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Adoptive T-cell therapies, using expanded autologous T cells, have shown promise as an immunotherapeutic for patients with tumors characterized by high mutational burdens. However, this approach has not been shown to be effective in pediatric leukemias. In this study, we analyzed samples from pediatric patients with fusion-driven acute lymphoblastic, acute myeloid, and mixed phenotypic leukemias, including those with\n                    <jats:italic>KMT2A<\/jats:italic>\n                    -rearrangements. T cells were attained from bone marrow samples, expanded, and their reactivity against autologous leukemic blasts was tested. Strikingly, we observed leukemia-reactive T cells in nearly all patients (33 of 34) at diagnosis or relapse. Furthermore, some patients contained clones reactive to fusion neoantigens and other tumor-associated antigens, and candidate samples were further enriched by selecting for PD1\n                    <jats:sup>hi<\/jats:sup>\n                    and CD39\n                    <jats:sup>+<\/jats:sup>\n                    T-cell populations. These clones were only present at the initial diagnostic timepoint and could not be detected at later times after treatment, even with deep sequence profiling. Altogether, our data suggest that adoptive T cell therapy, using expanded leukemia-reactive T cells identified at diagnosis, has potential as a novel therapeutic for these patients.\n                  <\/jats:p>","DOI":"10.1038\/s41375-025-02710-7","type":"journal-article","created":{"date-parts":[[2025,7,24]],"date-time":"2025-07-24T08:06:58Z","timestamp":1753344418000},"page":"2419-2431","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Endogenous T cell responses to fusion-derived neoantigens in pediatric acute leukemias"],"prefix":"10.1038","volume":"39","author":[{"given":"Ricky","family":"Tirtakusuma","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9404-2698","authenticated-orcid":false,"given":"Mohamed A.","family":"Ghonim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6860-5079","authenticated-orcid":false,"given":"Stefan","family":"Schattgen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bradley","family":"Muller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee Ann","family":"Van de Velde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanya M.","family":"Khan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4096-6048","authenticated-orcid":false,"given":"Jeremy Chase","family":"Crawford","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sherif","family":"Abdelhamed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kasi","family":"Vegesana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walid","family":"Awad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. 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