{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T16:42:01Z","timestamp":1793032921640,"version":"4.5.0"},"reference-count":25,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T00:00:00Z","timestamp":1786147200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T00:00:00Z","timestamp":1786147200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["npj Precis. Onc."],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Ewing sarcoma is a rare, fusion-driven malignancy with poor prognosis in the metastatic setting, for which no established immunotherapeutic treatment is currently available. Fusion breakpoints are rational precision immunotherapy targets, yet clinical evidence of immunogenicity is scarce. We administered an off-the-shelf multi-peptide vaccine spanning the type 1 EWSR1\u2013FLI1 breakpoint to a patient with high-burden metastatic Ewing sarcoma following multimodal therapy. Vaccinations were combined with GM-CSF and topical imiquimod. Longitudinal immune monitoring by in vitro peptide stimulation and intracellular cytokine staining revealed de novo polyfunctional CD4\u207a T-cell responses against all four fusion-derived peptides, first detectable by month 7 and persisting beyond two years. Treatment was well tolerated with only grade 1 local reactions. Durable disease stability was maintained for more than 26 months. These first-in-human data support the feasibility, safety, and immunogenicity of a fusion-derived peptide vaccine and warrant further evaluation of precision immunotherapy in sarcomas driven by recurrent gene fusions.<\/jats:p>","DOI":"10.1038\/s41698-026-01642-4","type":"journal-article","created":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T11:34:15Z","timestamp":1786188855000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Durable clinical and immunologic response to an off-the-shelf EWSR1\u2013FLI1 peptide vaccine in metastatic Ewing sarcoma"],"prefix":"10.1038","volume":"10","author":[{"given":"Branko","family":"Calukovic","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrin","family":"Benzler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henning","family":"Zelba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Seitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Kayser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Feldhahn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Borong","family":"Shao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Schulze","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Maksimovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veit","family":"Scheble","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Battke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Zender","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrich M.","family":"Lauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saskia","family":"Biskup","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph K. W.","family":"Deinzer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,8]]},"reference":[{"key":"1642_CR1","doi-asserted-by":"publisher","first-page":"1054","DOI":"10.1002\/ijc.33674","volume":"149","author":"LG Spector","year":"2021","unstructured":"Spector, L. G. et al. Comparative international incidence of Ewing sarcoma 1988 to 2012. Int. J. Cancer 149, 1054\u201366 (2021).","journal-title":"Int. J. Cancer"},{"key":"1642_CR2","doi-asserted-by":"publisher","first-page":"1513","DOI":"10.1016\/S0140-6736(22)01790-1","volume":"400","author":"B Brennan","year":"2022","unstructured":"Brennan, B. et al. Comparison of two chemotherapy regimens in patients with newly diagnosed Ewing sarcoma (EE2012): an open-label, randomised, phase 3 trial. Lancet 400, 1513\u201321 (2022).","journal-title":"Lancet"},{"key":"1642_CR3","doi-asserted-by":"publisher","first-page":"2098","DOI":"10.1200\/JCO.22.01815","volume":"41","author":"SG DuBois","year":"2023","unstructured":"DuBois, S. G. et al. Randomized phase III trial of Ganitumab with interval-compressed chemotherapy for patients with newly diagnosed metastatic Ewing sarcoma: a report from the Children\u2019s Oncology Group. J. Clin. Oncol. 41, 2098\u2013107 (2023).","journal-title":"J. Clin. Oncol."},{"key":"1642_CR4","doi-asserted-by":"publisher","first-page":"3363","DOI":"10.1002\/cncr.34942","volume":"129","author":"A Gupta","year":"2023","unstructured":"Gupta, A. et al. Consensus recommendations in the management of Ewing sarcoma from the National Ewing Sarcoma Tumor Board. Cancer 129, 3363\u201371 (2023).","journal-title":"Cancer"},{"key":"1642_CR5","doi-asserted-by":"publisher","first-page":"1138","DOI":"10.1302\/0301-620X.98B8.37346","volume":"98-B","author":"JI Albergo","year":"2016","unstructured":"Albergo, J. I. et al. Ewing\u2019s sarcoma: only patients with 100% of necrosis after chemotherapy should be classified as having a good response. Bone Jt. J. 98-B, 1138\u201344 (2016).","journal-title":"Bone Jt. J."},{"key":"1642_CR6","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1097\/MPH.0b013e31802d3e3e","volume":"29","author":"G De Angulo","year":"2007","unstructured":"De Angulo, G. et al. Early lymphocyte recovery as a prognostic indicator for high-risk Ewing sarcoma. J. Pediatr. Hematol. Oncol. 29, 48\u201352 (2007).","journal-title":"J. Pediatr. Hematol. Oncol."},{"key":"1642_CR7","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1097\/MPH.0b013e3180590627","volume":"29","author":"SG DuBois","year":"2007","unstructured":"DuBois, S. G., Elterman, K. & Grier, H. E. Early lymphocyte recovery in Ewing sarcoma. J. Pediatr. Hematol. Oncol. 29, 351\u20132 (2007).","journal-title":"J. Pediatr. Hematol. Oncol."},{"key":"1642_CR8","doi-asserted-by":"publisher","first-page":"1096","DOI":"10.1002\/pbc.22673","volume":"55","author":"C Moore","year":"2010","unstructured":"Moore, C. et al. Prognostic significance of early lymphocyte recovery in pediatric osteosarcoma. Pediatr. Blood Cancer 55, 1096\u2013102 (2010).","journal-title":"Pediatr. Blood Cancer"},{"key":"1642_CR9","doi-asserted-by":"publisher","first-page":"1041","DOI":"10.1002\/pbc.22715","volume":"55","author":"P Anderson","year":"2010","unstructured":"Anderson, P. Predicting and facilitating survival of pediatric cancer patients: the ALC story. Pediatr. Blood Cancer 55, 1041\u20132 (2010).","journal-title":"Pediatr. Blood Cancer"},{"key":"1642_CR10","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1038\/s41586-023-06063-y","volume":"618","author":"LA Rojas","year":"2023","unstructured":"Rojas, L. A. et al. Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Nature 618, 144\u201350 (2023).","journal-title":"Nature"},{"key":"1642_CR11","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.696791","volume":"12","author":"AJ Stephens","year":"2021","unstructured":"Stephens, A. J., Burgess-Brown, N. A. & Jiang, S. Beyond just peptide antigens: the complex world of peptide-based cancer vaccines. Front. Immunol. 12, 696791 (2021).","journal-title":"Front. Immunol."},{"key":"1642_CR12","doi-asserted-by":"publisher","first-page":"4850","DOI":"10.1158\/1078-0432.CCR-07-4065","volume":"14","author":"CL Mackall","year":"2008","unstructured":"Mackall, C. L. et al. A pilot study of consolidative immunotherapy in patients with high-risk pediatric sarcomas. Clin. Cancer Res. 14, 4850\u20138 (2008).","journal-title":"Clin. Cancer Res."},{"key":"1642_CR13","doi-asserted-by":"publisher","first-page":"1623","DOI":"10.3390\/cancers15051623","volume":"15","author":"PM Anderson","year":"2023","unstructured":"Anderson, P. M. et al. Routine EWS fusion analysis in the oncology clinic to identify cancer-specific peptide sequence patterns that span breakpoints in Ewing sarcoma and DSRCT. Cancers 15, 1623 (2023).","journal-title":"Cancers"},{"key":"1642_CR14","doi-asserted-by":"publisher","first-page":"1254","DOI":"10.1038\/nm.2883","volume":"18","author":"S Walter","year":"2012","unstructured":"Walter, S. et al. Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival. Nat. Med. 18, 1254\u201361 (2012).","journal-title":"Nat. Med."},{"key":"1642_CR15","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1038\/nature23003","volume":"547","author":"U Sahin","year":"2017","unstructured":"Sahin, U. et al. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature 547, 222\u20136 (2017).","journal-title":"Nature"},{"key":"1642_CR16","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1038\/nature22991","volume":"547","author":"PA Ott","year":"2017","unstructured":"Ott, P. A. et al. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature 547, 217\u201321 (2017).","journal-title":"Nature"},{"key":"1642_CR17","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-51315-8","volume":"15","author":"P Latzer","year":"2024","unstructured":"Latzer, P. et al. A real-world observation of patients with glioblastoma treated with a personalized peptide vaccine. Nat. Commun. 15, 6870 (2024).","journal-title":"Nat. Commun."},{"key":"1642_CR18","doi-asserted-by":"publisher","first-page":"2770","DOI":"10.1016\/j.cell.2022.06.035","volume":"185","author":"MC Sellars","year":"2022","unstructured":"Sellars, M. C., Wu, C. J. & Fritsch, E. F. Cancer vaccines: building a bridge over troubled waters. Cell 185, 2770\u201388 (2022).","journal-title":"Cell"},{"key":"1642_CR19","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2026.116825","volume":"243","author":"P Heesen","year":"2026","unstructured":"Heesen, P. et al. Treatment effect heterogeneity of radiotherapy in localized Ewing sarcoma: a secondary analysis of the EURO-E.W.I.N.G. 99 and Ewing 2008 trial. Eur. J. Cancer 243, 116825 (2026).","journal-title":"Eur. J. Cancer"},{"key":"1642_CR20","doi-asserted-by":"publisher","first-page":"334","DOI":"10.1002\/pbc.21618","volume":"51","author":"PJ Leavey","year":"2008","unstructured":"Leavey, P. J. et al. Prognostic factors for patients with Ewing sarcoma (EWS) at first recurrence following multi-modality therapy: a report from the Children\u2019s Oncology Group. Pediatr. Blood Cancer 51, 334\u20138 (2008).","journal-title":"Pediatr. Blood Cancer"},{"key":"1642_CR21","doi-asserted-by":"publisher","first-page":"1689","DOI":"10.1158\/1078-0432.CCR-22-2292","volume":"29","author":"P Anderson","year":"2023","unstructured":"Anderson, P. et al. Pilot study of recurrent Ewing\u2019s sarcoma management with vigil\/temozolomide\/irinotecan and assessment of circulating tumor (ct) DNA. Clin. Cancer Res. 29, 1689\u201397 (2023).","journal-title":"Clin. Cancer Res."},{"key":"1642_CR22","doi-asserted-by":"publisher","first-page":"45","DOI":"10.15212\/bioi-2023-0005","volume":"4","author":"B Wu","year":"2023","unstructured":"Wu, B. & Wang, H. Peptide assemblies as promising tumor vaccines: current platforms and progress. BIO Integr. 4, 45\u201351 (2023).","journal-title":"BIO Integr."},{"key":"1642_CR23","doi-asserted-by":"publisher","first-page":"433","DOI":"10.15212\/bioi-2024-0002","volume":"5","author":"J Trivedi","year":"2024","unstructured":"Trivedi, J., Yasir, M., Maurya, R. K. & Tripathi, A. S. Aptamer-based theranostics in oncology: design strategies and limitations. BIO Integr. 5, 433\u2013454 (2024).","journal-title":"BIO Integr."},{"key":"1642_CR24","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1271449","volume":"14","author":"H Zelba","year":"2023","unstructured":"Zelba, H. et al. Case report: targeting of individual somatic tumor mutations by multipeptide vaccination tailored for HLA class I and II presentation induces strong CD4 and CD8 T-cell responses in a patient with metastatic castration sensitive prostate cancer. Front Immunol. 14, 1271449 (2023).","journal-title":"Front Immunol."},{"key":"1642_CR25","doi-asserted-by":"publisher","first-page":"580","DOI":"10.4049\/jimmunol.2000811","volume":"206","author":"H Zelba","year":"2021","unstructured":"Zelba, H. et al. A highly specific assay for the detection of SARS-CoV-2-reactive CD4(+) and CD8(+) T cells in COVID-19 patients. J. Immunol. 206, 580\u20137 (2021).","journal-title":"J. Immunol."}],"container-title":["npj Precision Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41698-026-01642-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41698-026-01642-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41698-026-01642-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T11:55:06Z","timestamp":1786190106000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41698-026-01642-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,8]]},"references-count":25,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["1642"],"URL":"https:\/\/doi.org\/10.1038\/s41698-026-01642-4","relation":{},"ISSN":["2397-768X"],"issn-type":[{"value":"2397-768X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,8]]},"assertion":[{"value":"24 September 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 July 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 August 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"C.K.W.D. has served on advisory boards for Boehringer Ingelheim and received lecture honoraria from PharmaMar. He has also received reimbursement for travel, accommodation, or conference registration from Boehringer Ingelheim, Sanofi, Lilly, Deciphera, and Pierre Fabre (all outside the submitted work). K.B. has received reimbursement for travel, accommodation, or conference registration from Boehringer Ingelheim, Pierre Fabre, Deciphera, and Lilly (all outside the submitted work). S.B. has ownership interests in CeGaT GmbH. F.B. and M.F. are employees of CeGaT GmbH. The remaining authors declare no competing financial or non-financial interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}],"article-number":"305"}}