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.
{"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}
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.
{"title":"Characterisation of circulating tumor-associated and immune cells in patients with advanced-stage non-small cell lung cancer","authors":"Vahid Yaghoubi Naei, Ekaterina Ivanova, William Mullally, Connor G O'Leary, Rahul Ladwa, Ken O'Byrne, Majid E Warkiani, Arutha Kulasinghe","doi":"10.1002/cti2.1516","DOIUrl":"https://doi.org/10.1002/cti2.1516","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 6","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1516","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141245980","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}
Primary pulmonary lymphoepithelioma-like carcinoma (PLELC) is a subtype of lung carcinoma associated with the Epstein–Barr virus (EBV). The clinical predictive biomarkers of immune checkpoint blockade (ICB) in PLELC require further investigation.
Methods
We prospectively analysed EBV levels in the blood and immune tumor biomarkers of 31 patients with ICB-treated PLELC. Viral EBNA-1 and BamHI-W DNA fragments in the plasma were quantified in parallel using quantitative polymerase chain reaction.
Results
Progression-free survival (PFS) was significantly longer in EBNA-1 high or BamHI-W high groups. A longer PFS was also observed in patients with both high plasma EBNA-1 or BamHI-W and PD-L1 ≥ 1%. Intriguingly, the tumor mutational burden was inversely correlated with EBNA-1 and BamHI-W. Plasma EBV load was negatively associated with intratumoral CD8+ immune cell infiltration. Dynamic changes in plasma EBV DNA level were in accordance with the changes in tumor volume. An increase in EBV DNA levels during treatment indicated molecular progression that preceded the imaging progression by several months.
Conclusions
Plasma EBV DNA could be a useful and easy-to-use biomarker for predicting the clinical activity of ICB in PLELC and could serve to monitor disease progression earlier than computed tomography imaging.
{"title":"Plasma EBV quantification is associated with the efficacy of immune checkpoint blockade and disease monitoring in patients with primary pulmonary lymphoepithelioma-like carcinoma","authors":"Yu-Min Zhong, Ji Chen, Jie Jiang, Wen-Bin Zhou, Ling-Ling Gao, Shui-Lian Zhang, Wen-Qing Yan, Yu Chen, Dong-Kun Zhang, Dan-Xia Lu, Zhi-Yi Lv, Zhi Xie, Ying Huang, Wei-Bang Guo, Bin-Chao Wang, Jin-Ji Yang, Xue-Ning Yang, Yi-Long Wu, Xu-Chao Zhang","doi":"10.1002/cti2.1515","DOIUrl":"https://doi.org/10.1002/cti2.1515","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Primary pulmonary lymphoepithelioma-like carcinoma (PLELC) is a subtype of lung carcinoma associated with the Epstein–Barr virus (EBV). The clinical predictive biomarkers of immune checkpoint blockade (ICB) in PLELC require further investigation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We prospectively analysed EBV levels in the blood and immune tumor biomarkers of 31 patients with ICB-treated PLELC. Viral <i>EBNA-1</i> and <i>BamHI-W</i> DNA fragments in the plasma were quantified in parallel using quantitative polymerase chain reaction.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Progression-free survival (PFS) was significantly longer in <i>EBNA-1</i> high or <i>BamHI-W</i> high groups. A longer PFS was also observed in patients with both high plasma <i>EBNA-1</i> or <i>BamHI-W</i> and PD-L1 ≥ 1%. Intriguingly, the tumor mutational burden was inversely correlated with <i>EBNA-1</i> and <i>BamHI-W</i>. Plasma EBV load was negatively associated with intratumoral CD8<sup>+</sup> immune cell infiltration. Dynamic changes in plasma EBV DNA level were in accordance with the changes in tumor volume. An increase in EBV DNA levels during treatment indicated molecular progression that preceded the imaging progression by several months.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Plasma EBV DNA could be a useful and easy-to-use biomarker for predicting the clinical activity of ICB in PLELC and could serve to monitor disease progression earlier than computed tomography imaging.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 6","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1515","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141245979","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}
Veronika Bandara, Victoria M Niktaras, Vasiliki J Willett, Hayley Chapman, Noor A Lokman, Anne M Macpherson, Silvana Napoli, Batjargal Gundsambuu, Jade Foeng, Timothy J Sadlon, Justin Coombs, Shaun R McColl, Simon C Barry, Martin K Oehler, Carmela Ricciardelli
Objectives
Recent studies have identified expression of the non-functional P2X7 (nfP2X7) receptor on various malignant cells including ovarian cancer, but not on normal cells, which makes it a promising tumour-associated antigen candidate for chimeric antigen receptor (CAR)-T-cell immunotherapies. In this study, we assessed the cytotoxic effects of nfP2X7-CAR-T cells on ovarian cancer using in vitro and in vivo models.
Methods
We evaluated the effects of nfP2X7-CAR-T cells on ovarian cancer cell lines (SKOV-3, OVCAR3, OVCAR5), normal peritoneal cells (LP-9) and primary serous ovarian cancer cells derived from patient ascites in vitro using monolayer and 3D spheroid assays. We also evaluated the effects of nfP2X7-CAR-T cells on patient-derived tissue explants, which recapitulate an intact tumour microenvironment. In addition, we investigated the effect of nfP2X7-CAR-T cells in vivo using the OVCAR-3 xenograft model in NOD-scid IL2Rγnull (NSG) mice.
Results
Our study found that nfP2X7-CAR-T cells were cytotoxic and significantly inhibited survival of OVCAR3, OVCAR5 and primary serous ovarian cancer cells compared with un-transduced CD3+ T cells in vitro. However, no significant effects of nfP2X7-CAR-T cells were observed for SKOV3 or normal peritoneal cells (LP-9) cells with low P2X7 receptor expression. Treatment with nfP2X7-CAR-T cells increased apoptosis compared with un-transduced T cells in patient-derived explants and correlated with CD3 positivity. Treatment with nfP2X7-CAR-T cells significantly reduced OVCAR3 tumour burden in mice compared with un-transduced CD3 cells for 7–8 weeks.
Conclusion
This study demonstrates that nfP2X7-CAR-T cells have great potential to be developed as a novel immunotherapy for ovarian cancer.
{"title":"Engineered CAR-T cells targeting the non-functional P2X purinoceptor 7 (P2X7) receptor as a novel treatment for ovarian cancer","authors":"Veronika Bandara, Victoria M Niktaras, Vasiliki J Willett, Hayley Chapman, Noor A Lokman, Anne M Macpherson, Silvana Napoli, Batjargal Gundsambuu, Jade Foeng, Timothy J Sadlon, Justin Coombs, Shaun R McColl, Simon C Barry, Martin K Oehler, Carmela Ricciardelli","doi":"10.1002/cti2.1512","DOIUrl":"https://doi.org/10.1002/cti2.1512","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Recent studies have identified expression of the non-functional P2X7 (nfP2X7) receptor on various malignant cells including ovarian cancer, but not on normal cells, which makes it a promising tumour-associated antigen candidate for chimeric antigen receptor (CAR)-T-cell immunotherapies. In this study, we assessed the cytotoxic effects of nfP2X7-CAR-T cells on ovarian cancer using <i>in vitro</i> and <i>in vivo</i> models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We evaluated the effects of nfP2X7-CAR-T cells on ovarian cancer cell lines (SKOV-3, OVCAR3, OVCAR5), normal peritoneal cells (LP-9) and primary serous ovarian cancer cells derived from patient ascites <i>in vitro</i> using monolayer and 3D spheroid assays. We also evaluated the effects of nfP2X7-CAR-T cells on patient-derived tissue explants, which recapitulate an intact tumour microenvironment. In addition, we investigated the effect of nfP2X7-CAR-T cells <i>in vivo</i> using the OVCAR-3 xenograft model in NOD-scid IL2Rγnull (NSG) mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Our study found that nfP2X7-CAR-T cells were cytotoxic and significantly inhibited survival of OVCAR3, OVCAR5 and primary serous ovarian cancer cells compared with un-transduced CD3<sup>+</sup> T cells <i>in vitro</i>. However, no significant effects of nfP2X7-CAR-T cells were observed for SKOV3 or normal peritoneal cells (LP-9) cells with low P2X7 receptor expression. Treatment with nfP2X7-CAR-T cells increased apoptosis compared with un-transduced T cells in patient-derived explants and correlated with CD3 positivity. Treatment with nfP2X7-CAR-T cells significantly reduced OVCAR3 tumour burden in mice compared with un-transduced CD3 cells for 7–8 weeks.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This study demonstrates that nfP2X7-CAR-T cells have great potential to be developed as a novel immunotherapy for ovarian cancer.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 5","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1512","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141091440","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}
Ge Jin, Runze Wang, Yi Jin, Yingqiu Song, Tianlu Wang
Coronavirus disease 2019, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected 700 million people worldwide since its outbreak in 2019. The current pandemic strains, including Omicron and its large subvariant series, exhibit strong transmission and stealth. After entering the human body, the virus first infects nasal epithelial cells and invades host cells through the angiotensin-converting enzyme 2 receptor and transmembrane serine protease 2 on the host cell surface. The nasal cavity is an important body part that protects against the virus. Immunisation of the nasal mucosa produces immunoglobulin A antibodies that effectively neutralise viruses. Saline nasal irrigation, a type of physical therapy, can reduce the viral load in the nasal cavity and prevent viral infections to some extent. As a commonly used means to fight SARS-CoV-2, the intramuscular (IM) vaccine can induce the human body to produce a systemic immune response and immunoglobulin G antibody; however, the antibody is difficult to distribute to the nasal mucosa in time and cannot achieve a good preventive effect. Intranasal (IN) vaccines compensate for the shortcomings of IM vaccines, induce mucosal immune responses, and have a better effect in preventing infection. In this review, we discuss the nasal defence barrier, the harm caused by SARS-CoV-2, the mechanism of its invasion into host cells, nasal cleaning, IM vaccines and IN vaccines, and suggest increasing the development of IN vaccines, and use of IN vaccines as a supplement to IM vaccines.
由严重急性呼吸系统综合征冠状病毒 2（SARS-CoV-2）引起的冠状病毒病 2019 年自爆发以来已影响全球 7 亿人。目前流行的毒株，包括Omicron及其大型亚变种系列，表现出很强的传播性和隐蔽性。病毒进入人体后，首先感染鼻腔上皮细胞，通过宿主细胞表面的血管紧张素转换酶2受体和跨膜丝氨酸蛋白酶2侵入宿主细胞。鼻腔是人体抵御病毒的重要部位。鼻黏膜免疫可产生免疫球蛋白 A 抗体，有效中和病毒。生理盐水鼻腔冲洗是一种物理疗法，可以减少鼻腔内的病毒载量，在一定程度上预防病毒感染。作为抗击 SARS-CoV-2 的常用手段，肌肉注射（IM）疫苗可诱导人体产生全身免疫反应和免疫球蛋白 G 抗体，但抗体难以及时分布到鼻黏膜，达不到良好的预防效果。鼻内（IN）疫苗弥补了IM疫苗的不足，可诱导粘膜免疫反应，预防感染效果更好。在这篇综述中，我们讨论了鼻腔防御屏障、SARS-CoV-2 的危害、其侵入宿主细胞的机制、鼻腔清洁、IM 疫苗和 IN 疫苗，并建议加大 IN 疫苗的开发力度，将 IN 疫苗作为 IM 疫苗的补充。
{"title":"From intramuscular to nasal: unleashing the potential of nasal spray vaccines against coronavirus disease 2019","authors":"Ge Jin, Runze Wang, Yi Jin, Yingqiu Song, Tianlu Wang","doi":"10.1002/cti2.1514","DOIUrl":"https://doi.org/10.1002/cti2.1514","url":null,"abstract":"<p>Coronavirus disease 2019, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected 700 million people worldwide since its outbreak in 2019. The current pandemic strains, including Omicron and its large subvariant series, exhibit strong transmission and stealth. After entering the human body, the virus first infects nasal epithelial cells and invades host cells through the angiotensin-converting enzyme 2 receptor and transmembrane serine protease 2 on the host cell surface. The nasal cavity is an important body part that protects against the virus. Immunisation of the nasal mucosa produces immunoglobulin A antibodies that effectively neutralise viruses. Saline nasal irrigation, a type of physical therapy, can reduce the viral load in the nasal cavity and prevent viral infections to some extent. As a commonly used means to fight SARS-CoV-2, the intramuscular (IM) vaccine can induce the human body to produce a systemic immune response and immunoglobulin G antibody; however, the antibody is difficult to distribute to the nasal mucosa in time and cannot achieve a good preventive effect. Intranasal (IN) vaccines compensate for the shortcomings of IM vaccines, induce mucosal immune responses, and have a better effect in preventing infection. In this review, we discuss the nasal defence barrier, the harm caused by SARS-CoV-2, the mechanism of its invasion into host cells, nasal cleaning, IM vaccines and IN vaccines, and suggest increasing the development of IN vaccines, and use of IN vaccines as a supplement to IM vaccines.</p>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 5","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1514","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141069092","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}
Samuel Liwei Leong, Lawton Murdolo, Janesha C Maddumage, Marios Koutsakos, Katherine Kedzierska, Anthony W Purcell, Stephanie Gras, Emma J Grant
Objectives
Seasonal influenza viruses cause roughly 650 000 deaths annually despite available vaccines. CD8+ T cells typically recognise influenza-derived peptides from internal structural and non-structural influenza proteins and are an attractive avenue for future vaccine design as they could reduce the severity of disease following infection with diverse influenza strains. CD8+ T cells recognise peptides presented by the highly polymorphic Human Leukocyte Antigens class I molecules (HLA-I). Each HLA-I variant has distinct peptide binding preferences, representing a significant obstacle for designing vaccines that elicit CD8+ T cell responses across broad populations. Consequently, the rational design of a CD8+ T cell-mediated vaccine would require the identification of highly immunogenic peptides restricted to a range of different HLA molecules.
Methods
Here, we assessed the immunogenicity of six recently published novel influenza-derived peptides identified by mass-spectrometry and predicted to bind to the prevalent HLA-B*18:01 molecule.
Results
Using CD8+ T cell activation assays and protein biochemistry, we showed that 3/6 of the novel peptides were immunogenic in several HLA-B*18:01+ individuals and confirmed their HLA-B*18:01 restriction. We subsequently compared CD8+ T cell responses towards the previously identified highly immunogenic HLA-B*18:01-restricted NP219 peptide. Using X-ray crystallography, we solved the first crystal structures of HLA-B*18:01 presenting immunogenic influenza-derived peptides. Finally, we dissected the first TCR repertoires specific for HLA-B*18:01 restricted pathogen-derived peptides, identifying private and restricted repertoires against each of the four peptides.
Conclusion
Overall the characterisation of these novel immunogenic peptides provides additional HLA-B*18:01-restricted vaccine targets derived from the Matrix protein 1 and potentially the non-structural protein and the RNA polymerase catalytic subunit of influenza viruses.
尽管有疫苗可用，但季节性流感病毒每年仍会导致大约 65 万人死亡。CD8+ T 细胞通常能识别来自内部结构和非结构性流感蛋白的流感衍生肽，是未来疫苗设计的一个有吸引力的途径，因为它们能降低感染不同流感病毒株后的疾病严重程度。CD8+ T 细胞能识别由高度多态的人类白细胞抗原 I 类分子（HLA-I）呈现的肽。每种 HLA-I 变体都有不同的肽结合偏好，这对设计能在广泛人群中引起 CD8+ T 细胞反应的疫苗构成了重大障碍。因此，要合理设计 CD8+ T 细胞介导的疫苗，就必须鉴定出限制于一系列不同 HLA 分子的高免疫原性肽。 方法 在此，我们评估了最近发表的六种新型流感衍生肽的免疫原性，这些肽是通过质谱分析鉴定的，并预测能与流行的 HLA-B*18:01 分子结合。 结果 我们使用 CD8+ T 细胞活化试验和蛋白质生物化学方法表明，3/6 种新型多肽在几个 HLA-B*18:01+ 的个体中具有免疫原性，并证实了它们的 HLA-B*18:01 限制。随后，我们比较了 CD8+ T 细胞对之前发现的高免疫原性 HLA-B*18:01 限制性 NP219 肽的反应。通过 X 射线晶体学，我们首次解析了 HLA-B*18:01 呈现免疫原性流感衍生肽的晶体结构。最后，我们剖析了首个针对 HLA-B*18:01 限制性病原体衍生肽的特异性 TCR 反应谱，确定了针对四种肽中每一种肽的私有和限制性反应谱。 结论 总的来说，这些新型免疫原性多肽的特征描述提供了更多的 HLA-B*18:01 限制性疫苗靶标，这些靶标来自基质蛋白 1，也可能来自流感病毒的非结构蛋白和 RNA 聚合酶催化亚基。
{"title":"Characterisation of novel influenza-derived HLA-B*18:01-restricted epitopes","authors":"Samuel Liwei Leong, Lawton Murdolo, Janesha C Maddumage, Marios Koutsakos, Katherine Kedzierska, Anthony W Purcell, Stephanie Gras, Emma J Grant","doi":"10.1002/cti2.1509","DOIUrl":"https://doi.org/10.1002/cti2.1509","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Seasonal influenza viruses cause roughly 650 000 deaths annually despite available vaccines. CD8<sup>+</sup> T cells typically recognise influenza-derived peptides from internal structural and non-structural influenza proteins and are an attractive avenue for future vaccine design as they could reduce the severity of disease following infection with diverse influenza strains. CD8<sup>+</sup> T cells recognise peptides presented by the highly polymorphic Human Leukocyte Antigens class I molecules (HLA-I). Each HLA-I variant has distinct peptide binding preferences, representing a significant obstacle for designing vaccines that elicit CD8<sup>+</sup> T cell responses across broad populations. Consequently, the rational design of a CD8<sup>+</sup> T cell-mediated vaccine would require the identification of highly immunogenic peptides restricted to a range of different HLA molecules.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Here, we assessed the immunogenicity of six recently published novel influenza-derived peptides identified by mass-spectrometry and predicted to bind to the prevalent HLA-B*18:01 molecule.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Using CD8<sup>+</sup> T cell activation assays and protein biochemistry, we showed that 3/6 of the novel peptides were immunogenic in several HLA-B*18:01<sup>+</sup> individuals and confirmed their HLA-B*18:01 restriction. We subsequently compared CD8<sup>+</sup> T cell responses towards the previously identified highly immunogenic HLA-B*18:01-restricted NP<sub>219</sub> peptide. Using X-ray crystallography, we solved the first crystal structures of HLA-B*18:01 presenting immunogenic influenza-derived peptides. Finally, we dissected the first TCR repertoires specific for HLA-B*18:01 restricted pathogen-derived peptides, identifying private and restricted repertoires against each of the four peptides.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Overall the characterisation of these novel immunogenic peptides provides additional HLA-B*18:01-restricted vaccine targets derived from the Matrix protein 1 and potentially the non-structural protein and the RNA polymerase catalytic subunit of influenza viruses.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 5","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1509","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140907042","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}
Dhanapal Govindaraj, Georg Bach Jensen, Khaleda Rahman Qazi, Eva Sverremark-Ekström, Thomas Abrahamsson, Maria C Jenmalm
Objectives
Extremely preterm (EPT; gestational week < 28 + 0, < 1000 g) neonates are vulnerable to infections and necrotising enterocolitis, important contributors to mortality and morbidity. However, knowledge regarding their immune maturation remains limited. We here investigated the longitudinal development of functional T-cell capacity in EPT infants.
Methods
Peripheral blood mononuclear cells were isolated at 14th and 28th day (D) and at gestational week 36 + 0 (Gw36) from EPT infants, participated in a randomised, double-blind, placebo-controlled study of Lactobacillus reuteri DSM 17938 probiotic supplementation. Blood collected from 25 full-term (FT) infants at D14 was used as control. The secretion of immune mediators was determined through comprehensive Luminex panels after stimulation with human T-cell activator CD3/CD28 beads.
Results
The levels of many mediators were low in EPT infants at D14, whereas the secretion of several chemokines was higher in EPT than in FT infants. Furthermore, Th2:Th1 cytokine ratios were higher in EPT than in FT infants. Progressively elevated secretion of, for example, IFN-γ, TNF and IL-17A in EPT infants was observed from D14 to D28 and then at Gw36. Elevated levels were observed for many proinflammatory mediators at D28. Probiotic supplementation or perinatal factors (e.g. clinical chorioamnionitis, preeclampsia and delivery mode) did not influence the cytokine and chemokine responses.
Conclusions
Immune mediators induced by T-cell activation in EPT infants were mainly reduced at D14 and Th2 skewed compared to those in FT infants, but mostly recovered at Gw36, indicating immune maturation. Increased proinflammatory responses at D28 may be related to the heightened risk of severe immune-associated complications seen in EPT infants.
{"title":"Effects of extremely preterm birth on cytokine and chemokine responses induced by T-cell activation during infancy","authors":"Dhanapal Govindaraj, Georg Bach Jensen, Khaleda Rahman Qazi, Eva Sverremark-Ekström, Thomas Abrahamsson, Maria C Jenmalm","doi":"10.1002/cti2.1510","DOIUrl":"https://doi.org/10.1002/cti2.1510","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Extremely preterm (EPT; gestational week < 28 + 0, < 1000 g) neonates are vulnerable to infections and necrotising enterocolitis, important contributors to mortality and morbidity. However, knowledge regarding their immune maturation remains limited. We here investigated the longitudinal development of functional T-cell capacity in EPT infants.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Peripheral blood mononuclear cells were isolated at 14th and 28th day (D) and at gestational week 36 + 0 (Gw36) from EPT infants, participated in a randomised, double-blind, placebo-controlled study of <i>Lactobacillus reuteri</i> DSM 17938 probiotic supplementation. Blood collected from 25 full-term (FT) infants at D14 was used as control. The secretion of immune mediators was determined through comprehensive Luminex panels after stimulation with human T-cell activator CD3/CD28 beads.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The levels of many mediators were low in EPT infants at D14, whereas the secretion of several chemokines was higher in EPT than in FT infants. Furthermore, Th2:Th1 cytokine ratios were higher in EPT than in FT infants. Progressively elevated secretion of, for example, IFN-γ, TNF and IL-17A in EPT infants was observed from D14 to D28 and then at Gw36. Elevated levels were observed for many proinflammatory mediators at D28. Probiotic supplementation or perinatal factors (e.g. clinical chorioamnionitis, preeclampsia and delivery mode) did not influence the cytokine and chemokine responses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Immune mediators induced by T-cell activation in EPT infants were mainly reduced at D14 and Th2 skewed compared to those in FT infants, but mostly recovered at Gw36, indicating immune maturation. Increased proinflammatory responses at D28 may be related to the heightened risk of severe immune-associated complications seen in EPT infants.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 5","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1510","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140907041","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}
Xaquin Castro Dopico, Mariia Guryleva, Marco Mandolesi, Martin Corcoran, Jonathan M Coquet, Ben Murrell, Gunilla B Karlsson Hedestam
Objectives
The caecum bridges the small and large intestine and plays a front-line role in discriminating gastrointestinal antigens. Although dysregulated in acute and chronic conditions, the tissue is often overlooked immunologically.
Methods
To address this issue, we applied single-cell transcriptomic-V(D)J sequencing to FACS-isolated CD45+ caecal patch/lamina propria leukocytes from a healthy (5-year-old) female rhesus macaque ex vivo and coupled these data to VDJ deep sequencing reads from haematopoietic tissues.
Results
We found caecal NK cells and ILC3s to co-exist with a spectrum of effector T cells partially derived from SOX4+ recent thymic emigrants. Tolerogenic Vγ8Vδ1-T cells, plastic CD4+ T helper cells and GZMK+EOMES+ and TMIGD2+ tissue-resident memory CD8+ T cells were present and differed metabolically. An IL13+GATA3+ Th2 subset expressing eicosanoid pathway enzymes was accompanied by IL1RL1+GATA3+ regulatory T cells and a minor proportion of IgE+ plasma cells (PCs), illustrating tightly regulated type 2 immunity devoid of ILC2s. In terms of B lymphocyte lineages, caecal patch antigen-presenting memory B cells sat alongside germinal centre cells undergoing somatic hypermutation and differentiation into IGF1+ PCs. Prototypic gene expression signatures decreased across PC clusters, and notably, expanded IgA clonotypes could be traced in VDJ deep sequencing reads from additional compartments, including the bone marrow, supporting that these cells contribute a steady stream of systemic antibodies.
Conclusions
The data advance our understanding of caecal immunological function, revealing processes involved in barrier maintenance and molecular networks relevant to disease.
目的 盲肠是连接小肠和大肠的桥梁，在分辨胃肠道抗原方面发挥着前线作用。虽然该组织在急性和慢性疾病中失调，但在免疫学上却经常被忽视。 方法 为了解决这个问题，我们应用单细胞转录组-V(D)J 测序技术检测了从一只健康（5 岁）雌性恒河猴体内分离出的 CD45+ 盲肠斑块/固有膜白细胞，并将这些数据与来自造血组织的 VDJ 深度测序读数结合起来。 结果 我们发现盲肠 NK 细胞和 ILC3s 与效应 T 细胞谱系共存，部分效应 T 细胞来自 SOX4+ 近期胸腺移民。耐受性 Vγ8Vδ1-T 细胞、可塑性 CD4+ T 辅助细胞以及 GZMK+EOMES+ 和 TMIGD2+ 组织驻留记忆 CD8+ T 细胞都存在，并且在新陈代谢方面存在差异。表达二十碳烷途径酶的 IL13+GATA3+ Th2 亚群伴随着 IL1RL1+GATA3+ 调节性 T 细胞和小部分 IgE+ 浆细胞（PCs），这说明第二型免疫受到严格调控，不存在 ILC2s。在 B 淋巴细胞系方面，盲肠补片抗原递呈记忆 B 细胞与生殖中心细胞并存，后者正在经历体细胞超突变并分化为 IGF1+ PCs。各 PC 群的原型基因表达特征均有所下降，值得注意的是，从包括骨髓在内的其他分区的 VDJ 深度测序读数中可追踪到扩大的 IgA 克隆型，这支持了这些细胞可源源不断地产生全身抗体。 结论 这些数据增进了我们对盲肠免疫功能的了解，揭示了盲肠屏障维持过程以及与疾病相关的分子网络。
{"title":"Maintenance of caecal homeostasis by diverse adaptive immune cells in the rhesus macaque","authors":"Xaquin Castro Dopico, Mariia Guryleva, Marco Mandolesi, Martin Corcoran, Jonathan M Coquet, Ben Murrell, Gunilla B Karlsson Hedestam","doi":"10.1002/cti2.1508","DOIUrl":"https://doi.org/10.1002/cti2.1508","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>The caecum bridges the small and large intestine and plays a front-line role in discriminating gastrointestinal antigens. Although dysregulated in acute and chronic conditions, the tissue is often overlooked immunologically.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>To address this issue, we applied single-cell transcriptomic-V(D)J sequencing to FACS-isolated CD45<sup>+</sup> caecal patch/lamina propria leukocytes from a healthy (5-year-old) female rhesus macaque <i>ex vivo</i> and coupled these data to VDJ deep sequencing reads from haematopoietic tissues.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We found caecal NK cells and ILC3s to co-exist with a spectrum of effector T cells partially derived from <i>SOX4</i><sup>+</sup> recent thymic emigrants. Tolerogenic Vγ8Vδ1-T cells, plastic CD4<sup>+</sup> T helper cells and <i>GZMK</i><sup>+</sup><i>EOMES</i><sup>+</sup> and <i>TMIGD2</i><sup>+</sup> tissue-resident memory CD8<sup>+</sup> T cells were present and differed metabolically. An <i>IL13</i><sup>+</sup><i>GATA3</i><sup>+</sup> Th<sub>2</sub> subset expressing eicosanoid pathway enzymes was accompanied by <i>IL1RL1</i><sup>+</sup><i>GATA3</i><sup>+</sup> regulatory T cells and a minor proportion of IgE<sup>+</sup> plasma cells (PCs), illustrating tightly regulated type 2 immunity devoid of ILC2s. In terms of B lymphocyte lineages, caecal patch antigen-presenting memory B cells sat alongside germinal centre cells undergoing somatic hypermutation and differentiation into <i>IGF1</i><sup>+</sup> PCs. Prototypic gene expression signatures decreased across PC clusters, and notably, expanded IgA clonotypes could be traced in VDJ deep sequencing reads from additional compartments, including the bone marrow, supporting that these cells contribute a steady stream of systemic antibodies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The data advance our understanding of caecal immunological function, revealing processes involved in barrier maintenance and molecular networks relevant to disease.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 5","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1508","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140818974","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}
Aline Pfefferle, Julian Contet, Kahlia Wong, Charlotte Chen, Els Verhoeyen, Chloe K Slichter, Kimberly S Schluns, Joseph Cursons, Richard Berry, Iva Nikolic, Jai Rautela, Nicholas D Huntington
Objectives
Autologous chimeric antigen receptor (CAR) T-cell therapy of B-cell malignancies achieves long-term disease remission in a high fraction of patients and has triggered intense research into translating this successful approach into additional cancer types. However, the complex logistics involved in autologous CAR-T manufacturing, the compromised fitness of patient-derived T cells, the high rates of serious toxicities and the overall cost involved with product manufacturing and hospitalisation have driven innovation to overcome such hurdles. One alternative approach is the use of allogeneic natural killer (NK) cells as a source for CAR-NK cell therapy. However, this source has traditionally faced numerous manufacturing challenges.
Methods
To address this, we have developed an optimised expansion and transduction protocol for primary human NK cells primed for manufacturing scaling and clinical evaluation. We have performed an in-depth comparison of primary human NK cell sources as a starting material by characterising their phenotype, functionality, expansion potential and transduction efficiency at crucial timepoints of our CAR-NK manufacturing pipeline.
Results
We identified adult peripheral blood-derived NK cells to be the superior source for generating a CAR-NK cell product because of a higher maximum yield of CAR-expressing NK cells combined with potent natural, as well as CAR-mediated anti-tumor effector functions.
Conclusions
Our optimised manufacturing pipeline dramatically improves lentiviral transduction efficiency of primary human NK cells. We conclude that the exponential expansion pre- and post-transduction and high on-target cytotoxicity make peripheral blood-derived NK cells a feasible and attractive CAR-NK cell product for clinical utility.
目标 B 细胞恶性肿瘤的自体嵌合抗原受体（CAR）T 细胞疗法能使大量患者的疾病得到长期缓解，并引发了将这一成功疗法转化为其他癌症类型的深入研究。然而，自体 CAR-T 生产所涉及的复杂物流、患者来源 T 细胞的适配性、严重毒性反应的高发率以及产品生产和住院所涉及的总体成本，都推动了克服这些障碍的创新。一种替代方法是使用异体自然杀伤（NK）细胞作为 CAR-NK 细胞疗法的来源。然而，这种来源在传统上面临着许多制造难题。 方法 为了解决这个问题，我们为原代人类 NK 细胞开发了一套优化的扩增和转导方案，以便进行规模化生产和临床评估。我们对作为起始材料的原代人 NK 细胞来源进行了深入比较，在 CAR-NK 生产流水线的关键时间点对其表型、功能、扩增潜力和转导效率进行了鉴定。 结果 我们发现成人外周血来源的 NK 细胞是生产 CAR-NK 细胞产品的上佳来源，因为它们具有更高的 CAR 表达 NK 细胞最大产量，同时具有强大的天然和 CAR 介导的抗肿瘤效应功能。 结论 我们优化的生产流水线显著提高了原代人类 NK 细胞的慢病毒转导效率。我们的结论是，转导前后的指数扩增和高靶向细胞毒性使外周血来源的 NK 细胞成为一种可行且有吸引力的 CAR-NK 细胞产品，可用于临床。
{"title":"Optimisation of a primary human CAR-NK cell manufacturing pipeline","authors":"Aline Pfefferle, Julian Contet, Kahlia Wong, Charlotte Chen, Els Verhoeyen, Chloe K Slichter, Kimberly S Schluns, Joseph Cursons, Richard Berry, Iva Nikolic, Jai Rautela, Nicholas D Huntington","doi":"10.1002/cti2.1507","DOIUrl":"https://doi.org/10.1002/cti2.1507","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Autologous chimeric antigen receptor (CAR) T-cell therapy of B-cell malignancies achieves long-term disease remission in a high fraction of patients and has triggered intense research into translating this successful approach into additional cancer types. However, the complex logistics involved in autologous CAR-T manufacturing, the compromised fitness of patient-derived T cells, the high rates of serious toxicities and the overall cost involved with product manufacturing and hospitalisation have driven innovation to overcome such hurdles. One alternative approach is the use of allogeneic natural killer (NK) cells as a source for CAR-NK cell therapy. However, this source has traditionally faced numerous manufacturing challenges.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>To address this, we have developed an optimised expansion and transduction protocol for primary human NK cells primed for manufacturing scaling and clinical evaluation. We have performed an in-depth comparison of primary human NK cell sources as a starting material by characterising their phenotype, functionality, expansion potential and transduction efficiency at crucial timepoints of our CAR-NK manufacturing pipeline.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We identified adult peripheral blood-derived NK cells to be the superior source for generating a CAR-NK cell product because of a higher maximum yield of CAR-expressing NK cells combined with potent natural, as well as CAR-mediated anti-tumor effector functions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our optimised manufacturing pipeline dramatically improves lentiviral transduction efficiency of primary human NK cells. We conclude that the exponential expansion pre- and post-transduction and high on-target cytotoxicity make peripheral blood-derived NK cells a feasible and attractive CAR-NK cell product for clinical utility.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 5","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1507","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140818975","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}
Bo Wang, Ke Chen, Mingchao Gao, Xi Sun, Wang He, Junyu Chen, Wenjuan Yang, Tenghao Yang, Haide Qin, Honglian Ruan, Hao Huang, Tianxin Lin, Jian Huang
Objectives
Lymphatic metastasis, an early stage of the metastasis process, is associated with adverse clinical outcomes in urothelial carcinoma of the bladder (UCB). However, the role of inflammation in triggering lymphatic metastasis remains unclear.
Methods
We employed an RNA-sequencing cohort (n = 50) from Sun Yat-Sen Memorial Hospital (SYMH) to identify the most highly upregulated inflammatory gene associated with lymphatic metastasis. Using immunohistochemistry and immunofluorescence analyses, we validated the association of the identified molecule with clinical features and prognosis in an independent UCB cohort (n = 244) from SYMH. We also analysed TCGA-BLCA cohort (n = 408) to identify its potential biological pathways and immune landscape.
Results
In our study, chitinase 3-like 1 (CHI3L1) emerged as a significantly overexpressed proinflammatory mediator in UCB tissues with lymphatic metastasis compared to those without lymphatic metastasis (81.1% vs. 47.8%, P < 0.001). Within UCB tissues, CHI3L1 was expressed in both stromal cells (52.8%) and tumor cells (7.3%). Moreover, CHI3L1+ stromal cells, but not tumor cells, exhibited independent prognostic significance for both overall survival (P < 0.001) and recurrence-free survival (P = 0.006). CHI3L1+ stromal cells were positively associated with D2-40+ lymphatic vessel density (P < 0.001) and the immunosuppressive PD-L1/PD-1/CD8 axis in UCB tissues (all P < 0.05). A bioinformatics analysis also identified a positive association between CHI3L1 expression and lymphangiogenesis or immunosuppression pathways.
Conclusion
Our study established a clear association between stromal CHI3L1 expression and lymphatic metastasis, suggesting that stromal CHI3L1 expression is a potential prognostic marker for bladder cancer patients.
{"title":"Chitinase 3-like 1 expression associated with lymphatic metastasis and prognosis in urothelial carcinoma of the bladder","authors":"Bo Wang, Ke Chen, Mingchao Gao, Xi Sun, Wang He, Junyu Chen, Wenjuan Yang, Tenghao Yang, Haide Qin, Honglian Ruan, Hao Huang, Tianxin Lin, Jian Huang","doi":"10.1002/cti2.1505","DOIUrl":"https://doi.org/10.1002/cti2.1505","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Lymphatic metastasis, an early stage of the metastasis process, is associated with adverse clinical outcomes in urothelial carcinoma of the bladder (UCB). However, the role of inflammation in triggering lymphatic metastasis remains unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We employed an RNA-sequencing cohort (<i>n</i> = 50) from Sun Yat-Sen Memorial Hospital (SYMH) to identify the most highly upregulated inflammatory gene associated with lymphatic metastasis. Using immunohistochemistry and immunofluorescence analyses, we validated the association of the identified molecule with clinical features and prognosis in an independent UCB cohort (<i>n</i> = 244) from SYMH. We also analysed TCGA-BLCA cohort (<i>n</i> = 408) to identify its potential biological pathways and immune landscape.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In our study, chitinase 3-like 1 (CHI3L1) emerged as a significantly overexpressed proinflammatory mediator in UCB tissues with lymphatic metastasis compared to those without lymphatic metastasis (81.1% vs. 47.8%, <i>P</i> < 0.001). Within UCB tissues, CHI3L1 was expressed in both stromal cells (52.8%) and tumor cells (7.3%). Moreover, CHI3L1<sup>+</sup> stromal cells, but not tumor cells, exhibited independent prognostic significance for both overall survival (<i>P</i> < 0.001) and recurrence-free survival (<i>P</i> = 0.006). CHI3L1<sup>+</sup> stromal cells were positively associated with D2-40<sup>+</sup> lymphatic vessel density (<i>P</i> < 0.001) and the immunosuppressive PD-L1/PD-1/CD8 axis in UCB tissues (all <i>P</i> < 0.05). A bioinformatics analysis also identified a positive association between CHI3L1 expression and lymphangiogenesis or immunosuppression pathways.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our study established a clear association between stromal CHI3L1 expression and lymphatic metastasis, suggesting that stromal CHI3L1 expression is a potential prognostic marker for bladder cancer patients.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 4","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1505","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140553107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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