healthy controls on whom we performed blood cell phenotyping and transcriptomics.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Unlike sarcoidosis, active TU is characterised by marked CXCR5 down-regulation on B cells and CD4<sup>+</sup> T cells that normalises on remission. TCR-VDJ sequencing reveals an antigen-driven response in sarcoidosis, but not in TU, with clonally expanded cytotoxic and terminally differentiated CD8<sup>+</sup> effectors. Both active TU and sarcoidosis exhibit gene signatures of epithelial-to-mesenchymal transition (EMT) in circulating monocytes, whereas epithelioid macrophages are a hallmark of active granulomas.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>We have identified both shared and specific phenotypes in TU and sarcoidosis. Marked CXCR5 down-regulation occurs in active TU and could explain the unique absence of lymphadenopathy. Both TU and sarcoidosis are characterised by inflammatory monocyte phenotypes and transcriptional signatures of EMT.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"14 6","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70039","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144206837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jason Isaacson, Prajakta Bhanap, Nicholas Putnam, Jasmine Padilla, Nujhat Fatima, Max Dotson, Danny Hayoun, Moloud Ahmadi, Gertrude Nonterah, Yongchang Ji
<div> <section> <h3> Objectives</h3> <p>Chimeric antigen receptor (CAR) T-cell therapies have revolutionised the treatment of blood-based malignancies. The use of manual CAR T-cell manufacturing methods is one of the challenges that contributes to these delays. As CAR T therapy emerges as a potential first- or second-line treatment option for these cancers, the demand for these therapies continues to rise. However, challenges persist in ensuring that the patients who need these therapies receive them in a timely manner. Automated CAR T-cell manufacturing methods that use software to control the equipment used in the process can help overcome the roadblocks associated with manual manufacturing, ultimately enabling a reduction in variability, increased efficiency, improved product quality and better data management. This paper aims to present an end-to-end semi-automated methodology for manufacturing CAR T cells using the Cell Therapy Systems (CTS™) Cellmation software – an off-the-shelf software solution – to control physically connected modular cell therapy instruments that eliminates the roadblocks associated with manual manufacturing.</p> </section> <section> <h3> Methods</h3> <p>T cells from healthy donors were isolated and processed into CAR T cells using a semi-automated, connected, multi-instrument setup that leveraged electroporation and a CRISPR/Cas system for delivering the CD19-CAR construct to the T cells. Flow cytometry was used to assess cell type composition, cell viability and expression of T-cell activation markers throughout the process. We also measured exhaustion marker expression on T cells, T-cell receptor (TCR) knock-out, CAR knock-in and cytotoxic activity against NALM6 cells.</p> </section> <section> <h3> Results</h3> <p>The results demonstrated the successful generation of functional CAR T cells using a semi-automated instrument workflow. The results were similar to the results from CAR T cells manufactured using non-automated processes; however, the successful connection and control of the instruments using automated software present an exciting opportunity for process developers and manufacturers who want to reduce manual touchpoints in their cell therapy manufacturing process.</p> </section> <section> <h3> Conclusion</h3> <p>The method that we describe in this paper could be beneficial to process development and manufacturing teams that might require flexibility in their CAR T cell manufacturing workflow and want to take advantage of modular systems that can be automated using the Cellmation software to reduce the proble
{"title":"Enhancing CAR T-cell therapy manufacturing efficiency through semi-automated bioprocessing","authors":"Jason Isaacson, Prajakta Bhanap, Nicholas Putnam, Jasmine Padilla, Nujhat Fatima, Max Dotson, Danny Hayoun, Moloud Ahmadi, Gertrude Nonterah, Yongchang Ji","doi":"10.1002/cti2.70025","DOIUrl":"https://doi.org/10.1002/cti2.70025","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Chimeric antigen receptor (CAR) T-cell therapies have revolutionised the treatment of blood-based malignancies. The use of manual CAR T-cell manufacturing methods is one of the challenges that contributes to these delays. As CAR T therapy emerges as a potential first- or second-line treatment option for these cancers, the demand for these therapies continues to rise. However, challenges persist in ensuring that the patients who need these therapies receive them in a timely manner. Automated CAR T-cell manufacturing methods that use software to control the equipment used in the process can help overcome the roadblocks associated with manual manufacturing, ultimately enabling a reduction in variability, increased efficiency, improved product quality and better data management. This paper aims to present an end-to-end semi-automated methodology for manufacturing CAR T cells using the Cell Therapy Systems (CTS™) Cellmation software – an off-the-shelf software solution – to control physically connected modular cell therapy instruments that eliminates the roadblocks associated with manual manufacturing.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>T cells from healthy donors were isolated and processed into CAR T cells using a semi-automated, connected, multi-instrument setup that leveraged electroporation and a CRISPR/Cas system for delivering the CD19-CAR construct to the T cells. Flow cytometry was used to assess cell type composition, cell viability and expression of T-cell activation markers throughout the process. We also measured exhaustion marker expression on T cells, T-cell receptor (TCR) knock-out, CAR knock-in and cytotoxic activity against NALM6 cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The results demonstrated the successful generation of functional CAR T cells using a semi-automated instrument workflow. The results were similar to the results from CAR T cells manufactured using non-automated processes; however, the successful connection and control of the instruments using automated software present an exciting opportunity for process developers and manufacturers who want to reduce manual touchpoints in their cell therapy manufacturing process.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The method that we describe in this paper could be beneficial to process development and manufacturing teams that might require flexibility in their CAR T cell manufacturing workflow and want to take advantage of modular systems that can be automated using the Cellmation software to reduce the proble","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"14 6","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70025","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144197100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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