Clinical & Translational Immunology最新文献

From delivery to integration: CRISPR-mediated large insert gene editing in primary human T cells. 从传递到整合：crispr介导的大插入基因编辑在原代人T细胞中。

IF 3.4 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2026-10-18 eCollection Date: 2026-01-01 DOI: 10.1002/cti2.70124

Ben Buttle, Daniel Verdon, Hilary M Sheppard

Large insert gene editing in ex vivo, 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.

在离体、原代人T细胞中进行大插入基因编辑是设计下一代细胞免疫疗法的重要途径。虽然基于crispr的编辑在小型基因修饰方面已经得到了证实，但大型插入敲入仍然是一个技术瓶颈。本文综述了目前实现高效、精确和安全整合大型遗传元素的策略。我们比较了CRISPR组件的递送方法，强调Cas9核糖核蛋白的电穿孔是最有效但通常具有细胞毒性的方法；新兴的替代品，如细胞穿透肽和脂质纳米颗粒，以牺牲编辑效率为代价，提高了细胞活力。评估了基因组位点选择、引导RNA设计和染色质背景对编辑结果的影响，以及同源定向修复（HDR）模板设计的作用。各种模板格式——包括线性双链和单链DNA、质粒、环状单链DNA和重组腺相关病毒（rAAV）——评估了它们的效率、毒性和脱靶整合的风险。在可能的情况下，使用交叉研究归一化来进行有意义的比较。rAAV模板始终实现最高的插入率，但存在成本、大小限制和插入突变等问题，而非病毒方法（如cssDNA模板）则显示出前景。此外，我们回顾了使用小分子调节剂来提高HDR效率，注意到在提高插入率和潜在的基因组不稳定性之间的权衡。总的来说，成功的大插入编辑需要在编辑效率、细胞活力和基因组安全考虑之间取得平衡。持续优化递送系统、模板设计和修复途径调节对于推进可扩展和临床可行的t细胞疗法至关重要。

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引用次数: 0

Assessing CD8+ T cell cross-reactivity to influenza A, B and C virus-derived peptides presented by HLA-B*18:01 评估CD8+ T细胞对HLA-B*18:01呈递的甲型、乙型和丙型流感病毒衍生肽的交叉反应性

IF 3.4 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2026-10-13 DOI: 10.1002/cti2.70123

Lawton D Murdolo, Samuel Liwei Leong, Janesha C Maddumage, Lloyd D'Orsogna, Demetra SM Chatzileontiadou, Emma J Grant, Stephanie Gras

Objectives

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.

Methods

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.

Results

The structures of HLA-B*18:01 presenting each peptide were solved, including the first structure of HLA-B*18:01 presenting a Gammainfluenzavirus (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.

Conclusion

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.

尽管有疫苗，但流感病毒仍然造成大量发病率和死亡率。这突出表明需要改进疫苗和新疗法。CD8+ T细胞识别保守的病毒表位，并能提供广泛的保护，使它们成为下一代疫苗设计的有吸引力的靶标。这一过程的关键一步是识别流感病毒中的T细胞表位。在这里，我们从流感病毒中鉴定了三种同源流感聚合酶基础1 （PB1）衍生的肽（分别为PB1- a310， PB1- b310和PB1- c312），这些肽是由常见但尚未得到充分研究的HLA-B*18:01分子呈现的。方法采用热熔体分析和x射线晶体学对各肽的稳定性和结构特征进行评价。采用HLA-B*18:01+样品细胞内细胞因子染色评价CD8+ t细胞反应。结果确定了呈递各肽段的HLA-B*18:01的结构，包括呈递Gammainfluenzavirus（原流感C病毒）衍生肽段的HLA-B*18:01的首个结构。与PB1-A310和PB1-B310相比，PB1-C312表现出更高的热稳定性和不同的构象。CD8+ T细胞的反应因样品而异，PB1-A310的激活最强。观察到最小的T细胞交叉反应，主要发生在PB1-A310和PB1-B310之间，可能反映了共同的结构特征。结论这些发现进一步扩展了对常见HLA-B*18:01分子肽呈递的认识，以及CD8+ T细胞交叉识别pb1衍生表位在流感谱系中的局限性。这突出了对跨谱系T细胞交叉反应性进行更多研究的重要性，这可以为设计广泛保护性T细胞疫苗和治疗方法提供信息。

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引用次数: 0

Prolonged molecular control during intermittent reduced-intensity blinatumomab maintenance in a transplant-ineligible patient with Philadelphia chromosome-positive acute lymphoblastic leukaemia and IKZF1 deletion 在不适合移植的费城染色体阳性急性淋巴细胞白血病和IKZF1缺失患者的间歇性低强度blinatumab维持期间延长分子控制

IF 3.4 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2026-09-21 DOI: 10.1002/cti2.70121

Xiaoqian Duan, Jinjun Yang, Yufei Yang, Shuwen Guo, Yu Wu

Objectives

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.

Methods

Clinical, cytogenetic and molecular records were retrospectively reviewed. BCR::ABL1 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.

Results

A 64-year-old man with Ph⁺ ALL harbouring a heterozygous IKZF1 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. BCR::ABL1 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 (<20 cells/μL), indicating ongoing target engagement. Public transcriptomic data supported that intermittent bispecific exposure preserves progenitor/memory T-cell programmes while limiting exhaustion.

Conclusion

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.

目的：在不适合移植的高风险费城染色体阳性急性淋巴细胞白血病（Ph+ ALL）患者中，长期疾病控制仍然困难，特别是当不良遗传病变和获得性激酶结构域突变共存时。方法：回顾性分析临床、细胞遗传学和分子生物学资料。定量PCR检测BCR::ABL1转录本，并纵向跟踪外周血淋巴细胞亚群。对公开转录组数据（GSE196463）进行分析，比较连续和间歇双特异性抗体暴露下的t细胞表达谱。结果：一名携带IKZF1杂合缺失的64岁Ph+ ALL患者在接受达沙替尼治疗时复发，出现ABL1 E255K/V突变。尽管这种p环突变体对达沙替尼保持敏感性，但复发表明激酶独立逃逸；治疗重新定向到免疫介导的清除，一个周期的连续blinatumomab加达沙替尼，实现深度分子缓解。由于高龄、既往心功能障碍和累积感染负担，异体移植被推迟，门诊维持开始于每月24小时blinatumomab输注（35 μg）加达沙替尼（每天100 mg）和皮下干扰素α -2b （3 MIU，每周3次）。形态学缓解持续超过3.5年，无计划外住院，无≥3级神经毒性。在出现短暂的低水平波动（0.0024% IS）并在没有治疗升级的情况下稳定下来之前，近3年未检测到BCR: ABL1转录本。外周监测显示持续的CD8+优势和持续的b细胞耗竭(结论：在连续MRD监测指导下间歇性低强度blinatumumab维持对于不适合移植的高风险Ph+ ALL患者是可行的，并且与持久的分子控制相关。这一策略值得进行前瞻性评价。

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引用次数: 0

Manufacturing cost analysis and exploratory economic evaluation of natural killer cell immunotherapy for paediatric solid tumors 自然杀伤细胞免疫治疗小儿实体瘤的制造成本分析及探索性经济评价。

IF 3.4 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2026-09-20 DOI: 10.1002/cti2.70122

Sabera Tabassum Wahid, Melissa Elliott, Yufan Wang, Wayne Nicholls, Natacha Omer, Fernando Souza-Fonseca-Guimaraes, Haitham Tuffaha

Objectives

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.

Methods

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.

Results

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.

Conclusion

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.

目的：自然杀伤（NK）细胞疗法是一种很有前途的同种异体、现成的实体肿瘤免疫疗法，但缺乏指导其临床转化的经济证据。本研究旨在对其制造进行微观成本分析，并从澳大利亚卫生系统的角度对儿童实体瘤的NK细胞治疗进行探索性经济评估。方法：微观成本分析进行了主要实验室生产数据跨越六个制造步骤和类别。住院费用是根据专家意见估计的。有效性评估来自嵌合抗原受体(CAR)-T细胞治疗的经济评估。分析包括增量成本-效果比（ICERs）、净额分析、净货币效益（NMB）和概率敏感性分析。结果：制造成本为每批58681澳元（38143美元）（9780澳元；6357美元/剂）。88%的成本集中在三个步骤：NK细胞扩增（50.8%）、mRNA转染（25.1%）和t细胞消耗（11.7%），耗材/试剂占总生产成本的85%。结合制造（58 681澳元）和住院（75 000澳元；48 750美元）成本，NK细胞治疗的总成本为每位患者133 681澳元（86 893美元），根据代理有效性估计，每个QALY获得的解释性ICER为35 167澳元（22 859美元）。每位患者的经济净额为56 386澳元（36 651美元）。概率分析显示，5万澳元/QALY的成本效益概率为51.7%，至少需要2.67个QALY。结论：NK细胞治疗显示出指示性的早期经济信号，值得进一步的临床和经济研究。微观成本确定了可操作的制造成本驱动因素，为流程优化提供信息，这些探索性估计为临床证据的发展提供了迭代经济评估的基础。

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引用次数: 0

Parallel processing of T cells and natural killer cells to enhance in vivo CAR T cell activity against blood and solid cancers T细胞和自然杀伤细胞并行处理，增强体内CAR - T细胞抗血液和实体癌的活性

IF 3.4 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2026-09-01 DOI: 10.1002/cti2.70120

Lachlan J Dobson, Patrick W Marron, Ariana HT Drabble, Thiloma D Liyanage, Kristine C Pe, Clare Y Slaney, Barry D Hock, Alexander D McLellan

Objectives

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.

Methods

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-scid IL2Rgamma^null (NSG) mice.

Results

Applying feeder cells to residual PBMC stimulated 5000-fold expansions of pure NK cells. Expanded NK cells expressed various activation receptors and displayed strong in vitro cytotoxicity, which was further improved in CAR T-conditioned medium. A pretreatment of NK cells enhanced existing CAR T cell therapies, improving in vivo tumor clearance and survival against breast cancer, acute lymphoblastic leukaemia and non-Hodgkin's lymphoma. While NK cells eliminated CD19^−/− variants in vitro, they were unable to suppress antigen-escape relapse in vivo.

Conclusion

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.

尽管具有抗癌特性，自然杀伤细胞（NK）在CAR - T细胞制造过程中被丢弃。NK细胞作为细胞疗法显示出有希望的反应，在高剂量下表现出显著的安全性。此外，NK细胞具有互补的细胞因子谱和独特的抗原识别途径来补充CAR - T细胞疗法。我们证明NK细胞平行扩增来自CAR - T细胞产生的通常被丢弃的PBMC，用于针对实体和血源性恶性肿瘤的下游联合治疗。方法从PBMC中分离T细胞，用黄皮制备CAR - T细胞。通过膜结合（mb）IL-21 + mbIL-15喂料细胞刺激剩余的PBMC， NK细胞迅速平行扩增。通过光谱流式细胞术评估扩增NK细胞，并将其作为CAR - t细胞输注抗NOD-scid IL2Rgammanull （NSG）小鼠异种移植肿瘤模型的预处理。结果将饲养细胞应用于残余PBMC，可使纯NK细胞扩增5000倍。扩增的NK细胞表达多种激活受体，并表现出较强的体外细胞毒性，在CAR - t条件下进一步增强。NK细胞预处理增强了现有的CAR - T细胞疗法，提高了乳腺癌、急性淋巴细胞白血病和非霍奇金淋巴瘤的体内肿瘤清除率和生存率。虽然NK细胞在体外消除CD19−/−变异，但它们在体内无法抑制抗原逃逸复发。结论本研究促进了白细胞分离产品的优化使用。通过将废弃的PBMC回收为NK细胞，可以有效增强CAR - T细胞疗法，提高肿瘤清除率和生存率。

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引用次数: 0

Peripheral immune dynamics during treatment predict prognosis in HCC receiving TACE plus ICIs and anti-VEGF/TKIs 治疗期间的外周免疫动力学预测肝癌患者接受TACE + ICIs和抗vegf /TKIs的预后

IF 3.4 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2026-08-14 DOI: 10.1002/cti2.70115

Lihao Qin, Linzhou Zhu, Hao Yang, Wanci Li, Shuai Zhang, Jian Shen, Xiaoli Zhu

<div> <section> <h3> Objectives</h3> <p>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).</p> </section> <section> <h3> Methods</h3> <p>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.</p> </section> <section> <h3> Results</h3> <p>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, <i>p</i> = 0.035), Δ2 NLR (HR = 1.66, <i>p</i> = 0.014), and Δ2 CD3⁺CD4⁺ (HR = 0.04, <i>p</i> = 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

{"title":"Peripheral immune dynamics during treatment predict prognosis in HCC receiving TACE plus ICIs and anti-VEGF/TKIs","authors":"Lihao Qin, Linzhou Zhu, Hao Yang, Wanci Li, Shuai Zhang, Jian Shen, Xiaoli Zhu","doi":"10.1002/cti2.70115","DOIUrl":"https://doi.org/10.1002/cti2.70115","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>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).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>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, <i>p</i> = 0.035), Δ2 NLR (HR = 1.66, <i>p</i> = 0.014), and Δ2 CD3⁺CD4⁺ (HR = 0.04, <i>p</i> = 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}

引用次数: 0

Sustained response to rituximab in an ANCA-negative necrotizing vasculitis with initial detection of Corynebacterium kroppenstedtii 最初检测到克氏棒状杆菌的anca阴性坏死性血管炎患者对利妥昔单抗的持续反应。

IF 3.4 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2026-08-11 DOI: 10.1002/cti2.70119

Nadine Al-Azem, Anna Knothe, Jan-Dirk Raguse, Inga Nierkamp, Achim Georg Beule, Claudia Rudack, Friedericke Müller, Anne Kerlikowki, Eva Wardelmann, Hermann Pavenstädt, Martin A Kriegel, Rebecca Hasseli

Objectives

In this case, we present a patient with rapidly progressive unilateral destructive orbital and midface inflammation. Initial detection of Corynebacterium kroppenstedtii was followed by a consistent course of localised necrotizing small-vessel vasculitis, which was responsive to B-cell depletion.

Methods

A 79-year-old woman presented with acute left periorbital pain, tearing and purulent discharge. The workup included serial microbiological cultures, fungal and mycobacterial testing, molecular diagnostics, CT/MRI/PET-CT imaging, multiple surgical biopsies with histopathology and special stains, ANCA testing, and multidisciplinary treatments (antimicrobials, glucocorticoids, methotrexate and rituximab). The clinical course, laboratory work, imaging studies, histological analysis and response to treatment were thoroughly reviewed.

Results

Initial conjunctival culture revealed C. kroppenstedtii and clindamycin and vancomycin was initiated. Despite escalating antimicrobials, the patient developed progressive inflammation with sinus destruction, cutaneous fistula and cheek abscess, requiring orbital exenteration. The biopsies revealed chronic inflammation with multinucleated giant cells, focal necrosis and small-vessel vasculitis. ANCA remained negative, and subsequent testing was negative. High-dose prednisolone improved the patient, prompting the discontinuation of methotrexate because of pancytopenia. Rituximab-induced remission allowed for steroid tapering and rituximab maintenance, which controlled the disease without complications.

Conclusion

This case illustrates a rare, localised ANCA-negative necrotizing small-vessel vasculitis with destructive orbital involvement and initial detection of C. kroppenstedtii. Although the pathogenic significance of this finding remains uncertain, the case highlights the importance of comprehensive microbiological and immunological evaluation in atypical destructive inflammatory disease. Sustained disease control was achieved with immunosuppressive therapy including rituximab after persistent infection had been excluded.

目的：在这个病例中，我们提出了一个快速进展的单侧破坏性眼眶和中脸炎症的患者。最初检测到克氏棒状杆菌之后，出现了一致的局部坏死性小血管炎，这是对b细胞耗竭的反应。方法：一名79岁女性，以急性左眶周疼痛、撕裂和脓性分泌物为主。检查包括一系列微生物培养、真菌和分枝杆菌检测、分子诊断、CT/MRI/PET-CT成像、多次手术活检、组织病理学和特殊染色、ANCA检测和多学科治疗（抗菌药物、糖皮质激素、甲氨蝶呤和利妥昔单抗）。临床过程，实验室工作，影像学检查，组织学分析和对治疗的反应进行了全面的回顾。结果：初始结膜培养显示克氏梭菌、克林霉素和万古霉素起始。尽管不断增加抗菌素治疗，患者仍出现进行性炎症，伴有鼻窦破坏、皮肤瘘管和脸颊脓肿，需要眼眶摘除。活检显示慢性炎症伴多核巨细胞，局灶性坏死和小血管炎。ANCA为阴性，后续检测为阴性。大剂量强的松龙改善了患者的病情，但由于全细胞减少症，促使患者停用甲氨蝶呤。利妥昔单抗诱导的缓解允许类固醇逐渐减少和利妥昔单抗维持，这控制了疾病，没有并发症。结论：本病例为罕见的局部anca阴性坏死性小血管炎，累及眼眶，初步发现为克氏支原体。尽管这一发现的致病意义仍不确定，但该病例强调了在非典型破坏性炎症性疾病中进行综合微生物学和免疫学评估的重要性。在排除持续感染后，通过免疫抑制治疗（包括利妥昔单抗）实现了持续的疾病控制。

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引用次数: 0

Humoral and cellular responses to SARS-CoV-2 variants after ancestral COVID-19 vaccines in people with HIV and lung transplant recipients HIV感染者和肺移植受者接种祖传COVID-19疫苗后对SARS-CoV-2变体的体液和细胞反应

IF 3.4 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2026-08-03 DOI: 10.1002/cti2.70117

David WJ Griffin, Paul A Gill, Irene Boo, Shir Sun, Raffi Gugasyan, Alina Wang, Scott J Bornheimer, Stuart Turville, Anupriya Aggarwal, Greg I Snell, Glen P Westall, Emily SJ Edwards, Anna Coldham, Menno C van Zelm, Heidi E Drummer, James H McMahon

Objectives

Immunocompromised hosts have reduced immune responses to COVID-19 vaccination, and more severe disease. Antibody responses correlate with protection but markers of immunity vary across a spectrum of immunocompromise. We compared serologic and cellular responses following Ancestral COVID-19 vaccines in healthy controls (HC), people with HIV (PWH) and lung transplant (LTx) recipients.

Methods

Anti-spike receptor binding domain (RBD) IgG, neutralising antibodies (nAb) and T-cell responses were assessed one-month post-dose 2 and dose 3 of Ancestral COVID-19 vaccination in HC, PWH and LTx. NAb responses to Ancestral, Delta and Omicron BA.2 and BA.5 variants were assessed.

Results

Twenty-nine HC, 21 PWH and 12 LTx recipients were included. PWH demonstrated lower anti-RBD-IgG responses (median post-dose 3: 80.3 μg mL⁻¹ vs 43.3 μg mL⁻¹, P = 0.03) to mRNA COVID-19 vaccination than HC, while LTx recipients displayed diminished responses following any vaccine (15.3 μg mL⁻¹ vs 74.0 μg mL⁻¹, P = 0.01). Dose 3 increased anti-RBD-IgG concentrations and nAb responses in HC and PWH, though Omicron variant neutralisation was attenuated. LTx recipients mounted limited nAb responses. PWH and HC had no difference in nAb responses for Ancestral (median 1738 vs 486.2, P > 0.99) or BA.5 variants (median 34.0 vs 67.9, P > 0.99). Compared with HC, PWH and LTx demonstrated reduced frequencies of SARS-CoV-2-specific memory T cells and a reduced functional memory T-cell response in LTx.

Conclusion

Although Dose 3 was beneficial, LTx recipients demonstrated lower serological responses than HC, while reductions were modest in PWH. Immunocompromised groups had reduced but detectable SARS-CoV-2-specific T-cell responses, demonstrating the utility of COVID-19 vaccination despite poorer serological responses.

目的：免疫功能低下的宿主对COVID-19疫苗接种的免疫反应降低，疾病更加严重。抗体反应与保护相关，但免疫标记在免疫损害的范围内变化。我们比较了健康对照（HC）、HIV感染者（PWH）和肺移植（LTx）受者接种祖传COVID-19疫苗后的血清学和细胞反应。方法：对HC、PWH和LTx接种2剂和3剂后1个月的抗刺突受体结合域（RBD） IgG、中和抗体（nAb）和t细胞应答进行评估。评估NAb对祖代、Delta和Omicron BA.2和BA.5变异的反应。结果：HC 29例，PWH 21例，LTx 12例。与HC相比，PWH对mRNA - COVID-19疫苗的抗rdd - igg应答较低（剂量后中位数：80.3 μg mL-1 vs 43.3 μg mL-1, P = 0.03），而LTx接种者在接种任何疫苗后的应答均较低（15.3 μg mL-1 vs 74.0 μg mL-1, P = 0.01）。剂量3增加了HC和PWH的抗rbd - igg浓度和nAb反应，但Omicron变体中和作用减弱。LTx接受者的nAb反应有限。PWH和HC在祖代变异（中位数1738 vs 486.2， P值0.99）或BA.5变异（中位数34.0 vs 67.9， P值0.99）的nAb反应上没有差异。与HC相比，PWH和LTx表现出sars - cov -2特异性记忆T细胞频率降低，LTx的功能记忆T细胞反应降低。结论：虽然剂量3是有益的，但LTx受者的血清学反应低于HC，而PWH受者的血清学反应则略有降低。免疫功能低下组的sars - cov -2特异性t细胞反应减少，但可检测到，这表明尽管血清学反应较差，但COVID-19疫苗接种的效用。

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引用次数: 0

CD4+ T-cell responses directed towards A/H5N1-derived haemagglutinin peptides increase in patients with seasonal influenza A virus infection 季节性甲型流感病毒感染患者针对A/ h5n1衍生血凝素肽的CD4+ t细胞反应增加

IF 3.4 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2026-08-02 DOI: 10.1002/cti2.70118

Lilith F Allen, Louise C Rowntree, Mitchell Jenzen, Ruth R Hagen, Nathan P Croft, Fiona James, Genevieve E Martin, Anthony W Purcell, Patricia T Illing, Steven Y C Tong, Allen C Cheng, Tom C Kotsimbos, Jason A Trubiano, Katherine Kedzierska, Thi H O Nguyen

Objectives

Recent outbreak of influenza A/H5N1 viral infections in birds and mammals worldwide prompted renewed concerns over an emerging H5N1-related influenza pandemic in the generally immunologically-naive global population. Cross-reactive CD4⁺ T cells between A/H1N1 and A/H5N1 subtypes targeting internal and surface influenza proteins have been identified in humans, indicating some protection against severe and fatal A/H5N1 infection.

Methods

To detect T-cell responses towards H1 and H5 viruses, we stimulated PBMCs from patients hospitalised with seasonal influenza A viruses, alongside healthy individuals, with overlapping peptide pools spanning hemagglutinin (HA) and neuraminidase (NA) of A/Vietnam/1203/2004 (H5N1) and A/New York/18/2009 (H1N1-pdm09-like) viruses.

Results

Majority of acutely infected and healthy participants (100% and 75%, respectively) had detectable CD4⁺ and CD8⁺ T-cell responses towards H1-HA and H5-HA, whereas 30–80% of individuals had detectable H5-NA responses. H1 and H5 HA-specific CD4⁺ T-cell responses highly correlated, suggesting some level of cross-reactivity between T-cell responses directed against H1 and H5 subtypes. HA-specific CD4⁺ T-cell responses were increased in influenza patients compared to healthy participants. We found no differences in H1- and H5-specific T cell responses between those born pre- and post-1968, irrespective of infection status. Sequence alignment of H1 and H5 viruses identified high conservation in the HA2 stalk subunit (81.53%). CD4⁺ T-cell immunity towards immunodominant HA_306–318 epitope, restricted by several HLA-DRB1 molecules, revealed limited cross-reactivity between Group 1 and Group 2 HA-subtypes.

Conclusion

We define correlative H1- and H5-specific CD4⁺ T-cell responses during seasonal influenza A virus infection, likely reflecting some level of H1/H5 T cell cross-reactivity.

最近在全世界禽类和哺乳动物中暴发的甲型流感/H5N1病毒感染再次引起人们对全球普遍缺乏免疫的人群中新出现的H5N1相关流感大流行的担忧。在人类中发现了针对内部和表面流感蛋白的A/H1N1和A/H5N1亚型之间的交叉反应性CD4+ T细胞，表明对严重和致命的A/H5N1感染具有一定的保护作用。方法为了检测t细胞对H1和H5病毒的反应，我们刺激了来自季节性甲型流感住院患者的PBMCs，与健康个体一起，用重叠的肽池跨越A/Vietnam/1203/2004 （H5N1）和A/New York/18/2009 （h1n1 -pdm09样）病毒的血凝素（HA）和神经氨酸酶（NA）。结果大多数急性感染和健康参与者（分别为100%和75%）对H1-HA和H5-HA有可检测到的CD4+和CD8+ t细胞反应，而30-80%的个体有可检测到的H5-NA反应。H1和H5 ha特异性CD4+ t细胞反应高度相关，表明针对H1和H5亚型的t细胞反应之间存在一定程度的交叉反应。与健康参与者相比，流感患者ha特异性CD4+ t细胞反应增加。我们发现，无论感染状况如何，1968年前后出生的人在H1和h5特异性T细胞反应上没有差异。H1和H5病毒序列比对发现，HA2柄亚基高度保守（81.53%）。CD4+ t细胞对HA306-318表位的免疫，受几种HLA-DRB1分子的限制，显示出1组和2组ha亚型之间有限的交叉反应性。结论我们定义了季节性甲型流感病毒感染期间相关的H1和H5特异性CD4+ T细胞反应，可能反映了一定程度的H1/H5 T细胞交叉反应。

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引用次数: 0

High IL-10 levels during CRS are negatively associated with NK-cell recovery after CAR-T cell therapy CRS期间高IL-10水平与CAR-T细胞治疗后nk细胞恢复呈负相关。

IF 3.4 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2026-07-24 DOI: 10.1002/cti2.70116

Xindi Wang, Wenjing Luo, Yingying Li, Jianghua Wu, Lu Tang, Chenggong Li, Qiaolin Liu, Zhihan Chen, Yu Hu, Heng Mei

Objectives

Immune reconstitution following chimeric antigen receptor (CAR)-T cell therapy remains a critical clinical challenge, and the determinants of natural killer (NK)-cell recovery are not fully understood.

Methods

We longitudinally monitored natural killer (NK)-cell recovery in 64 patients during the first year after CD19-directed CAR-T cell therapy, analysing NK-cell counts and surface receptor expression. Associations between cytokine release syndrome (CRS), cytokine profiles, and NK-cell numerical reconstitution were evaluated, and mechanistic insights were explored using in vitro NK-cell assays.

Results

NK-cell numerical and phenotypic recovery was impaired within the first month after CAR-T cell infusion. Notably, NK-cell numerical recovery was significantly delayed in patients who developed CRS. A reduced NK-to-T cell ratio at one-month post-infusion was associated with a markedly increased risk of viral infection (hazard ratio = 4.512). Elevated interleukin (IL)-10 levels during CRS were inversely associated with NK-cell recovery. Patients with high IL-10 levels exhibited delayed NK-cell reconstitution, which was independently validated in two external cohorts. Mechanistically, in vitro exposure of NK cells to IL-10 promoted caspase-3 activation, increased apoptosis, and enhanced reactive oxygen species accumulation and lipid peroxidation. Rescue experiments using ferrostatin-1 and Z-VAD-FMK further supported the involvement of IL-10 in apoptosis and ferroptosis.

Conclusion

These findings highlight a previously underappreciated role of IL-10 in shaping NK-cell reconstitution post-CAR-T cell therapy, particularly in the setting of CRS. Patients with CRS accompanied by elevated IL-10 levels may benefit from anti-inflammatory interventions or therapeutic strategies aimed at promoting NK-cell recovery.

目的：嵌合抗原受体(CAR)-T细胞治疗后的免疫重建仍然是一个关键的临床挑战，自然杀伤（NK）细胞恢复的决定因素尚未完全了解。方法：我们纵向监测64例患者在cd19靶向CAR-T细胞治疗后第一年的自然杀伤（NK）细胞恢复情况，分析NK细胞计数和表面受体表达。研究人员评估了细胞因子释放综合征（CRS）、细胞因子谱和nk细胞数值重构之间的关系，并利用体外nk细胞实验探索了机制。结果：CAR-T细胞输注后1个月内，nk细胞数量和表型恢复受损。值得注意的是，发生CRS的患者的nk细胞数量恢复明显延迟。输注后1个月nk -t细胞比例降低与病毒感染风险显著增加相关（风险比= 4.512）。CRS期间白细胞介素(IL)-10水平升高与nk细胞恢复呈负相关。高IL-10水平的患者表现出延迟的nk细胞重建，这在两个外部队列中得到了独立验证。在机制上，NK细胞暴露于IL-10促进caspase-3活化，增加凋亡，增强活性氧积累和脂质过氧化。利用铁抑素-1和Z-VAD-FMK进行的救援实验进一步支持IL-10参与细胞凋亡和铁凋亡。结论：这些发现强调了之前被低估的IL-10在car - t细胞治疗后形成nk细胞重构中的作用，特别是在CRS的情况下。伴有IL-10水平升高的CRS患者可能受益于抗炎干预或旨在促进nk细胞恢复的治疗策略。

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引用次数: 0