{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T20:14:10Z","timestamp":1790108050137,"version":"4.0.1"},"reference-count":31,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T00:00:00Z","timestamp":1774310400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Immune checkpoint inhibitors (ICIs) targeting the PD-1 axis represent standard second-line therapy for metastatic non-small cell lung cancer (NSCLC). Emerging data suggest that SARS-CoV-2 mRNA vaccines may enhance antitumor immunity through innate immune activation and type I interferon signaling, potentially sensitizing tumors to PD-1 blockade. The clinical impact of patients initiating second-line nivolumab remains unclear. Methods: In this retrospective single-center cohort study, 88 patients with recurrent stage IV NSCLC who received second-line nivolumab between 1 January 2023 and 1 January 2026 were analyzed. Vaccination exposure was defined using a 6-month pre-treatment window prior to nivolumab initiation (T0). Patients were stratified according to receipt of \u22652 versus 0\u20131 mRNA COVID-19 vaccine doses within the 6 months preceding T0 (n = 45 and n = 43, respectively). The primary endpoint was progression-free survival from nivolumab initiation (PFS2). Survival outcomes were estimated using the Kaplan\u2013Meier method and evaluated using Cox regression models. Results: With a median follow-up of 22.4 months, median PFS2 for the overall cohort was 11.1 months (95% CI, 9.4\u201315.1). Patients receiving \u22652 mRNA doses had significantly longer PFS2 than those receiving 0\u20131 dose (14.0 vs. 9.6 months; p = 0.04). In multivariable analysis, \u22652 doses were independently associated with reduced risk of progression or death (aHR 0.52, 95% CI 0.31\u20130.88; p = 0.01). Non-adenocarcinoma histology and baseline brain metastasis were independently associated with shorter PFS2. Conclusions: Receipt of \u22652 mRNA vaccine doses within 6 months before nivolumab initiation was independently associated with prolonged PFS2 in metastatic NSCLC. Prospective multicenter validation is warranted.<\/jats:p>","DOI":"10.3390\/jcm15072475","type":"journal-article","created":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T12:58:59Z","timestamp":1774357139000},"page":"2475","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Impact of Prior mRNA COVID-19 Vaccination on PFS2 in NSCLC Patients Receiving Second-Line Immune Checkpoint Inhibitors: A Real-World Analysis"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5678-2633","authenticated-orcid":false,"given":"Selahattin","family":"\u00c7elik","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, Ankara Etlik City Training and Research Hospital, 06010 Ankara, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3247-5361","authenticated-orcid":false,"given":"Engin Eren","family":"Kavak","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Ankara Etlik City Training and Research Hospital, 06010 Ankara, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7200-9440","authenticated-orcid":false,"given":"Esra","family":"Zeynelgil","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Ankara Etlik City Training and Research Hospital, 06010 Ankara, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00f6k\u015fen \u0130nan\u00e7","family":"\u0130mamo\u011flu","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Ankara Etlik City Training and Research Hospital, 06010 Ankara, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u0130smail","family":"Dilli","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Ankara Etlik City Training and Research Hospital, 06010 Ankara, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4237-1606","authenticated-orcid":false,"given":"Salih","family":"Karatl\u0131","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Ankara Etlik City Training and Research Hospital, 06010 Ankara, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2263-2079","authenticated-orcid":false,"given":"Mehmetcan","family":"Atak","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Ankara Etlik City Training and Research Hospital, 06010 Ankara, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mustafa","family":"Alt\u0131nba\u015f","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Ankara Etlik City Training and Research Hospital, 06010 Ankara, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T\u00fclay","family":"Eren","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Ankara Etlik City Training and Research Hospital, 06010 Ankara, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1056\/NEJMoa1504627","article-title":"Nivolumab versus docetaxel in advanced squamous-cell non\u2013small-cell lung cancer","volume":"373","author":"Brahmer","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1016\/j.cell.2017.01.017","article-title":"Primary, adaptive, and acquired resistance to cancer immunotherapy","volume":"168","author":"Sharma","year":"2017","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/S0140-6736(16)32517-X","article-title":"Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): A phase 3, open-label, multicentre randomised controlled trial","volume":"389","author":"Rittmeyer","year":"2017","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1823","DOI":"10.1056\/NEJMoa1606774","article-title":"Pembrolizumab versus chemotherapy for PD-L1\u2013positive non\u2013small-cell lung cancer","volume":"375","author":"Reck","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1675","DOI":"10.1200\/JCO.2017.77.0412","article-title":"Five-year follow-up of nivolumab in previously treated advanced non\u2013small-cell lung cancer: Results from the CA209-003 study","volume":"36","author":"Gettinger","year":"2018","journal-title":"J. Clin. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1038\/s41568-024-00705-7","article-title":"Defining clinically useful biomarkers of immune checkpoint inhibitors in solid tumours","volume":"24","author":"Holder","year":"2024","journal-title":"Nat. Rev. Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1016\/j.immuni.2018.03.023","article-title":"The immune landscape of cancer","volume":"48","author":"Thorsson","year":"2018","journal-title":"Immunity"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2443","DOI":"10.1056\/NEJMoa1200690","article-title":"Safety, activity, and immune correlates of anti\u2013PD-1 antibody in cancer","volume":"366","author":"Topalian","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.immuni.2013.07.012","article-title":"Oncology meets immunology: The cancer-immunity cycle","volume":"39","author":"Chen","year":"2013","journal-title":"Immunity"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1016\/j.ccell.2017.04.003","article-title":"Tumor-residing Batf3 dendritic cells are required for effector T cell trafficking and adoptive T cell therapy","volume":"31","author":"Spranger","year":"2017","journal-title":"Cancer Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1038\/s41573-018-0007-y","article-title":"Approaches to treat immune hot, altered and cold tumours with combination immunotherapies","volume":"18","author":"Galon","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1126\/science.aaa6204","article-title":"T cell exclusion, immune privilege, and the tumor microenvironment","volume":"348","author":"Joyce","year":"2015","journal-title":"Science"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.it.2012.10.004","article-title":"Type I interferon response and innate immune sensing of cancer","volume":"34","author":"Fuertes","year":"2013","journal-title":"Trends Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1540","DOI":"10.1016\/j.cell.2016.11.022","article-title":"Tumor interferon signaling regulates a multigenic resistance program to immune checkpoint blockade","volume":"167","author":"Benci","year":"2016","journal-title":"Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/j.immuni.2018.03.007","article-title":"Combination cancer therapy with immune checkpoint blockade: Mechanisms and strategies","volume":"48","author":"Patel","year":"2018","journal-title":"Immunity"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Luan, X., Wang, L., Song, G., and Zhou, W. (2024). Innate immune responses to RNA: Sensing and signaling. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1287940"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1038\/nrd.2017.243","article-title":"mRNA vaccines\u2014A new era in vaccinology","volume":"17","author":"Pardi","year":"2018","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Park, H.-J., Ko, H.L., Won, D.-H., Hwang, D.-B., Shin, Y.-S., Kwak, H.-W., Kim, H.-J., Yun, J.-W., and Nam, J.-H. (2019). Comprehensive analysis of the safety profile of a single-stranded RNA nano-structure adjuvant. Pharmaceutics, 11.","DOI":"10.3390\/pharmaceutics11090464"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1038\/nature23003","article-title":"Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer","volume":"547","author":"Sahin","year":"2017","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1126\/science.aar4060","article-title":"Cancer immunotherapy using checkpoint blockade","volume":"359","author":"Ribas","year":"2018","journal-title":"Science"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1038\/nature18300","article-title":"Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy","volume":"534","author":"Kranz","year":"2016","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1038\/s41586-025-09655-y","article-title":"SARS-CoV-2 mRNA vaccines sensitize tumours to immune checkpoint blockade","volume":"647","author":"Grippin","year":"2025","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1038\/s41571-022-00610-8","article-title":"COVID-19 vaccines in patients with cancer: Immunogenicity, efficacy and safety","volume":"19","author":"Fendler","year":"2022","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.1016\/j.immuni.2018.09.024","article-title":"Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-\u03b3 and IL-12","volume":"49","author":"Garris","year":"2018","journal-title":"Immunity"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1016\/S1470-2045(21)00155-8","article-title":"Short-term safety of the BNT162b2 mRNA COVID-19 vaccine in patients with cancer treated with immune checkpoint inhibitors","volume":"22","author":"Waissengrin","year":"2021","journal-title":"Lancet Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2401631","DOI":"10.1002\/smll.202401631","article-title":"Cancer nanovaccines: Nanomaterials and clinical perspectives","volume":"20","author":"Desai","year":"2024","journal-title":"Small"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1038\/s41392-025-02521-3","article-title":"When vaccines reset tumors: SARS-CoV-2 mRNA shots create a transient checkpoint-sensitive state","volume":"10","author":"Chi","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"See, K.C. (2026). Vaccination Against Respiratory Infections in Adults with Cancer: A Concise Guide for Clinicians. Vaccines, 14.","DOI":"10.3390\/vaccines14010105"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/s13045-026-01778-7","article-title":"Lung cancer vaccines to enhance immune checkpoint inhibitor therapy: Evidence and future perspectives","volume":"19","author":"Tang","year":"2026","journal-title":"J. Hematol. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1038\/s41571-025-01105-y","article-title":"Could a COVID-19 vaccine improve the effectiveness of cancer immunotherapy?","volume":"23","author":"Gnjatic","year":"2026","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1093\/aje\/kwm324","article-title":"Immortal time bias in pharmaco-epidemiology","volume":"167","author":"Suissa","year":"2008","journal-title":"Am. J. Epidemiol."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/7\/2475\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T13:45:29Z","timestamp":1774359929000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/7\/2475"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,24]]},"references-count":31,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["jcm15072475"],"URL":"https:\/\/doi.org\/10.3390\/jcm15072475","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,24]]}}}