Clinical & Translational Immunology最新文献_第8页

Primary SARS-CoV-2 infection in children and adults results in similar Fc-mediated antibody effector function patterns 儿童和成人原发性 SARS-CoV-2 感染导致相似的 Fc 介导抗体效应器功能模式

IF 4.6 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2024-07-26 DOI: 10.1002/cti2.1521

Anne T Gelderloos, Anke J Lakerveld, Rutger M Schepp, Mioara Alina Nicolaie, Josine van Beek, Lisa Beckers, Robert S van Binnendijk, Nynke Y Rots, Puck B van Kasteren

Objectives

Increasing evidence suggests that Fc-mediated antibody effector functions have an important role in protection against respiratory viruses, including SARS-CoV-2. However, limited data are available on the potential differences in the development, heterogeneity and durability of these responses in children compared to adults.

Methods

Here, we assessed the development of spike S1-specific serum antibody-dependent cellular phagocytosis (ADCP), complement deposition (ADCD) and natural killer cell activation (ADNKA), alongside specific antibody binding concentrations (IgG, IgA and IgM) and IgG avidity in healthy adults (n = 38, 18–56 years) and children (n = 21, 5–16 years) following primary SARS-CoV-2 infection, with a 10-month longitudinal follow-up. Differences between groups were assessed using a nonparametric Kruskal–Wallis test with Dunn's multiple comparisons test.

Results

We found similar (functional) antibody responses in children compared to adults, with a tendency for increased durability in children, which was statistically significant for ADCD (P < 0.05). While ADNKA was strongly reduced in both adults (P < 0.001) and children (P < 0.05) at the latest time point, ADCP remained relatively stable over time, possibly relating to an increase in avidity of the spike-specific antibodies (P < 0.001). Finally, the ADNKA capacity relative to antibody concentration appeared to decrease over time in both children and adults.

Conclusion

In conclusion, our data provide novel insights into the development of SARS-CoV-2-specific antibody Fc-mediated effector functions in children and adults. An increased understanding of these characteristics in specific age populations is valuable for the future design of novel and improved vaccination strategies for respiratory viruses such as SARS-CoV-2.

目的越来越多的证据表明，Fc 介导的抗体效应器功能在抵御呼吸道病毒（包括 SARS-CoV-2 ）方面发挥着重要作用。然而，关于儿童与成人相比在这些反应的发展、异质性和持久性方面的潜在差异的数据却很有限。方法在此，我们评估了健康成人（n = 38，18-56 岁）和儿童（n = 21，5-16 岁）在原发性 SARS-CoV-2 感染后尖峰 S1 特异性血清抗体依赖性细胞吞噬（ADCP）、补体沉积（ADCD）和自然杀伤细胞激活（ADNKA）的发展情况，以及特异性抗体结合浓度（IgG、IgA 和 IgM）和 IgG 阳性，并进行了为期 10 个月的纵向随访。采用非参数 Kruskal-Wallis 检验和 Dunn's 多重比较检验对组间差异进行评估。成人和儿童的 ADNKA 在最近的时间点均显著降低（P <0.001），而 ADCP 随着时间的推移保持相对稳定，这可能与尖峰特异性抗体的亲和力增加有关（P <0.001）。最后，在儿童和成人中，相对于抗体浓度的 ADNKA 能力似乎随着时间的推移而降低。进一步了解特定年龄段人群的这些特征，对于今后设计新型和改良的呼吸道病毒（如 SARS-CoV-2 ）疫苗接种策略很有价值。

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引用次数: 0

Serological responses and clinical outcomes following a three-dose primary COVID-19 vaccine schedule in kidney transplant recipients and people on dialysis 肾移植受者和透析患者接种三剂 COVID-19 疫苗后的血清反应和临床结果。

IF 4.6 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2024-07-25 DOI: 10.1002/cti2.1523

Dhakshayini Tharmaraj, Irene Boo, Jessie O'Hara, Shir Sun, Kevan R Polkinghorne, Claire Dendle, Stephen J Turner, Menno C van Zelm, Heidi E Drummer, Gabriela Khoury, William R Mulley

Objectives

Despite vaccination strategies, people with chronic kidney disease, particularly kidney transplant recipients (KTRs), remained at high risk of poor COVID-19 outcomes. We assessed serological responses to the three-dose COVID-19 vaccine schedule in KTRs and people on dialysis, as well as seroresponse predictors and the relationship between responses and breakthrough infection.

Methods

Plasma from 30 KTRs and 17 people receiving dialysis was tested for anti-Spike receptor binding domain (RBD) IgG and neutralising antibodies (NAb) to the ancestral and Omicron BA.2 variant after Doses 2 and 3 of vaccination.

Results

After three doses, KTRs achieved lower anti-Spike RBD IgG levels (P < 0.001) and NAb titres than people receiving dialysis (P = 0.002). Seropositive cross-reactive Omicron neutralisation levels were achieved in 11/27 (40.7%) KTRs and 11/14 (78.6%) dialysis recipients. ChAdOx1/viral-vector vaccine type, higher mycophenolate dose (> 1 g per day) and lower absolute B-cell counts predicted poor serological responses in KTRs. ChAdOx-1 vaccine type and higher monocyte counts were negative predictors in dialysis recipients. Among ancestral NAb seroresponders, higher NAb levels positively correlated with higher Omicron neutralisation (R = 0.9, P < 0.001). More KTRs contracted SARS-CoV-2 infection (14/30; 47%) than dialysis recipients (5/17; 29%) and had more severe disease. Those with breakthrough infections had significantly lower median interdose incremental change in anti-Spike RBD IgG and ancestral NAb titres.

Conclusion

Serological responses to COVID-19 vaccines in KTRs lag behind their dialysis counterparts. KTRs remained at high risk of breakthrough infection after their primary vaccination schedule underlining their need for booster doses, strict infection prevention measures and close surveillance.

目标：尽管采取了疫苗接种策略，但慢性肾脏病患者，尤其是肾移植受者（KTR）仍面临COVID-19不良后果的高风险。我们评估了 KTR 和透析患者对三剂 COVID-19 疫苗计划的血清反应，以及血清反应预测因子和反应与突破性感染之间的关系：方法：在接种第二剂和第三剂疫苗后，对 30 名 KTR 和 17 名透析患者的血浆进行抗史派克受体结合域（RBD）IgG 和祖先抗体及 Omicron BA.2 变异体中和抗体（NAb）检测：接种三剂疫苗后，KTR 的抗史派克 RBD IgG 水平较低（P = 0.002）。11/27（40.7%）名 KTR 和 11/14（78.6%）名透析受者的血清交叉反应性 Omicron 中和水平呈阳性。ChAdOx1/ 病毒载体疫苗类型、较高的霉酚酸酯剂量（> 1 克/天）和较低的 B 细胞绝对计数预示着 KTR 的血清反应较差。ChAdOx-1 疫苗类型和较高的单核细胞计数对透析受者的血清学反应呈负向预测。在祖先 NAb 血清应答者中，较高的 NAb 水平与较高的 Omicron 中和度呈正相关（R = 0.9，P 结论：在祖先 NAb 血清应答者中，较高的 NAb 水平与较高的 Omicron 中和度呈正相关：KTR 对 COVID-19 疫苗的血清反应落后于透析受者。KTR 在完成初级疫苗接种后仍面临突破性感染的高风险，这表明他们需要加强剂量、严格的感染预防措施和密切监测。

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引用次数: 0

Spatial proteomic profiling of tumor and stromal compartments in non-small-cell lung cancer identifies signatures associated with overall survival 非小细胞肺癌肿瘤和基质区的空间蛋白质组学分析确定了与总生存率相关的特征。

IF 4.6 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2024-07-18 DOI: 10.1002/cti2.1522

Vahid Yaghoubi Naei, James Monkman, Habib Sadeghirad, Ahmed Mehdi, Tony Blick, William Mullally, Ken O'Byrne, Majid Ebrahimi Warkiani, Arutha Kulasinghe

Objectives

Non-small-cell lung carcinoma (NSCLC) is the most prevalent and lethal form of lung cancer. The need for biomarker-informed stratification of targeted therapies has underpinned the need to uncover the underlying properties of the tumor microenvironment (TME) through high-plex quantitative assays.

Methods

In this study, we profiled resected NSCLC tissues from 102 patients by targeted spatial proteomics of 78 proteins across tumor, immune activation, immune cell typing, immune-oncology, drug targets, cell death and PI3K/AKT modules to identify the tumor and stromal signatures associated with overall survival (OS).

Results

Survival analysis revealed that stromal CD56 (HR = 0.384, P = 0.06) and tumoral TIM3 (HR = 0.703, P = 0.05) were associated with better survival in univariate Cox models. In contrast, after adjusting for stage, BCLXL (HR = 2.093, P = 0.02) and cleaved caspase 9 (HR = 1.575, P = 0.1) negatively influenced survival. Delta testing indicated the protective effect of TIM-3 (HR = 0.614, P = 0.04) on OS. In multivariate analysis, CD56 (HR = 0.172, P = 0.001) was associated with better survival in the stroma, while B7.H3 (HR = 1.72, P = 0.008) was linked to poorer survival in the tumor.

Conclusions

Deciphering the TME using high-plex spatially resolved methods is giving us new insights into compartmentalised tumor and stromal protein signatures associated with clinical endpoints in NSCLC.

研究目的非小细胞肺癌（NSCLC）是发病率最高、致死率最高的肺癌。由于需要根据生物标志物对靶向疗法进行分层，因此需要通过高倍定量检测来揭示肿瘤微环境（TME）的基本特性：在这项研究中，我们通过对肿瘤、免疫激活、免疫细胞分型、免疫肿瘤学、药物靶点、细胞死亡和PI3K/AKT模块中的78种蛋白质进行靶向空间蛋白质组学研究，对102例患者切除的NSCLC组织进行了分析，以确定与总生存期（OS）相关的肿瘤和基质特征：结果：生存分析表明，在单变量Cox模型中，基质CD56（HR=0.384，P=0.06）和肿瘤TIM3（HR=0.703，P=0.05）与较好的生存率相关。相反，在调整分期后，BCLXL（HR = 2.093，P = 0.02）和裂解的caspase 9（HR = 1.575，P = 0.1）对生存率有负面影响。德尔塔测试表明，TIM-3（HR = 0.614，P = 0.04）对 OS 有保护作用。在多变量分析中，CD56（HR = 0.172，P = 0.001）与基质中较高的生存率相关，而B7.H3（HR = 1.72，P = 0.008）与肿瘤中较低的生存率相关：结论：利用高倍空间分辨方法对TME进行解密，让我们对与NSCLC临床终点相关的分区肿瘤和基质蛋白特征有了新的认识。

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引用次数: 0

Endogenous bystander killing mechanisms enhance the activity of novel FAP-specific CAR-T cells against glioblastoma 内源性旁观者杀伤机制增强了新型 FAP 特异性 CAR-T 细胞对抗胶质母细胞瘤的活性

IF 4.6 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2024-07-05 DOI: 10.1002/cti2.1519

Wenbo Yu, Nga TH Truong, Ruhi Polara, Tessa Gargett, Melinda N Tea, Stuart M Pitson, Michaelia P Cockshell, Claudine S Bonder, Lisa M Ebert, Michael P Brown

Objectives

CAR-T cells are being investigated as a novel immunotherapy for glioblastoma, but clinical success has been limited. We recently described fibroblast activation protein (FAP) as an ideal target antigen for glioblastoma immunotherapy, with expression on both tumor cells and tumor blood vessels. However, CAR-T cells targeting FAP have never been investigated as a therapy for glioblastoma.

Methods

We generated a novel FAP targeting CAR with CD3ζ and CD28 signalling domains and tested the resulting CAR-T cells for their lytic activity and cytokine secretion function in vitro (using real-time impedance, flow cytometry, imaging and bead-based cytokine assays), and in vivo (using a xenograft mimicking the natural heterogeneity of human glioblastoma).

Results

FAP-CAR-T cells exhibited target specificity against model cell lines and potent cytotoxicity against patient-derived glioma neural stem cells, even when only a subpopulation expressed FAP, indicating a bystander killing mechanism. Using co-culture assays, we confirmed FAP-CAR-T cells mediate bystander killing of antigen-negative tumor cells, but only after activation by FAP-positive target cells. This bystander killing was at least partially mediated by soluble factors and amplified by IL-2 which activated the non-transduced fraction of the CAR-T product. Finally, a low dose of intravenously administered FAP-CAR-T cells controlled, without overt toxicity, the growth of subcutaneous tumors created using a mixture of antigen-negative and antigen-positive glioblastoma cells.

Conclusions

Our findings advance FAP as a leading candidate for clinical CAR-T therapy of glioblastoma and highlight under-recognised antigen nonspecific mechanisms that may contribute meaningfully to the antitumor activity of CAR-T cells.

目的 CAR-T 细胞作为一种治疗胶质母细胞瘤的新型免疫疗法正在接受研究，但临床成功率有限。我们最近描述了成纤维细胞活化蛋白（FAP），它是胶质母细胞瘤免疫疗法的理想靶抗原，在肿瘤细胞和肿瘤血管上都有表达。然而，以 FAP 为靶点的 CAR-T 细胞从未作为胶质母细胞瘤的疗法进行过研究。方法我们生成了一种带有 CD3ζ 和 CD28 信号结构域的新型 FAP 靶向 CAR，并在体外（使用实时阻抗、流式细胞仪、成像和基于微珠的细胞因子测定）和体内（使用模拟人类胶质母细胞瘤天然异质性的异种移植）测试了所生成的 CAR-T 细胞的溶解活性和细胞因子分泌功能。结果 FAP-CAR-T 细胞对模型细胞系具有靶向特异性，对源自患者的胶质瘤神经干细胞具有强大的细胞毒性，即使只有亚群表达 FAP，这表明存在旁观者杀伤机制。通过共培养试验，我们证实了 FAP-CAR-T 细胞对抗原阴性肿瘤细胞的旁观者杀伤作用，但只有在 FAP 阳性靶细胞激活后才能起作用。这种旁观者杀伤作用至少部分由可溶性因子介导，并由 IL-2 激活 CAR-T 产物的非转化部分而放大。最后，静脉注射低剂量的 FAP-CAR-T 细胞可控制使用抗原阴性和抗原阳性胶质母细胞瘤细胞混合物生成的皮下肿瘤的生长，且无明显毒性。结论我们的研究结果推动了 FAP 成为胶质母细胞瘤临床 CAR-T 疗法的主要候选者，并强调了未被充分认识的抗原非特异性机制，这种机制可能会对 CAR-T 细胞的抗肿瘤活性做出有意义的贡献。

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引用次数: 0

Metabolic requirements of CD160 expressing memory-like NK cells in Gram-negative bacterial infection 表达 CD160 的记忆样 NK 细胞在革兰氏阴性细菌感染中的代谢需求。

IF 4.6 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2024-07-02 DOI: 10.1002/cti2.1513

Anucha Preechanukul, Natnaree Saiprom, Kitilak Rochaikun, Boonthanom Moonmueangsan, Rungnapa Phunpang, Orawan Ottiwet, Yuphin Kongphrai, Soonthon Wapee, Rachan Janon, Susanna Dunachie, Barbara Kronsteiner, Narisara Chantratita

Objective

Unique metabolic requirements accompany the development and functional fates of immune cells. How cellular metabolism is important in natural killer (NK) cells and their memory-like differentiation in bacterial infections remains elusive.

Methods

Here, we utilise our established NK cell memory assay to investigate the metabolic requirement for memory-like NK cell formation and function in response to the Gram-negative intracellular bacteria Burkholderia pseudomallei (BP), the causative agent of melioidosis.

Results

We demonstrate that CD160⁺ memory-like NK cells upon BP stimulation upregulate glucose and amino acid transporters in a cohort of recovered melioidosis patients which is maintained at least 3-month post-hospital admission. Using an in vitro assay, human BP-specific CD160⁺ memory-like NK cells show metabolic priming including increased expression of glucose and amino acid transporters with elevated glucose uptake, increased mTOR activation and mitochondrial membrane potential upon BP re-stimulation. Antigen-specific and cytokine-induced IFN-γ production of this memory-like NK cell subset are highly dependent on oxidative phosphorylation (OXPHOS) with some dependency on glycolysis, whereas the formation of CD160⁺ memory-like NK cells in vitro is dependent on fatty acid oxidation and OXPHOS and further increased by metformin.

Conclusion

This study reveals the link between metabolism and cellular function of memory-like NK cells, which can be exploited for vaccine design and for monitoring protection against Gram-negative bacterial infection.

目的：免疫细胞的发育和功能命运伴随着独特的代谢要求。方法：在此，我们利用已建立的 NK 细胞记忆试验来研究记忆样 NK 细胞形成和功能对革兰氏阴性细胞内细菌假丝状伯克霍尔德氏菌（Burkholderia pseudomallei，BP）（美拉菌病的致病菌）的代谢要求：结果：我们证明，在一组已康复的类鼻疽患者中，CD160+记忆样NK细胞在受到BP刺激后会上调葡萄糖和氨基酸转运体，这种情况在入院后至少维持了3个月。通过体外试验，人类 BP 特异性 CD160+ 记忆样 NK 细胞在 BP 再刺激时表现出新陈代谢启动，包括葡萄糖和氨基酸转运体表达增加，葡萄糖摄取量升高，mTOR 激活和线粒体膜电位升高。这种记忆样 NK 细胞亚群的抗原特异性和细胞因子诱导的 IFN-γ 生成高度依赖于氧化磷酸化（OXPHOS），并在一定程度上依赖于糖酵解，而体外 CD160+ 记忆样 NK 细胞的形成依赖于脂肪酸氧化和 OXPHOS，二甲双胍可进一步提高其生成：这项研究揭示了记忆样 NK 细胞的代谢与细胞功能之间的联系，可用于疫苗设计和监测对革兰氏阴性细菌感染的保护。

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引用次数: 0

Advances in bacteria-based drug delivery systems for anti-tumor therapy 基于细菌的抗肿瘤给药系统的进展。

IF 4.6 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2024-06-26 DOI: 10.1002/cti2.1518

Han Shuwen, Song Yifei, Wu Xinyue, Qu Zhanbo, Yu Xiang, Yang Xi

In recent years, bacteria have gained considerable attention as a promising drug carrier that is critical in improving the effectiveness and reducing the side effects of anti-tumor drugs. Drug carriers can be utilised in various forms, including magnetotactic bacteria, bacterial biohybrids, minicells, bacterial ghosts and bacterial spores. Additionally, functionalised and engineered bacteria obtained through gene engineering and surface modification could provide enhanced capabilities for drug delivery. This review summarises the current studies on bacteria-based drug delivery systems for anti-tumor therapy and discusses the prospects and challenges of bacteria as drug carriers. Furthermore, our findings aim to provide new directions and guidance for the research on bacteria-based drug systems.

近年来，细菌作为一种前景广阔的药物载体，在提高抗肿瘤药物的疗效和减少副作用方面发挥着至关重要的作用，因而受到了广泛关注。药物载体的形式多种多样，包括趋磁细菌、细菌生物杂交体、微型细胞、细菌幽灵和细菌孢子。此外，通过基因工程和表面修饰获得的功能化和工程化细菌也能增强药物输送能力。本综述总结了目前有关基于细菌的抗肿瘤给药系统的研究，并讨论了细菌作为药物载体的前景和挑战。此外，我们的研究结果旨在为基于细菌的药物系统研究提供新的方向和指导。

引用次数: 0

Siglec-1, an easy and contributory inflammation marker in rheumatology Siglec-1，风湿病学中一种简便易行的炎症标志物。

IF 4.6 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2024-06-26 DOI: 10.1002/cti2.1520

Valentina Boz, Alessandra Tesser, Francesca Burlo, Nicola Donadel, Serena Pastore, Alessandro Amaddeo, Francesca Vittoria, Matteo Padovan, Marianna Di Rosa, Alberto Tommasini, Erica Valencic

Objectives

Inflammatory markers such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are poorly informative about interferon (IFN)-related disorders. In these conditions, the measure of the interferon score (IS), obtained by measuring the expression of IFN-stimulated genes, has been proposed. Flow cytometry-based assays measuring sialic-acid-binding Ig-like lectin 1 (Siglec-1) expression could be a more practical tool for evaluating IFN-inflammation. The study compared Siglec-1 measures with IS and other inflammatory indexes. We compared Siglec-1 measures with IS and other inflammatory indexes in real-world paediatric rheumatology experience.

Methods

We recruited patients with immuno-rheumatological conditions, acute infectious illness and patients undergoing orthopaedic surgery as controls. Siglec-1 expression was measured in all samples, and IS, ESR and CRP were also recorded if available.

Results

Overall, 98 subjects were enrolled in the study, with a total of 104 measures of Siglec-1. Compared with IS, Siglec-1 expression showed good accuracy (86.0%), specificity (72.7%) and sensitivity (85.7%). The measure of the percentage of Siglec-1-positive cells performed best at low levels of IFN-inflammation, while the measure of mean fluorescence intensity performed best at higher levels. Ex vivo studies on IFN-stimulated monocytes confirmed this behaviour. There was no link between Siglec-1 expression and either ESR or CRP, and positive Siglec-1 results were found even when ESR and CRP were normal. A high Siglec-1 expression was also recorded in subjects with acute infections.

Conclusion

Siglec-1 measurement by flow cytometry is an easy tool to detect IFN-related inflammation, even in subjects with normal results of common inflammation indexes.

目的：红细胞沉降率（ESR）和C反应蛋白（CRP）等炎症标志物对干扰素（IFN）相关疾病的参考价值很低。在这种情况下，有人提出了通过测量 IFN 刺激基因的表达来获得干扰素评分（IS）的方法。基于流式细胞术的测定法可测量硅烷基酸结合 Ig 样凝集素 1（Siglec-1）的表达，是评估 IFN-炎症的一种更实用的工具。该研究将 Siglec-1 测量值与 IS 及其他炎症指标进行了比较。我们将 Siglec-1 与 IS 及其他炎症指标进行了比较：我们招募了免疫风湿病患者、急性传染病患者和骨科手术患者作为对照。测量所有样本中 Siglec-1 的表达，如果有 IS、ESR 和 CRP，也会记录下来：结果：共有 98 名受试者参加了这项研究，共测量了 104 个 Siglec-1 表达量。与 IS 相比，Siglec-1 表达的准确性（86.0%）、特异性（72.7%）和敏感性（85.7%）均表现良好。Siglec-1阳性细胞百分比的测量方法在低水平的IFN炎症中表现最佳，而平均荧光强度的测量方法在较高水平的IFN炎症中表现最佳。对 IFN 刺激的单核细胞进行的体内外研究证实了这种行为。Siglec-1 的表达与血沉或 CRP 之间没有联系，即使血沉和 CRP 正常，也能发现 Siglec-1 的阳性结果。在急性感染的受试者中也发现了 Siglec-1 的高表达：结论：通过流式细胞术测量 Siglec-1 是检测 IFN 相关炎症的简便工具，即使受试者的普通炎症指标结果正常。

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引用次数: 0

Serum AZD7442 (tixagevimab–cilgavimab) concentrations and in vitro IC50 values predict SARS-CoV-2 neutralising antibody titres 血清 AZD7442（tixagevimab-cilgavimab）浓度和体外 IC50 值可预测 SARS-CoV-2 中和抗体滴度。

IF 5.8 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2024-06-13 DOI: 10.1002/cti2.1517

Lindsay E Clegg, Oleg Stepanov, Sam Matthews, Tom White, Seth Seegobin, Steven Thomas, Kevin M Tuffy, Mats Någård, Mark T Esser, Katie Streicher, Taylor S Cohen, Anastasia A Aksyuk

Objectives

The evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) necessitates rapid methods for assessing monoclonal antibody (mAb) potency against emerging variants. Authentic virus neutralisation assays are considered the gold standard for measuring virus-neutralising antibody (nAb) titres in serum. However, authentic virus-based assays pose inherent practical challenges for measuring nAb titres against emerging SARS-CoV-2 variants (e.g. storing infectious viruses and testing at biosafety level-3 facilities). Here, we demonstrate the utility of pseudovirus neutralisation assay data in conjunction with serum mAb concentrations to robustly predict nAb titres in serum.

Methods

SARS-CoV-2 nAb titres were determined via authentic- and lentiviral pseudovirus-based neutralisation assays using serological data from three AZD7442 (tixagevimab–cilgavimab) studies: PROVENT (NCT04625725), TACKLE (NCT04723394) and a phase 1 dose-ranging study (NCT04507256). AZD7442 serum concentrations were assessed using immunocapture. Serum-based half-maximal inhibitory concentration (IC₅₀) values were derived from pseudovirus nAb titres and serum mAb concentrations, and compared with in vitro IC₅₀ measurements.

Results

nAb titres measured via authentic- and lentiviral pseudovirus-based neutralisation assays were strongly correlated for the ancestral SARS-CoV-2 virus and SARS-CoV-2 Alpha. Serum AZD7442 concentrations and pseudovirus nAb titres were strongly correlated for multiple SARS-CoV-2 variants with all Spearman correlation coefficients ≥ 0.78. Serum-based IC₅₀ values were similar to in vitro IC₅₀ values for AZD7442, for ancestral SARS-CoV-2 and Alpha, Delta, Omicron BA.2 and Omicron BA.4/5 variants.

Conclusions

These data highlight that serum mAb concentrations and pseudovirus in vitro IC₅₀ values can be used to rapidly predict nAb titres in serum for emerging and historical SARS-CoV-2 variants.

目的：随着严重急性呼吸系统综合征冠状病毒 2（SARS-CoV-2）的发展，有必要采用快速方法来评估单克隆抗体（mAb）对新变种的效价。真实病毒中和试验被认为是测量血清中病毒中和抗体（nAb）滴度的黄金标准。然而，基于真实病毒的检测方法在测量针对新出现的 SARS-CoV-2 变体的 nAb 滴度时面临固有的实际挑战（例如，储存传染性病毒和在生物安全三级设施中进行检测）。在此，我们展示了假病毒中和检测数据与血清 mAb 浓度相结合的效用，以有力地预测血清中的 nAb 滴度：方法：利用三项 AZD7442（tixagevimab-cilgavimab）研究的血清学数据，通过基于真病毒和慢病毒的假病毒中和检测确定 SARS-CoV-2 nAb 滴度：PROVENT（NCT04625725）、TACKLE（NCT04723394）和一期剂量范围研究（NCT04507256）的血清数据。AZD7442的血清浓度采用免疫捕获法进行评估。结果：通过基于真病毒和慢病毒的伪病毒中和试验测得的 nAb 滴度与 SARS-CoV-2 病毒祖先和 SARS-CoV-2 Alpha 的 nAb 滴度密切相关。对于多种 SARS-CoV-2 变体，血清 AZD7442 浓度和伪病毒 nAb 滴度密切相关，所有 Spearman 相关系数均≥ 0.78。血清 IC50 值与 AZD7442 的体外 IC50 值相似，适用于 SARS-CoV-2 祖先和 Alpha、Delta、Omicron BA.2 和 Omicron BA.4/5 变种：这些数据突出表明，血清 mAb 浓度和伪病毒体外 IC50 值可用于快速预测血清中新出现和历史 SARS-CoV-2 变体的 nAb 滴度。

{"title":"Serum AZD7442 (tixagevimab–cilgavimab) concentrations and in vitro IC50 values predict SARS-CoV-2 neutralising antibody titres","authors":"Lindsay E Clegg, Oleg Stepanov, Sam Matthews, Tom White, Seth Seegobin, Steven Thomas, Kevin M Tuffy, Mats Någård, Mark T Esser, Katie Streicher, Taylor S Cohen, Anastasia A Aksyuk","doi":"10.1002/cti2.1517","DOIUrl":"10.1002/cti2.1517","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>The evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) necessitates rapid methods for assessing monoclonal antibody (mAb) potency against emerging variants. Authentic virus neutralisation assays are considered the gold standard for measuring virus-neutralising antibody (nAb) titres in serum. However, authentic virus-based assays pose inherent practical challenges for measuring nAb titres against emerging SARS-CoV-2 variants (e.g. storing infectious viruses and testing at biosafety level-3 facilities). Here, we demonstrate the utility of pseudovirus neutralisation assay data in conjunction with serum mAb concentrations to robustly predict nAb titres in serum.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>SARS-CoV-2 nAb titres were determined via authentic- and lentiviral pseudovirus-based neutralisation assays using serological data from three AZD7442 (tixagevimab–cilgavimab) studies: PROVENT (NCT04625725), TACKLE (NCT04723394) and a phase 1 dose-ranging study (NCT04507256). AZD7442 serum concentrations were assessed using immunocapture. Serum-based half-maximal inhibitory concentration (IC<sub>50</sub>) values were derived from pseudovirus nAb titres and serum mAb concentrations, and compared with <i>in vitro</i> IC<sub>50</sub> measurements.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>nAb titres measured via authentic- and lentiviral pseudovirus-based neutralisation assays were strongly correlated for the ancestral SARS-CoV-2 virus and SARS-CoV-2 Alpha. Serum AZD7442 concentrations and pseudovirus nAb titres were strongly correlated for multiple SARS-CoV-2 variants with all Spearman correlation coefficients ≥ 0.78. Serum-based IC<sub>50</sub> values were similar to <i>in vitro</i> IC<sub>50</sub> values for AZD7442, for ancestral SARS-CoV-2 and Alpha, Delta, Omicron BA.2 and Omicron BA.4/5 variants.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>These data highlight that serum mAb concentrations and pseudovirus <i>in vitro</i> IC<sub>50</sub> values can be used to rapidly predict nAb titres in serum for emerging and historical SARS-CoV-2 variants.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 6","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11175839/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141316242","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

Dupilumab improves outcomes in patients with chronic rhinosinusitis with nasal polyps irrespective of gender: results from the SINUS-52 trial 杜比鲁单抗改善了伴有鼻息肉的慢性鼻炎患者的治疗效果（不分男女）：SINUS-52 试验的结果

IF 5.8 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2024-06-08 DOI: 10.1002/cti2.1511

Wytske J Fokkens, Claus Bachert, Claire Hopkins, Osama Marglani, Amy Praestgaard, Scott Nash, Yamo Deniz, Paul J Rowe, Harry Sacks, Juby A Jacob-Nara

Objectives

This post hoc analysis assessed disease characteristics and response to dupilumab treatment in male and female patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP) (SINUS-52 study; NCT02898454).

Methods

Patients received dupilumab 300 mg or placebo every 2 weeks for 52 weeks on background intranasal corticosteroids. Efficacy was assessed through Week 52 using nasal polyp score (NPS), nasal congestion/obstruction score, loss of smell score and University of Pennsylvania Smell Identification Test score. Disease-specific health-related quality of life (HRQoL) was assessed using the 22-item Sino-Nasal Outcome Test (SNOT-22).

Results

The analysis included 192 male and 111 female patients. Female patients had higher mean SNOT-22 total score (56.6 vs. 49.1, P < 0.01) and more coexisting asthma (78.4% vs. 46.4%, P < 0.0001) and non-steroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD) (38.7% vs. 18.8%, P = 0.0001) than male patients, but other baseline characteristics were similar. Dupilumab significantly improved CRSwNP outcomes vs. placebo at Week 52, regardless of gender: least squares mean differences (95% confidence interval) for NPS were −2.33 (−2.80, −1.86) in male and −2.54 (−3.18, −1.90) in female patients (both P < 0.0001 vs. placebo), and for SNOT-22 were −19.2 (−24.1, −14.2) in male and −24.4 (−31.5, −17.3) in female patients (both P < 0.0001 vs. placebo). There were no significant efficacy-by-gender interactions.

Conclusion

Female patients had greater asthma, NSAID-ERD and HRQoL burden at baseline than male patients. Dupilumab treatment significantly improved objective and subjective outcomes compared with placebo, irrespective of gender.

目的这项事后分析评估了男性和女性重症慢性鼻炎伴鼻息肉（CRSwNP）患者的疾病特征和对杜比单抗治疗的反应（SINUS-52 研究；NCT02898454）。方法患者在接受鼻内皮质类固醇治疗的基础上，每两周接受一次 300 毫克的杜比鲁单抗或安慰剂治疗，共 52 周。通过鼻息肉评分（NPS）、鼻塞/阻塞评分、嗅觉减退评分和宾夕法尼亚大学气味识别测试评分来评估第52周的疗效。疾病特异性健康相关生活质量（HRQoL）采用 22 项中鼻结果测验（SNOT-22）进行评估。结果分析对象包括 192 名男性患者和 111 名女性患者。与男性患者相比，女性患者的平均 SNOT-22 总分更高（56.6 vs. 49.1，P < 0.01），合并哮喘（78.4% vs. 46.4%，P < 0.0001）和非甾体抗炎药加重呼吸系统疾病（NSAID-ERD）（38.7% vs. 18.8%，P = 0.0001）的患者更多，但其他基线特征相似。与安慰剂相比，Dupilumab 在第 52 周明显改善了 CRSwNP 结果，无论性别如何：男性 NPS 的最小二乘法均值差异（95% 置信区间）为 -2.33 (-2.80, -1.86) ，女性为 -2.54 (-3. 18, -1.90) 。18，-1.90）（与安慰剂相比，P 均为 0.0001）；SNOT-22 男性患者为-19.2（-24.1，-14.2），女性患者为-24.4（-31.5，-17.3）（与安慰剂相比，P 均为 0.0001）。不同性别之间没有明显的疗效交互作用。结论与男性患者相比，女性患者的哮喘、非甾体抗炎药物引起的ERD和HRQoL负担在基线时更重。与安慰剂相比，无论性别如何，杜匹单抗治疗都能明显改善客观和主观疗效。

{"title":"Dupilumab improves outcomes in patients with chronic rhinosinusitis with nasal polyps irrespective of gender: results from the SINUS-52 trial","authors":"Wytske J Fokkens, Claus Bachert, Claire Hopkins, Osama Marglani, Amy Praestgaard, Scott Nash, Yamo Deniz, Paul J Rowe, Harry Sacks, Juby A Jacob-Nara","doi":"10.1002/cti2.1511","DOIUrl":"https://doi.org/10.1002/cti2.1511","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>This <i>post hoc</i> analysis assessed disease characteristics and response to dupilumab treatment in male and female patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP) (SINUS-52 study; NCT02898454).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Patients received dupilumab 300 mg or placebo every 2 weeks for 52 weeks on background intranasal corticosteroids. Efficacy was assessed through Week 52 using nasal polyp score (NPS), nasal congestion/obstruction score, loss of smell score and University of Pennsylvania Smell Identification Test score. Disease-specific health-related quality of life (HRQoL) was assessed using the 22-item Sino-Nasal Outcome Test (SNOT-22).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The analysis included 192 male and 111 female patients. Female patients had higher mean SNOT-22 total score (56.6 vs. 49.1, <i>P</i> < 0.01) and more coexisting asthma (78.4% vs. 46.4%, <i>P</i> < 0.0001) and non-steroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD) (38.7% vs. 18.8%, <i>P</i> = 0.0001) than male patients, but other baseline characteristics were similar. Dupilumab significantly improved CRSwNP outcomes vs. placebo at Week 52, regardless of gender: least squares mean differences (95% confidence interval) for NPS were −2.33 (−2.80, −1.86) in male and −2.54 (−3.18, −1.90) in female patients (both <i>P</i> < 0.0001 vs. placebo), and for SNOT-22 were −19.2 (−24.1, −14.2) in male and −24.4 (−31.5, −17.3) in female patients (both <i>P</i> < 0.0001 vs. placebo). There were no significant efficacy-by-gender interactions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Female patients had greater asthma, NSAID-ERD and HRQoL burden at baseline than male patients. Dupilumab treatment significantly improved objective and subjective outcomes compared with placebo, irrespective of gender.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 6","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1511","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141292571","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

Characterisation of circulating tumor-associated and immune cells in patients with advanced-stage non-small cell lung cancer 晚期非小细胞肺癌患者体内循环肿瘤相关细胞和免疫细胞的特征

IF 5.8 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2024-06-03 DOI: 10.1002/cti2.1516

Vahid Yaghoubi Naei, Ekaterina Ivanova, William Mullally, Connor G O'Leary, Rahul Ladwa, Ken O'Byrne, Majid E Warkiani, Arutha Kulasinghe

Objectives

Globally, non-small cell lung cancer (NSCLC) is the most prevalent form of lung cancer and the leading cause of cancer-related deaths. Tumor-associated circulating cells in NSCLC can have a wide variety of morphological and phenotypic characteristics, including epithelial, immunological or hybrid subtypes. The distinctive characteristics and potential clinical significance of these cells in patients with NSCLC are explored in this study.

Methods

We utilised a spiral microfluidic device to enrich large cells and cell aggregates from the peripheral blood samples of NSCLC patients. These cells were characterised through high-resolution immunofluorescent imaging and statistical analysis, correlating findings with clinical information from our patient cohort.

Results

We have identified varied populations of heterotypic circulating tumor cell clusters with differing immune cell composition that included a distinct class of atypical tumor-associated macrophages that exhibits unique morphology and cell size. This subtype's prevalence is positively correlated with the tumor stage, progression and metastasis.

Conclusions

Our study reveals a heterogeneous landscape of circulating tumor cells and their clusters, underscoring the complexity of NSCLC pathobiology. The identification of a unique subtype of atypical tumor-associatedmacrophages that simultaneously express both tumor and immune markers and whose presence correlates with late disease stages, poor clinical outcomes and metastatic risk infers the potential of these cells as biomarkers for NSCLC staging and prognosis. Future studies should focus on the role of these cells in the tumor microenvironment and their potential as therapeutic targets. Additionally, longitudinal studies tracking these cell types through disease progression could provide further insights into their roles in NSCLC evolution and response to treatment.

目标在全球范围内，非小细胞肺癌（NSCLC）是最常见的肺癌形式，也是导致癌症相关死亡的主要原因。NSCLC 中的肿瘤相关循环细胞具有多种形态和表型特征，包括上皮亚型、免疫亚型或混合亚型。本研究探讨了这些细胞在 NSCLC 患者中的独特特征和潜在临床意义。方法我们利用螺旋微流控装置从 NSCLC 患者的外周血样本中富集大细胞和细胞聚集体。通过高分辨率免疫荧光成像和统计分析对这些细胞进行特征描述，并将研究结果与患者队列中的临床信息进行关联。结果我们发现了具有不同免疫细胞组成的异型循环肿瘤细胞集群，其中包括一类不同的非典型肿瘤相关巨噬细胞，它们具有独特的形态和细胞大小。这种亚型的发生率与肿瘤的分期、进展和转移呈正相关。结论我们的研究揭示了循环肿瘤细胞及其集群的异质性，凸显了 NSCLC 病理生物学的复杂性。非典型肿瘤相关巨噬细胞是一种独特的亚型，同时表达肿瘤和免疫标记物，它们的存在与疾病晚期、临床疗效差和转移风险相关，因此这些细胞有可能成为 NSCLC 分期和预后的生物标记物。未来的研究应重点关注这些细胞在肿瘤微环境中的作用及其作为治疗靶点的潜力。此外，通过对这些细胞类型在疾病进展过程中的跟踪研究，可以进一步了解它们在 NSCLC 演变和治疗反应中的作用。

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引用次数: 0