Pub Date : 2026-02-02DOI: 10.1038/s41591-026-04200-4
{"title":"Integration of health check-ups into school and healthcare systems can improve adolescent health in LMICs.","authors":"","doi":"10.1038/s41591-026-04200-4","DOIUrl":"https://doi.org/10.1038/s41591-026-04200-4","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":50.0,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146106303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-02DOI: 10.1038/s41591-025-04156-x
Aoife M. Doyle, Farirai Nzvere, Salome Manyau, Victoria Simms, Ines Li Lin, Faith R. Kandiye, Chipo Ashley Nyamayaro, Michaela Takawira, Rudo M. S. Chingono, Mandikudza Tembo, Ronald Manhibi, Ethel Dauya, Chido Dziva Chikwari, Giulia Greco, Sarah Bernays, Valentina Baltag, Hannah Maisiri, Tonderai Kasu, Wenceslas Nyamayaro, Tsitsi Bandason, Constance R. S. Mackworth-Young, Prerna Banati, Helen A. Weiss, David A. Ross, Rashida A. Ferrand
Routine adolescent health check-ups can support healthy development and well-being, but evidence on the feasibility, acceptability and effectiveness of contextually relevant comprehensive check-ups in low- and middle-income settings is limited. We conducted a hybrid implementation-effectiveness study incorporating a mixed-methods pre−post design of Y-Check, a comprehensive health check-up intervention in Zimbabwe, as part of a multicountry study developed and coordinated by the World Health Organization. Eligible participants were 10–19-year-old adolescents attending school or community venues. We used self-administered digital questionnaires, provider-led clinical tests and nurse reviews to screen for 25 conditions/behaviors. We provided health promotion, on-site care and referral to relevant providers. From October 2022 to September 2023, 2,097 adolescents were enrolled, of whom 1,843 (87.9%) were seen at 6 months. The primary outcome of appropriate care and/or referral(s) for all identified issues was achieved for 70.8% (95% confidence interval: 68.7–72.9%) of 1,865 participants with at least one issue. At follow-up, there were improvements in nutrition, health-related quality of life, self-esteem, behaviors and educational outcomes. The intervention was feasible and largely acceptable. Uptake of referral services varied by issue. Y-Check cost US$47 per participant. Through Y-Check, we identified untreated conditions and risk behaviors and successfully treated and linked adolescents to services. Here we provide evidence on the potential of the intervention to positively impact health and well-being.
{"title":"Implementation and evaluation of the Y-Check comprehensive adolescent health check-up intervention in Zimbabwe: a pre−post mixed-methods study","authors":"Aoife M. Doyle, Farirai Nzvere, Salome Manyau, Victoria Simms, Ines Li Lin, Faith R. Kandiye, Chipo Ashley Nyamayaro, Michaela Takawira, Rudo M. S. Chingono, Mandikudza Tembo, Ronald Manhibi, Ethel Dauya, Chido Dziva Chikwari, Giulia Greco, Sarah Bernays, Valentina Baltag, Hannah Maisiri, Tonderai Kasu, Wenceslas Nyamayaro, Tsitsi Bandason, Constance R. S. Mackworth-Young, Prerna Banati, Helen A. Weiss, David A. Ross, Rashida A. Ferrand","doi":"10.1038/s41591-025-04156-x","DOIUrl":"https://doi.org/10.1038/s41591-025-04156-x","url":null,"abstract":"Routine adolescent health check-ups can support healthy development and well-being, but evidence on the feasibility, acceptability and effectiveness of contextually relevant comprehensive check-ups in low- and middle-income settings is limited. We conducted a hybrid implementation-effectiveness study incorporating a mixed-methods pre−post design of Y-Check, a comprehensive health check-up intervention in Zimbabwe, as part of a multicountry study developed and coordinated by the World Health Organization. Eligible participants were 10–19-year-old adolescents attending school or community venues. We used self-administered digital questionnaires, provider-led clinical tests and nurse reviews to screen for 25 conditions/behaviors. We provided health promotion, on-site care and referral to relevant providers. From October 2022 to September 2023, 2,097 adolescents were enrolled, of whom 1,843 (87.9%) were seen at 6 months. The primary outcome of appropriate care and/or referral(s) for all identified issues was achieved for 70.8% (95% confidence interval: 68.7–72.9%) of 1,865 participants with at least one issue. At follow-up, there were improvements in nutrition, health-related quality of life, self-esteem, behaviors and educational outcomes. The intervention was feasible and largely acceptable. Uptake of referral services varied by issue. Y-Check cost US$47 per participant. Through Y-Check, we identified untreated conditions and risk behaviors and successfully treated and linked adolescents to services. Here we provide evidence on the potential of the intervention to positively impact health and well-being.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"87 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146102154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-02DOI: 10.1038/s41591-025-04181-w
Zhe Huang, Liang Zeng, Zhaohui Ruan, Qun Zeng, Huan Yan, Wenjuan Jiang, Yi Xiong, Chunhua Zhou, Haiyan Yang, Li Liu, Jiacheng Dai, Nachuan Zou, Shidong Xu, Ya Wang, Zhan Wang, Jun Deng, Xue Chen, Jing Wang, Hua Xiang, Xiaomei Li, Boris Duchemann, Guoqiang Chen, Yang Xia, Tony Mok, Christoph Scheiermann, Francis Lévi, Nong Yang, Yongchang Zhang
Retrospective studies suggest that early time-of-day (ToD) infusions of immunochemotherapy may improve efficacy. However, prospective randomized controlled trials are needed to validate it. In this randomized phase 3 LungTIME-C01 trial, 210 patients with treatment naive stage IIIC–IV nonsmall cell lung cancer (NSCLC) lacking driver mutations were randomly assigned in a 1:1 ratio to either an early or late ToD group, defined by the administration of the first four cycles of an anti-PD-1 agent before or after 15:00 h. The primary endpoint was progression-free survival (PFS), while secondary endpoints included overall survival (OS) and objective response rate (ORR). After a median follow-up of 28.7 months, the median PFS was 11.3 months (95% confidence interval (CI) = 9.2–13.4) in the early ToD group and 5.7 months (95% CI = 5.2–6.2) in the late ToD group, corresponding to a hazard ratio (HR) for earlier disease progression of 0.40 (95% CI = 0.29–0.55; P < 0.001). The median OS was 28.0 months (95% CI = not estimable (NE)–NE) in the early ToD group and 16.8 months (95% CI = 13.7–19.9) in the late ToD group, corresponding to an HR of an earlier death of 0.42 (95% CI = 0.29–0.60; P < 0.001). Treatment-related adverse events were consistent with the established safety profile, with no new safety signals observed. No significant differences in immune-related adverse events were observed between the two groups. Over the first four cycles, morning circulating CD8+ T cells increased in the early ToD group, whereas they declined in the late ToD group (P < 0.001). Furthermore, the ratio of activated (CD38+ HLA-DR+) versus exhausted (TIM-3+PD-1+) CD8+ T cells was higher in the early ToD group (P < 0.001) compared with the late ToD group (P < 0.001). In summary, our study indicates that early ToD immunochemotherapy substantially improves PFS and OS and is associated with enhanced antitumor CD8+ T cell characteristics compared with late ToD treatment. ClinicalTrials.gov registration: NCT05549037.
回顾性研究表明，每天早时间（ToD）输注免疫化疗可提高疗效。然而，需要前瞻性随机对照试验来验证它。在这项随机的3期临床试验中，210例缺乏驱动突变的初始IIIC-IV期非小细胞肺癌（NSCLC）患者被按1:1的比例随机分配到早期或晚期ToD组，通过在15:00之前或之后施用抗pd -1药物的前四个周期来定义。主要终点是无进展生存期（PFS），次要终点包括总生存期（OS）和客观缓解率（ORR）。中位随访28.7个月后，ToD早期组的中位PFS为11.3个月（95%可信区间(CI) = 9.2-13.4）， ToD晚期组的中位PFS为5.7个月（95% CI = 5.2-6.2），对应于早期疾病进展的风险比（HR）为0.40 （95% CI = 0.29-0.55; P < 0.001）。ToD早期组的中位OS为28.0个月（95% CI =不可估计(NE) -NE）， ToD晚期组的中位OS为16.8个月（95% CI = 13.7-19.9），对应于早期死亡的HR为0.42 （95% CI = 0.29-0.60; P < 0.001）。与治疗相关的不良事件与既定的安全性一致，未观察到新的安全性信号。两组之间免疫相关不良事件无显著差异。在前四个周期中，ToD早期组的晨循环CD8+ T细胞增加，而ToD晚期组的晨循环CD8+ T细胞减少（P < 0.001）。此外，与ToD晚期组相比，ToD早期组活化（CD38+ HLA-DR+）和耗尽（TIM-3+PD-1+） CD8+ T细胞的比例（P < 0.001）更高。综上所述，我们的研究表明，与晚期ToD治疗相比，早期ToD免疫化疗显著改善了PFS和OS，并与增强的抗肿瘤CD8+ T细胞特征相关。ClinicalTrials.gov注册：NCT05549037。
{"title":"Time-of-day immunochemotherapy in nonsmall cell lung cancer: a randomized phase 3 trial","authors":"Zhe Huang, Liang Zeng, Zhaohui Ruan, Qun Zeng, Huan Yan, Wenjuan Jiang, Yi Xiong, Chunhua Zhou, Haiyan Yang, Li Liu, Jiacheng Dai, Nachuan Zou, Shidong Xu, Ya Wang, Zhan Wang, Jun Deng, Xue Chen, Jing Wang, Hua Xiang, Xiaomei Li, Boris Duchemann, Guoqiang Chen, Yang Xia, Tony Mok, Christoph Scheiermann, Francis Lévi, Nong Yang, Yongchang Zhang","doi":"10.1038/s41591-025-04181-w","DOIUrl":"https://doi.org/10.1038/s41591-025-04181-w","url":null,"abstract":"Retrospective studies suggest that early time-of-day (ToD) infusions of immunochemotherapy may improve efficacy. However, prospective randomized controlled trials are needed to validate it. In this randomized phase 3 LungTIME-C01 trial, 210 patients with treatment naive stage IIIC–IV nonsmall cell lung cancer (NSCLC) lacking driver mutations were randomly assigned in a 1:1 ratio to either an early or late ToD group, defined by the administration of the first four cycles of an anti-PD-1 agent before or after 15:00 h. The primary endpoint was progression-free survival (PFS), while secondary endpoints included overall survival (OS) and objective response rate (ORR). After a median follow-up of 28.7 months, the median PFS was 11.3 months (95% confidence interval (CI) = 9.2–13.4) in the early ToD group and 5.7 months (95% CI = 5.2–6.2) in the late ToD group, corresponding to a hazard ratio (HR) for earlier disease progression of 0.40 (95% CI = 0.29–0.55; P < 0.001). The median OS was 28.0 months (95% CI = not estimable (NE)–NE) in the early ToD group and 16.8 months (95% CI = 13.7–19.9) in the late ToD group, corresponding to an HR of an earlier death of 0.42 (95% CI = 0.29–0.60; P < 0.001). Treatment-related adverse events were consistent with the established safety profile, with no new safety signals observed. No significant differences in immune-related adverse events were observed between the two groups. Over the first four cycles, morning circulating CD8+ T cells increased in the early ToD group, whereas they declined in the late ToD group (P < 0.001). Furthermore, the ratio of activated (CD38+ HLA-DR+) versus exhausted (TIM-3+PD-1+) CD8+ T cells was higher in the early ToD group (P < 0.001) compared with the late ToD group (P < 0.001). In summary, our study indicates that early ToD immunochemotherapy substantially improves PFS and OS and is associated with enhanced antitumor CD8+ T cell characteristics compared with late ToD treatment. ClinicalTrials.gov registration: NCT05549037.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"67 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146102153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-30DOI: 10.1038/d41591-026-00004-8
Karen O'Leary
{"title":"Base editing enables off-the-shelf CAR T cells for leukemia.","authors":"Karen O'Leary","doi":"10.1038/d41591-026-00004-8","DOIUrl":"https://doi.org/10.1038/d41591-026-00004-8","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"37 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146089091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-30DOI: 10.1038/d41591-026-00005-7
Karen O'Leary
{"title":"New analysis shows no link between autism and paracetamol.","authors":"Karen O'Leary","doi":"10.1038/d41591-026-00005-7","DOIUrl":"https://doi.org/10.1038/d41591-026-00005-7","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"3 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146089005","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-29DOI: 10.1038/s41591-026-04234-8
Pawel K Mazur, Alexander Herner, Stephano S Mello, Matthias Wirth, Simone Hausmann, Francisco J Sánchez-Rivera, Shane M Lofgren, Timo Kuschma, Stephan A Hahn, Deepak Vangala, Marija Trajkovic-Arsic, Aayush Gupta, Irina Heid, Peter B Noël, Rickmer Braren, Mert Erkan, Jörg Kleeff, Bence Sipos, Leanne C Sayles, Mathias Heikenwalder, Elisabeth Heßmann, Volker Ellenrieder, Irene Esposito, Tyler Jacks, James E Bradner, Purvesh Khatri, E Alejandro Sweet-Cordero, Laura D Attardi, Roland M Schmid, Guenter Schneider, Julien Sage, Jens T Siveke
{"title":"Author Correction: Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma.","authors":"Pawel K Mazur, Alexander Herner, Stephano S Mello, Matthias Wirth, Simone Hausmann, Francisco J Sánchez-Rivera, Shane M Lofgren, Timo Kuschma, Stephan A Hahn, Deepak Vangala, Marija Trajkovic-Arsic, Aayush Gupta, Irina Heid, Peter B Noël, Rickmer Braren, Mert Erkan, Jörg Kleeff, Bence Sipos, Leanne C Sayles, Mathias Heikenwalder, Elisabeth Heßmann, Volker Ellenrieder, Irene Esposito, Tyler Jacks, James E Bradner, Purvesh Khatri, E Alejandro Sweet-Cordero, Laura D Attardi, Roland M Schmid, Guenter Schneider, Julien Sage, Jens T Siveke","doi":"10.1038/s41591-026-04234-8","DOIUrl":"https://doi.org/10.1038/s41591-026-04234-8","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":50.0,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146086482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-28DOI: 10.1038/s41591-025-04189-2
Serena Porcari, Chiara Ciccarese, Vitor Heidrich, Debora Rondinella, Gianluca Quaranta, Andrea Severino, Daniela Arduini, Sebastiano Buti, Giuseppe Fornarini, Francesca Primi, Luciano Stumbo, Diana Giannarelli, Giulia Claire Giudice, Alessandra Damassi, Julio Rodrigo Giron Berríos, Michal Punčochář, Thomas B. Barbazuk, Gianmarco Piccinno, Federica Pinto, Federica Armanini, Francesco Asnicar, Giovanni Schinzari, Lisa Derosa, Guido Kroemer, Maurizio Sanguinetti, Luca Masucci, Antonio Gasbarrini, Giampaolo Tortora, Giovanni Cammarota, Laurence Zitvogel, Nicola Segata, Roberto Iacovelli, Gianluca Ianiro
Renal cell carcinoma (RCC) is a common malignancy with limited durable responses to first-line immune checkpoint inhibitor (ICI)-based therapies. Emerging evidence implicates the gut microbiome in modulating ICI efficacy. In the investigator-initiated, randomized, double-blind placebo-controlled phase 2a TACITO trial, we evaluated whether fecal microbiota transplantation (FMT) from complete ICI responders enhances clinical outcomes in treatment-naive patients with metastatic RCC (mRCC) receiving pembrolizumab + axitinib. The primary endpoint was the rate of patients free from disease progression at 12 months after randomization (12-month progression-free survival (PFS)). Secondary endpoints were median PFS and median overall survival, objective response rate (ORR), safety and microbiome changes, after randomization. Forty-five patients randomly received donor FMT (d-FMT) or placebo FMT (p-FMT). Although the primary endpoint was not met (70% versus 41% for d-FMT versus p-FMT, respectively, P = 0.053), the secondary endpoint of median PFS was significantly longer with d-FMT (24.0 months in the d-FMT arm versus 9.0 months in the p-FMT arm; hazard ratio = 0.50, P = 0.035). The ORR was 52% of patients in the d-FMT arm and 32% of patients receiving placebo. Microbiome analysis confirmed donor strain engraftment and increased α-diversity and larger microbiome shifts (β-diversity) compared with baseline composition in the d-FMT treatment group. Acquisition or loss of specific strains, but not total engraftment, was associated with the primary endpoint. Our findings support the safety and potential efficacy of selected donor FMT to enhance ICI-based treatment in mRCC, which deserves further investigations. ClinicalTrials.gov identifier: NCT04758507.
{"title":"Fecal microbiota transplantation plus pembrolizumab and axitinib in metastatic renal cell carcinoma: the randomized phase 2 TACITO trial","authors":"Serena Porcari, Chiara Ciccarese, Vitor Heidrich, Debora Rondinella, Gianluca Quaranta, Andrea Severino, Daniela Arduini, Sebastiano Buti, Giuseppe Fornarini, Francesca Primi, Luciano Stumbo, Diana Giannarelli, Giulia Claire Giudice, Alessandra Damassi, Julio Rodrigo Giron Berríos, Michal Punčochář, Thomas B. Barbazuk, Gianmarco Piccinno, Federica Pinto, Federica Armanini, Francesco Asnicar, Giovanni Schinzari, Lisa Derosa, Guido Kroemer, Maurizio Sanguinetti, Luca Masucci, Antonio Gasbarrini, Giampaolo Tortora, Giovanni Cammarota, Laurence Zitvogel, Nicola Segata, Roberto Iacovelli, Gianluca Ianiro","doi":"10.1038/s41591-025-04189-2","DOIUrl":"https://doi.org/10.1038/s41591-025-04189-2","url":null,"abstract":"Renal cell carcinoma (RCC) is a common malignancy with limited durable responses to first-line immune checkpoint inhibitor (ICI)-based therapies. Emerging evidence implicates the gut microbiome in modulating ICI efficacy. In the investigator-initiated, randomized, double-blind placebo-controlled phase 2a TACITO trial, we evaluated whether fecal microbiota transplantation (FMT) from complete ICI responders enhances clinical outcomes in treatment-naive patients with metastatic RCC (mRCC) receiving pembrolizumab + axitinib. The primary endpoint was the rate of patients free from disease progression at 12 months after randomization (12-month progression-free survival (PFS)). Secondary endpoints were median PFS and median overall survival, objective response rate (ORR), safety and microbiome changes, after randomization. Forty-five patients randomly received donor FMT (d-FMT) or placebo FMT (p-FMT). Although the primary endpoint was not met (70% versus 41% for d-FMT versus p-FMT, respectively, P = 0.053), the secondary endpoint of median PFS was significantly longer with d-FMT (24.0 months in the d-FMT arm versus 9.0 months in the p-FMT arm; hazard ratio = 0.50, P = 0.035). The ORR was 52% of patients in the d-FMT arm and 32% of patients receiving placebo. Microbiome analysis confirmed donor strain engraftment and increased α-diversity and larger microbiome shifts (β-diversity) compared with baseline composition in the d-FMT treatment group. Acquisition or loss of specific strains, but not total engraftment, was associated with the primary endpoint. Our findings support the safety and potential efficacy of selected donor FMT to enhance ICI-based treatment in mRCC, which deserves further investigations. ClinicalTrials.gov identifier: NCT04758507.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"296 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146057197","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-28DOI: 10.1038/s41591-025-04158-9
Lotte L. Hoeijmakers, Petros Dimitriadis, Steven C. M. A. Wijnen, Irene L. M. Reijers, Marta Lopez-Yurda, Alexander M. Menzies, Annegien Broeks, Sten Cornelissen, Alejandro Torres Acosta, Anja van der Wal, Robyn P. M. Saw, Judith M. Versluis, Winan J. van Houdt, Michel W. Wouters, Jurriaan Romano, Eliza A. Rozeman, Lindsay G. Grijpink-Ongering, Ellen Kapiteijn, Astrid A. M. van der Veldt, Karijn P. M. Suijkerbuijk, Hanna Eriksson, Geke A. P. Hospers, Jos A. van der Hage, Dirk J. Grünhagen, Arjen J. Witkamp, Judith M. Lijnsvelt, Willem M. C. Klop, Charlotte L. Zuur, Annemarie Bruining, Abrahim Al-Mamgani, Thomas E. Pennington, Kerwin F. Shannon, Sydney Ch’ng, Andrew J. Colebatch, Maria Gonzalez, Andrew J. Spillane, John B. A. G. Haanen, Robert V. Rawson, Richard A. Scolyer, Bart A. van de Wiel, Alexander C. J. van Akkooi, Georgina V. Long, Christian U. Blank
Neoadjuvant ipilimumab plus nivolumab has become standard therapy for stage III melanoma based on the NADINA trial, although long-term data are lacking. In the phase 2 PRADO cohort of OpACIN-neo, 99 patients with stage III macroscopic melanoma received this regimen. Here we report first-time 5-year survival data: 71% event-free survival, 74% relapse-free survival, 79% distant metastasis-free survival and 86% overall survival. Ongoing grade 1−2 immune-related adverse events occurred in 69% of patients alive, predominantly vitiligo and hypothyroidism. Major pathologic response (MPR), high tumor mutational burden (TMB), high interferon-gamma (IFNγ) signature and programmed cell death ligand 1 (PD-L1) expression of 1% or higher were associated with favorable outcomes. Combined high TMB, IFNγ and PD-L1 expression yielded 100% MPR and 100% 5-year event-free survival, whereas triple low expression had only 18% MPR and 41% event-free survival. Our findings demonstrate favorable long-term outcomes for patients with an MPR and identify IFNγ and PD-L1 as promising baseline biomarkers. ClinicalTrials.gov identifier: NCT02977052.
{"title":"Neoadjuvant ipilimumab plus nivolumab in melanoma: 5-year survival and biomarker analysis from the phase 2 PRADO-trial","authors":"Lotte L. Hoeijmakers, Petros Dimitriadis, Steven C. M. A. Wijnen, Irene L. M. Reijers, Marta Lopez-Yurda, Alexander M. Menzies, Annegien Broeks, Sten Cornelissen, Alejandro Torres Acosta, Anja van der Wal, Robyn P. M. Saw, Judith M. Versluis, Winan J. van Houdt, Michel W. Wouters, Jurriaan Romano, Eliza A. Rozeman, Lindsay G. Grijpink-Ongering, Ellen Kapiteijn, Astrid A. M. van der Veldt, Karijn P. M. Suijkerbuijk, Hanna Eriksson, Geke A. P. Hospers, Jos A. van der Hage, Dirk J. Grünhagen, Arjen J. Witkamp, Judith M. Lijnsvelt, Willem M. C. Klop, Charlotte L. Zuur, Annemarie Bruining, Abrahim Al-Mamgani, Thomas E. Pennington, Kerwin F. Shannon, Sydney Ch’ng, Andrew J. Colebatch, Maria Gonzalez, Andrew J. Spillane, John B. A. G. Haanen, Robert V. Rawson, Richard A. Scolyer, Bart A. van de Wiel, Alexander C. J. van Akkooi, Georgina V. Long, Christian U. Blank","doi":"10.1038/s41591-025-04158-9","DOIUrl":"https://doi.org/10.1038/s41591-025-04158-9","url":null,"abstract":"Neoadjuvant ipilimumab plus nivolumab has become standard therapy for stage III melanoma based on the NADINA trial, although long-term data are lacking. In the phase 2 PRADO cohort of OpACIN-neo, 99 patients with stage III macroscopic melanoma received this regimen. Here we report first-time 5-year survival data: 71% event-free survival, 74% relapse-free survival, 79% distant metastasis-free survival and 86% overall survival. Ongoing grade 1−2 immune-related adverse events occurred in 69% of patients alive, predominantly vitiligo and hypothyroidism. Major pathologic response (MPR), high tumor mutational burden (TMB), high interferon-gamma (IFNγ) signature and programmed cell death ligand 1 (PD-L1) expression of 1% or higher were associated with favorable outcomes. Combined high TMB, IFNγ and PD-L1 expression yielded 100% MPR and 100% 5-year event-free survival, whereas triple low expression had only 18% MPR and 41% event-free survival. Our findings demonstrate favorable long-term outcomes for patients with an MPR and identify IFNγ and PD-L1 as promising baseline biomarkers. ClinicalTrials.gov identifier: NCT02977052.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"272 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146057193","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-28DOI: 10.1038/s41591-025-04186-5
Sreya Duttagupta, Meriem Messaoudene, Sebastian Hunter, Antoine Desilets, Rahima Jamal, Catalin Mihalcioiu, Wiam Belkaid, Nicolas Marcoux, Marine Fidelle, Deborah Suissa, Mayra Ponce, Mallia Geiger, Julie Malo, Gianmarco Piccinno, Michal Punčochář, Alysé Filin, Vitor Heidrich, Diana Rusu, Babacar Mbaye, Sylvere Durand, Imen Ben Aissa, Vadim Puller, Raynald de Lahondès, Normand Blais, Mustapha Tehfe, Scott Owen, Karl Bélanger, Seema Nair Parvathy, Benjamin Shieh, Jacques Raphael, John Lenehan, Daniel Breadner, Jeffrey Rothenstein, Nicholas Rozza, Jade Maillou, Somayeh Nili, Diogjena Katerina Prifti, Federica Pinto, Federica Armanini, Seunghee Kim-Schulze, Thomas U. Marron, Guido Kroemer, Lisa Derosa, Laurence Zitvogel, Michael Silverman, Nicola Segata, Saman Maleki Vareki, Bertrand Routy, Arielle Elkrief
Immune checkpoint inhibitors (ICI) have improved outcomes for patients with non-small cell lung cancer (NSCLC) and melanoma, yet over half of patients exhibit primary resistance. Fecal microbiota transplantation (FMT) may overcome resistance to anti-programmed cell death protein 1 (PD-1) therapy. The clinical activity and safety of FMT plus anti-PD-1 in NSCLC or anti-PD-1 plus anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) therapy in melanoma have not been evaluated. Here we report results from FMT-LUMINate, a multicenter, open-label, phase 2 trial assessing healthy donor FMT plus anti-PD-1 in NSCLC (n = 20) or anti-PD-1 plus anti-CTLA-4 (dual ICI) in melanoma (n = 20), in the first-line setting. Eligible patients received a single FMT via oral capsules prior to ICI initiation. The primary endpoint was objective response rate (ORR) in NSCLC. Secondary endpoints included ORR in melanoma, safety and donor−host microbiome similarity. In NSCLC, the ORR was 80% (16/20), meeting the study primary endpoint. In melanoma, the ORR was 75% (15/20). FMT was deemed safe in both cohorts by an independent data and safety monitoring committee, with no grade 3 or higher adverse events (AEs) in NSCLC and 13 (65%) patients experiencing grade 3 or higher AEs in melanoma. Shotgun metagenomic sequencing revealed that responders developed a distinct post-FMT gut microbiome composition, independent of acquired donor−recipient similarity or strain-level engraftment. Responders exhibited significantly greater loss of baseline bacterial species compared to non-responders, with frequent depletion of Enterocloster citroniae, E. lavalensis and Clostridium innocuum. This finding was reproduced across three published FMT oncology trials. We recolonized antibiotic-treated, tumor-bearing mice with post-FMT stool from two responder patients, and reintroduction of the specific bacterial species that were lost after FMT abrogated the antitumor effect of ICI. Taken together, these findings confirm the clinical activity of FMT in combination with ICI and suggest that the elimination of deleterious taxa is required for FMT-mediated therapeutic benefit. ClinicalTrials.gov identifier: NCT04951583.
{"title":"Fecal microbiota transplantation plus immunotherapy in non-small cell lung cancer and melanoma: the phase 2 FMT-LUMINate trial","authors":"Sreya Duttagupta, Meriem Messaoudene, Sebastian Hunter, Antoine Desilets, Rahima Jamal, Catalin Mihalcioiu, Wiam Belkaid, Nicolas Marcoux, Marine Fidelle, Deborah Suissa, Mayra Ponce, Mallia Geiger, Julie Malo, Gianmarco Piccinno, Michal Punčochář, Alysé Filin, Vitor Heidrich, Diana Rusu, Babacar Mbaye, Sylvere Durand, Imen Ben Aissa, Vadim Puller, Raynald de Lahondès, Normand Blais, Mustapha Tehfe, Scott Owen, Karl Bélanger, Seema Nair Parvathy, Benjamin Shieh, Jacques Raphael, John Lenehan, Daniel Breadner, Jeffrey Rothenstein, Nicholas Rozza, Jade Maillou, Somayeh Nili, Diogjena Katerina Prifti, Federica Pinto, Federica Armanini, Seunghee Kim-Schulze, Thomas U. Marron, Guido Kroemer, Lisa Derosa, Laurence Zitvogel, Michael Silverman, Nicola Segata, Saman Maleki Vareki, Bertrand Routy, Arielle Elkrief","doi":"10.1038/s41591-025-04186-5","DOIUrl":"https://doi.org/10.1038/s41591-025-04186-5","url":null,"abstract":"Immune checkpoint inhibitors (ICI) have improved outcomes for patients with non-small cell lung cancer (NSCLC) and melanoma, yet over half of patients exhibit primary resistance. Fecal microbiota transplantation (FMT) may overcome resistance to anti-programmed cell death protein 1 (PD-1) therapy. The clinical activity and safety of FMT plus anti-PD-1 in NSCLC or anti-PD-1 plus anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) therapy in melanoma have not been evaluated. Here we report results from FMT-LUMINate, a multicenter, open-label, phase 2 trial assessing healthy donor FMT plus anti-PD-1 in NSCLC (n = 20) or anti-PD-1 plus anti-CTLA-4 (dual ICI) in melanoma (n = 20), in the first-line setting. Eligible patients received a single FMT via oral capsules prior to ICI initiation. The primary endpoint was objective response rate (ORR) in NSCLC. Secondary endpoints included ORR in melanoma, safety and donor−host microbiome similarity. In NSCLC, the ORR was 80% (16/20), meeting the study primary endpoint. In melanoma, the ORR was 75% (15/20). FMT was deemed safe in both cohorts by an independent data and safety monitoring committee, with no grade 3 or higher adverse events (AEs) in NSCLC and 13 (65%) patients experiencing grade 3 or higher AEs in melanoma. Shotgun metagenomic sequencing revealed that responders developed a distinct post-FMT gut microbiome composition, independent of acquired donor−recipient similarity or strain-level engraftment. Responders exhibited significantly greater loss of baseline bacterial species compared to non-responders, with frequent depletion of Enterocloster citroniae, E. lavalensis and Clostridium innocuum. This finding was reproduced across three published FMT oncology trials. We recolonized antibiotic-treated, tumor-bearing mice with post-FMT stool from two responder patients, and reintroduction of the specific bacterial species that were lost after FMT abrogated the antitumor effect of ICI. Taken together, these findings confirm the clinical activity of FMT in combination with ICI and suggest that the elimination of deleterious taxa is required for FMT-mediated therapeutic benefit. ClinicalTrials.gov identifier: NCT04951583.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"2 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146057196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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