Clinical & Translational Immunology最新文献

{"title":"Randomised controlled phase I trial of a SARS-CoV-2 monoclonal antibody","authors":"Wen Shi Lee,&nbsp;Kevin J Selva,&nbsp;Timothy E Schlub,&nbsp;Jennifer Audsley,&nbsp;Janavi S Rambhatla,&nbsp;Robyn Esterbauer,&nbsp;Jennifer A Juno,&nbsp;Andrew Kelly,&nbsp;Ellie Reilly,&nbsp;Thakshila Amarasena,&nbsp;Sarah Lee,&nbsp;Hyon-Xhi Tan,&nbsp;Chee Wah Tan,&nbsp;Lin-Fa Wang,&nbsp;Christina C Chang,&nbsp;Michael Gerometta,&nbsp;Judith A Scoble,&nbsp;Patrick F James,&nbsp;Arnold Reynaldi,&nbsp;Miles P Davenport,&nbsp;Kym Hoger,&nbsp;Karen Hughes,&nbsp;Martina L Jones,&nbsp;Ben Hughes,&nbsp;Adam K Wheatley,&nbsp;Stephen J Kent","doi":"10.1002/cti2.70126","DOIUrl":"10.1002/cti2.70126","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>SARS-CoV-2 infection remains a threat to vulnerable groups. Neutralising monoclonal antibodies (mAbs) have shown efficacy in the treatment and prevention of COVID-19, but most mAbs have lost activity against recent Omicron strains.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We previously isolated a receptor binding domain-specific mAb from a COVID-19 convalescent donor, PDI204, which retained activity against several early Omicron strains. This randomised, double-blind, placebo-controlled phase I clinical trial enrolled healthy adults (<i>n</i> = 32) to receive PDI204 intravenously (IV) at three different doses (200, 600, 1200 mg) or intramuscularly (IM) at 300 mg.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>PDI204 was safe and tolerable with only Grade 1 and 2 adverse events. High serum levels of PDI204 were detected in PDI204-dosed participants with a median elimination half-life of 17.7 days (IQR 16.3–22.1). Boosted neutralising activity and Fc receptor binding were observed in serum against ancestral and Omicron BA.5 SARS-CoV-2 strains, but not against the later Omicron strain XBB.1.5. IM-dosed subjects had peak PDI204 levels in serum 2–6 days later than IV-dosed subjects. Entry of PDI204 into saliva from blood was low and variable, and primarily detected in participants receiving 600 mg or 1200 mg doses. Three of 32 people acquired COVID-19 within 90 days of dosing, two receiving PDI204 and one in a placebo recipient.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Overall, the mAb PDI204 was safe but lost activity against later Omicron strains and did not prevent COVID-19 during this trial.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"15 11","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13735506/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149339992","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}

{"title":"M11-CAR T cells inhibit murine cytomegalovirus in vitro upon recognition of virion- and cell-associated glycoprotein B","authors":"Sabrina Kübel,&nbsp;Christopher Garçon,&nbsp;Hanna Menschikowski,&nbsp;Arne Cordsmeier,&nbsp;Jens-Christian Albrecht,&nbsp;Friederike Oltmanns,&nbsp;Larissa Bauer,&nbsp;Manuel Hermann,&nbsp;Kristina Holdt,&nbsp;Heinrich Sticht,&nbsp;Marco Thomas,&nbsp;Thomas H Winkler,&nbsp;Brigitte Scholz,&nbsp;Doris Jungnickl,&nbsp;Armin Ensser","doi":"10.1002/cti2.70128","DOIUrl":"10.1002/cti2.70128","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Viral infections are predominantly managed with conventional antiviral drugs, which, despite their efficacy, can cause toxicity and promote resistance. Cell-based immunotherapies offer an alternative, but cytomegaloviruses (CMV) profoundly interfere with MHC class I antigen presentation, thereby impairing conventional virus-specific T-cell responses towards infected cells. We therefore aimed to develop an MHC-unrestricted CAR T-cell approach for CMV infection and investigate its antiviral activity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We generated M11-CAR, a fully murine, second-generation CAR based on the M11 monoclonal antibody targeting glycoprotein B (gB) of murine CMV (MCMV). Primary splenocytes were transduced to assess CAR functionality following ectopic gB expression or MCMV infection. T-cell cytotoxicity, cytokine production and antiviral activity were evaluated and compared with human CD19-specific control CAR T cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>M11-CAR T cells specifically recognized gB following ectopic expression and MCMV infection, inducing cytotoxicity and cytokine production. CAR-mediated cytokine production, particularly interferon-γ, translated into robust MCMV inhibition. Increasing MCMV loads impaired cytokine responses of CD19-CAR T cells, whereas M11-CAR T cells maintained strong responses. This effect was partially attributable to direct recognition of virion-associated gB, resulting in activation of M11-CARs.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>M11-CAR T cells enable MHC-independent recognition of MCMV, providing a potential strategy to circumvent CMV-mediated disruption of antigen presentation and immune recognition. Our findings demonstrate that virions can directly shape virus-specific CAR T-cell responses and highlight the importance of antigen recognition mechanisms that are independent of MHC presentation. This provides a basis for refining CAR designs for persistent viral infections characterized by immune evasion.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"15 11","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13730814/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149316454","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}

{"title":"Staphylococcus aureus-derived xanthine exacerbates allergic rhinitis-induced olfactory dysfunction through promoting Th17 cell differentiation and IL-17A production","authors":"Yue Hu,&nbsp;Wenjing Wang,&nbsp;Ting Yang,&nbsp;Xiaoyu Song,&nbsp;Yao Wang,&nbsp;Yuanchao Cheng,&nbsp;Yakui Mou,&nbsp;Chao Ren,&nbsp;Xicheng Song","doi":"10.1002/cti2.70127","DOIUrl":"https://doi.org/10.1002/cti2.70127","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Allergic rhinitis (AR) is frequently accompanied by olfactory dysfunction (OD), yet the role of microbial metabolites in this process remains poorly elucidated. This study aimed to investigate how xanthine, a metabolite derived from <i>Staphylococcus aureus</i> (<i>Sa</i>), exacerbates AR-induced OD by promoting Th17 cell differentiation and IL-17A production.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Multi-omics analyses, comprising metabolomics, proteomics and 16S rRNA gene sequencing, were performed on AR patients and mouse models with AR. <i>Sa</i> was cultured and key metabolites in its supernatant were detected using untargeted metabolomics. AR mice were nasally challenged with <i>Sa</i> supernatant or xanthine, and comparisons were made with mice with chronic AR and OD. The therapeutic potential of an anti-IL-17A neutralising antibody was assessed in AR mice stimulated with <i>Sa</i> supernatant or xanthine.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Purine metabolism was significantly enriched, and xanthine levels were elevated in AR patients and mouse models, particularly those with OD. Airway microbial dysbiosis in AR mice was characterised by increased <i>Staphylococcus</i> abundance, and the <i>Sa</i> infection pathway was enriched in patients with AR. Untargeted metabolomics of <i>Sa</i> supernatant revealed increased xanthine levels and enrichment of purine metabolism. Nasal challenge with <i>Sa</i> supernatant or xanthine significantly exacerbated OD. Mechanistically, xanthine promoted Th17 cell differentiation and IL-17A production. Notably, IL-17A neutralisation effectively alleviated xanthine-exacerbated OD, indicating a pivotal role for the IL-17A pathway in this process.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p><i>Sa</i>-derived xanthine aggravates AR-induced OD by driving Th17 cell differentiation and IL-17A production. These findings highlight the xanthine–IL-17A pathway as a potential therapeutic target for improving olfactory function in AR.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"15 11","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70127","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149310911","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}

{"title":"Spatial and maturational characterisation of tertiary lymphoid structures predicts immunotherapy response in extensive-stage small cell lung cancer","authors":"Haoyu Wang,&nbsp;Xiaoling Shang,&nbsp;Yuanzhu Jiang,&nbsp;Chenglong Zhao,&nbsp;Zhenxiang Li,&nbsp;Chufeng Zhang,&nbsp;Qinhao Xu,&nbsp;Shanshan Du,&nbsp;Jiamao Lin,&nbsp;Haiyong Wang","doi":"10.1002/cti2.70125","DOIUrl":"10.1002/cti2.70125","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Extensive-stage small cell lung cancer (ES-SCLC) remains an aggressive malignancy with limited durable responses to immune checkpoint inhibitors (ICIs) and no established predictive biomarkers. This study aimed to evaluate the prognostic and predictive value of tertiary lymphoid structures (TLSs) in patients with ES-SCLC receiving ICI-based therapy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this multicenter retrospective study of 180 treatment-naïve ES-SCLC patients subsequently receiving ICI-based therapy, TLSs were systematically evaluated using H&amp;E staining, multiplex immunofluorescence, and spatial analysis to determine their prognostic and predictive value.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>TLSs were identified in 22.2% of cases and independently associated with improved overall survival (OS) in both univariate (HR = 0.365, 95% CI: 0.217–0.613, <i>P</i> &lt; 0.001) and multivariate (HR = 0.337, 95% CI: 0.199–0.569, <i>P</i> &lt; 0.001) analyses. Crucially, TLS maturation status was associated with clinical outcomes, as patients with mature TLSs containing CD21⁺ follicular dendritic cells and organized germinal centers experienced significantly longer survival than those with non-mature TLSs (<i>P</i> = 0.0049). Beyond mere presence, responders to ICIs exhibited distinct spatial characteristics, including higher TLS densities, denser immune infiltration, and shorter distances between TLS-resident CD20⁺ B cells, CD3⁺ T cells, and tumor cells, suggesting that immune–tumor spatial organization within TLSs reflects functional antitumor engagement.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>TLS maturation and spatial architecture may serve as candidate tissue biomarkers associated with clinical outcomes in ICI-treated ES-SCLC, warranting prospective validation alongside SCLC molecular subtyping.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"15 10","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13682280/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149236355","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}

{"title":"From delivery to integration: CRISPR-mediated large insert gene editing in primary human T cells","authors":"Ben Buttle,&nbsp;Daniel Verdon,&nbsp;Hilary M Sheppard","doi":"10.1002/cti2.70124","DOIUrl":"10.1002/cti2.70124","url":null,"abstract":"<p>Large insert gene editing in <i>ex vivo</i>, primary human T cells represents an important approach for engineering next-generation cellular immunotherapies. While CRISPR-based editing is well-established for small genetic modifications, large insert knock-in remains a technical bottleneck. This review examines current strategies for achieving efficient, precise and safe integration of large genetic elements. We compare delivery methods for CRISPR components, highlighting electroporation of Cas9 ribonucleoproteins as the most efficient but often cytotoxic approach; emerging alternatives such as cell-penetrating peptides and lipid nanoparticles offer improved cell viability at the expense of editing efficiency. The influence of genomic locus selection, guide RNA design and chromatin context on editing outcomes, as well as the role of homology-directed repair (HDR) template design is evaluated. Various template formats—including linear double- and single-stranded DNA, plasmids, circular single-stranded (css) DNA and recombinant adeno-associated virus (rAAV)—are assessed for their efficiency, toxicity and risk of off-target integration. Where possible, cross-study normalisation is used to enable meaningful comparisons. rAAV templates consistently achieve the highest insertion rates but come with concerns regarding cost, size limitations and insertional mutagenesis, whereas non-viral approaches such as cssDNA templates show promise. Additionally, we review the use of small-molecule modulators to enhance HDR efficiency, noting trade-offs between improved insertion rates and potential genomic instability. Overall, successful large insert editing requires balancing of editing efficiency, cell viability and genomic safety considerations. Continued optimisation of delivery systems, template design and repair pathway modulation will be critical for advancing scalable and clinically viable T-cell therapies.</p>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"15 10","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13677281/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149223041","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}

{"title":"Assessing CD8+ T cell cross-reactivity to influenza A, B and C virus-derived peptides presented by HLA-B*18:01","authors":"Lawton D Murdolo,&nbsp;Samuel Liwei Leong,&nbsp;Janesha C Maddumage,&nbsp;Lloyd D'Orsogna,&nbsp;Demetra SM Chatzileontiadou,&nbsp;Emma J Grant,&nbsp;Stephanie Gras","doi":"10.1002/cti2.70123","DOIUrl":"https://doi.org/10.1002/cti2.70123","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Despite the availability of vaccines, influenza viruses still cause substantial morbidity and mortality. This highlights the need for improved vaccines and novel therapeutics. CD8⁺ T cells recognise conserved viral epitopes and can provide broad protection, making them attractive targets for next-generation vaccine design. A key step in this process is to identify T cell epitopes across influenza viruses. Here, we characterised three homologous influenza Polymerase Basic 1 (PB1)-derived peptides from influenza viruses (PB1-A₃₁₀, PB1-B₃₁₀ and PB1-C₃₁₂, respectively) presented by the common, but understudied, HLA-B*18:01 molecule.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We used a thermal melt assay and X-ray crystallography to assess the stability and structural features of each peptide. CD8⁺ T-cell responses were evaluated using intracellular cytokine staining with HLA-B*18:01⁺ samples.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The structures of HLA-B*18:01 presenting each peptide were solved, including the first structure of HLA-B*18:01 presenting a <i>Gammainfluenzavirus</i> (formerly influenza C virus) derived peptide. PB1-C₃₁₂ exhibited a higher thermal stability and a different conformation compared to PB1-A₃₁₀ and PB1-B₃₁₀. CD8⁺ T cell responses varied among samples, with PB1-A₃₁₀ eliciting the strongest activation. Minimal T cell cross-reactivity was observed and was mostly between PB1-A₃₁₀ and PB1-B₃₁₀ likely reflecting shared structural features.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These findings further expand knowledge on peptide presentation by the common HLA-B*18:01 molecule, and the limitations on CD8⁺ T cell cross-recognition of this PB1-derived epitope across influenza lineages. This highlights the importance of more research on cross-lineage T cell cross-reactivity that could inform the design of broadly protective T cell-based vaccines and therapeutics.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"15 10","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70123","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149177069","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}

{"title":"Prolonged molecular control during intermittent reduced-intensity blinatumomab maintenance in a transplant-ineligible patient with Philadelphia chromosome-positive acute lymphoblastic leukaemia and IKZF1 deletion","authors":"Xiaoqian Duan,&nbsp;Jinjun Yang,&nbsp;Yufei Yang,&nbsp;Shuwen Guo,&nbsp;Yu Wu","doi":"10.1002/cti2.70121","DOIUrl":"10.1002/cti2.70121","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Long-term disease control in transplant-ineligible patients with high-risk Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph⁺ ALL) remains difficult, particularly when adverse genetic lesions and acquired kinase domain mutations coexist.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Clinical, cytogenetic and molecular records were retrospectively reviewed. <i>BCR::ABL1</i> transcripts were monitored by quantitative PCR, and peripheral lymphocyte subsets were followed longitudinally. Public transcriptomic data (GSE196463) were analysed to compare T-cell expression profiles under continuous versus intermittent bispecific antibody exposure.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A 64-year-old man with Ph⁺ ALL harbouring a heterozygous <i>IKZF1</i> deletion relapsed while receiving dasatinib, with emergence of an ABL1 E255K/V mutation. Although this P-loop mutant retains sensitivity to dasatinib, relapse suggested kinase-independent escape; treatment was redirected towards immune-mediated clearance with one cycle of continuous blinatumomab plus dasatinib, achieving deep molecular remission. Allogeneic transplantation was deferred because of advanced age, prior cardiac dysfunction and cumulative infectious burden, and outpatient maintenance was initiated with monthly 24-h blinatumomab infusions (35 μg) plus dasatinib (100 mg daily) and subcutaneous interferon alfa-2b (3 MIU thrice weekly). Morphologic remission was sustained for over 3.5 years with no unplanned hospitalizations and no grade ≥3 neurotoxicity. <i>BCR::ABL1</i> transcripts remained undetectable for nearly 3 years before a transient low-level fluctuation (0.0024% IS) appeared and stabilized without treatment escalation. Peripheral monitoring showed persistent CD8⁺ predominance and sustained B-cell depletion (&lt;20 cells/μL), indicating ongoing target engagement. Public transcriptomic data supported that intermittent bispecific exposure preserves progenitor/memory T-cell programmes while limiting exhaustion.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Intermittent reduced-intensity blinatumomab maintenance guided by serial MRD monitoring was feasible and associated with durable molecular control in a transplant-ineligible patient with high-risk Ph⁺ ALL. This strategy merits prospective evaluation.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"15 9","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13594394/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149023344","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}

{"title":"Manufacturing cost analysis and exploratory economic evaluation of natural killer cell immunotherapy for paediatric solid tumors","authors":"Sabera Tabassum Wahid,&nbsp;Melissa Elliott,&nbsp;Yufan Wang,&nbsp;Wayne Nicholls,&nbsp;Natacha Omer,&nbsp;Fernando Souza-Fonseca-Guimaraes,&nbsp;Haitham Tuffaha","doi":"10.1002/cti2.70122","DOIUrl":"10.1002/cti2.70122","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Natural killer (NK) cell therapy is a promising allogeneic, off-the-shelf immunotherapy for solid tumors, yet economic evidence to guide its clinical translation is absent. This study aimed to conduct a micro-costing analysis of their manufacturing and perform an exploratory economic evaluation of NK cell therapy for paediatric solid tumors from an Australian health system perspective.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A micro-costing analysis was conducted using primary laboratory production data across six manufacturing steps and categories. Hospitalisation costs were estimated by expert opinion. Effectiveness estimates were drawn from chimeric antigen receptor (CAR)-T cell therapy economic evaluations. Analyses included incremental cost-effectiveness ratios (ICERs), headroom analysis, net monetary benefit (NMB) and probabilistic sensitivity analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Manufacturing cost was AUD 58 681 (USD 38 143) per batch (AUD 9780; USD 6357 per dose). Eighty-eight per cent of costs were concentrated in three steps: NK cell expansion (50.8%), mRNA transfection (25.1%) and T-cell depletion (11.7%), with consumables/reagents comprising 85% of the total production cost. Combining manufacturing (AUD 58 681) and hospitalisation (AUD 75 000; USD 48 750) costs, the total NK cell therapy cost was AUD 133 681 (USD 86 893) per patient, yielding an illustrative ICER of AUD 35 167 (USD 22 859) per QALY gained, based on a proxy effectiveness estimate. Economic headroom was AUD 56 386 (USD 36 651) per patient. Probabilistic analysis showed 51.7% probability of cost-effectiveness at AUD 50 000/QALY, with a minimum of 2.67 QALYs required.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>NK cell therapy shows indicative early economic signals warranting further clinical and economic investigation. Micro-costing identifies actionable manufacturing cost drivers to inform process optimisation, and these exploratory estimates provide a foundation for iterative economic evaluation as clinical evidence develops.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"15 9","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13590241/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149015113","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}

{"title":"Parallel processing of T cells and natural killer cells to enhance in vivo CAR T cell activity against blood and solid cancers","authors":"Lachlan J Dobson,&nbsp;Patrick W Marron,&nbsp;Ariana HT Drabble,&nbsp;Thiloma D Liyanage,&nbsp;Kristine C Pe,&nbsp;Clare Y Slaney,&nbsp;Barry D Hock,&nbsp;Alexander D McLellan","doi":"10.1002/cti2.70120","DOIUrl":"https://doi.org/10.1002/cti2.70120","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Despite their anti-cancer properties, natural killer (NK) cells are discarded during CAR T cell manufacturing. NK cells display promising responses as a cell therapy, exhibiting remarkable safety at high doses. Moreover, NK cells have complementary cytokine profiles and distinct antigen-recognition pathways to supplement CAR T cell therapies. We demonstrate parallel expansion of NK cells from the normally discarded PBMC of CAR T cell production for downstream combination therapies against solid and blood-borne malignancies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>CAR T cells were manufactured from buffy coats with initial isolation of T cells from PBMC. NK cells were rapidly expanded in parallel by stimulating the remaining PBMC with membrane-bound (mb)IL-21 + mbIL-15 feeder cells. Expanded NK cells were assessed through spectral flow cytometry and applied as a pretreatment prior to CAR Tcell infusion against xenograft tumor models in NOD-<i>scid</i> IL2Rgamma^null (NSG) mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Applying feeder cells to residual PBMC stimulated 5000-fold expansions of pure NK cells. Expanded NK cells expressed various activation receptors and displayed strong <i>in vitro</i> cytotoxicity, which was further improved in CAR T-conditioned medium. A pretreatment of NK cells enhanced existing CAR T cell therapies, improving <i>in vivo</i> tumor clearance and survival against breast cancer, acute lymphoblastic leukaemia and non-Hodgkin's lymphoma. While NK cells eliminated CD19^−/− variants <i>in vitro</i>, they were unable to suppress antigen-escape relapse <i>in vivo</i>.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This study encourages the optimal use of leukapheresis product. By recycling discarded PBMC into NK cells, CAR T cell therapies can be effectively enhanced, improving tumor clearance and survival.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"15 9","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70120","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148862188","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}

{"title":"Peripheral immune dynamics during treatment predict prognosis in HCC receiving TACE plus ICIs and anti-VEGF/TKIs","authors":"Lihao Qin,&nbsp;Linzhou Zhu,&nbsp;Hao Yang,&nbsp;Wanci Li,&nbsp;Shuai Zhang,&nbsp;Jian Shen,&nbsp;Xiaoli Zhu","doi":"10.1002/cti2.70115","DOIUrl":"https://doi.org/10.1002/cti2.70115","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Objectives&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;To evaluate the prognostic value of peripheral immune markers and their static and dynamic changes during different treatment stages in patients with hepatitis B virus (HBV)-related unresectable hepatocellula carcinoma (uHCC) receiving transarterial chemoembolisation (TACE) combined with immune checkpoint inhibitors (ICIs) and anti-vascular endothelial growth factor (anti-VEGF) antibodies or tyrosine kinase inhibitors (TKIs).&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;This single-centre retrospective study included patients with HBV-related uHCC treated with TACE combined with ICls and anti-VEGF antibodies or TKIs between July 2019 and July 2024. Peripheral blood immune indicators were collected at baseline (Cycle 0), the second treatment cycle (Cycle 2) and the fourth treatment cycle (Cycle 4). The primary outcome was overall survival (OS), while secondary outcomes included progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR), with tumour response assessed at the first treatment evaluation (at the end of the fourth treatment cycle) based on mRECIST criteria. Longitudinal changes between adjacent time points were calculated (Δ: Cycle 2 - Cycle 0; Δ2: Cycle 4 - Cycle 2). Both static values and dynamic changes in immune markers were subjected to LASSO-Cox and stepwise multivariate Cox regression analyses to identify independent predictors of OS. Based on the significant variables, a prognostic nomogram and an immune-based risk score model were developed. To further assess prognostic heterogeneity, patients were stratified by K-means clustering according to the temporal patterns of the most predictive immune marker, and survival outcomes were compared across the resulting subgroups.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;A total of 67 HBV-related uHCC patients treated with TACE plus ICIs and anti-VEGF antibodies/TKIs were included. The cohort had a median follow-up of 18.2 months, with a median overall survival (mOS) of 30.4 months and a median progression-free survival (mPFS) of 11.0 months. At the first evaluation, the objective response rate (ORR) was 53.7%, and the disease control rate (DCR) was 86.6%. LASSO-Cox regression identified several static and dynamic immune markers associated with OS. Ultimately, CD4⁺/CD8⁺ ratio at Cycle 4 (HR = 0.58, &lt;i&gt;p&lt;/i&gt; = 0.035), Δ2 NLR (HR = 1.66, &lt;i&gt;p&lt;/i&gt; = 0.014), and Δ2 CD3⁺CD4⁺ (HR = 0.04, &lt;i&gt;p&lt;/i&gt; = 0.007) were confirmed by stepwise multivariate Cox regression. A prognostic nomogram incorporating these variables demonstrated favourable predictive performance (C-index = 0.72; AUCs = 0.750, 0.722 and 0.854 for 1-, 2- and","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"15 8","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70115","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148753852","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}