{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T20:27:23Z","timestamp":1793478443175,"version":"4.5.0"},"reference-count":44,"publisher":"American Society for Clinical Investigation","issue":"7","license":[{"start":{"date-parts":[[2024,4,8]],"date-time":"2024-04-08T00:00:00Z","timestamp":1712534400000},"content-version":"vor","delay-in-days":46,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["1R35NS105068"],"award-info":[{"award-number":["1R35NS105068"]}]},{"name":"Panattoni Family Foundation","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"DOI":"10.13039\/100014547","name":"Parker Institute for Cancer Immunotherapy","doi-asserted-by":"crossref","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100014547","id-type":"DOI","asserted-by":"crossref"}]},{"name":"JSPS","award":["Overseas Research Fellowships"],"award-info":[{"award-number":["Overseas Research Fellowships"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,4,8]]},"abstract":"<jats:p>\n                    The efficacy of chimeric antigen receptor T cell (CAR-T) therapy has been limited against brain tumors to date. CAR-T cells infiltrating syngeneic intracerebral SB28 EGFRvIII gliomas revealed impaired mitochondrial ATP production and a markedly hypoxic status compared with ones migrating to subcutaneous tumors. Drug screenings to improve metabolic states of T cells under hypoxic conditions led us to evaluate the combination of the AMPK activator metformin and the mTOR inhibitor rapamycin (Met+Rap). Met+Rap\u2013pretreated mouse CAR-T cells showed activated PPAR-\u03b3 coactivator 1\u03b1 (PGC-1\u03b1) through mTOR inhibition and AMPK activation, and a higher level of mitochondrial spare respiratory capacity than those pretreated with individual drugs or without pretreatment. Moreover, Met+Rap\u2013pretreated CAR-T cells demonstrated persistent and effective antiglioma cytotoxic activities in the hypoxic condition. Furthermore, a single intravenous infusion of Met+Rap\u2013pretreated CAR-T cells significantly extended the survival of mice bearing intracerebral SB28 EGFRvIII gliomas. Mass cytometric analyses highlighted increased glioma-infiltrating CAR-T cells in the Met+Rap group, with fewer Ly6c\n                    <jats:sup>+<\/jats:sup>\n                    CD11b\n                    <jats:sup>+<\/jats:sup>\n                    monocytic myeloid-derived suppressor cells in the tumors. Finally, human CAR-T cells pretreated with Met+Rap recapitulated the observations with murine CAR-T cells, demonstrating improved functions under in vitro hypoxic conditions. These findings advocate for translational and clinical exploration of Met+Rap\u2013pretreated CAR-T cells in human trials.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.177141","type":"journal-article","created":{"date-parts":[[2024,2,22]],"date-time":"2024-02-22T12:00:37Z","timestamp":1708603237000},"source":"Crossref","is-referenced-by-count":57,"title":["Enhancing CAR-T cell metabolism to overcome hypoxic conditions in the brain tumor microenvironment"],"prefix":"10.1172","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5636-8064","authenticated-orcid":true,"given":"Ryusuke","family":"Hatae","sequence":"first","affiliation":[{"name":"Department of Neurological Surgery,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith","family":"Kyewalabye","sequence":"additional","affiliation":[{"name":"Department of Neurological 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