{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T13:36:51Z","timestamp":1785418611929,"version":"3.56.0"},"posted":{"date-parts":[[2025,10,24]]},"group-title":"Immunology","reference-count":40,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,10,24]],"date-time":"2025-10-24T00:00:00Z","timestamp":1761264000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["P30CA033572"],"award-info":[{"award-number":["P30CA033572"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"award":["5K12CA001727\u201329"],"award-info":[{"award-number":["5K12CA001727\u201329"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/01f6q3121","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Margaret E. Early Medical Research Trust Award"},{"name":"Norman and Sadie Lee Foundation"},{"DOI":"10.13039\/100027093","name":"Albert and Bettie Sacchi Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100027093","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,10,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Although most patients with relapsed\/refractory B-cell acute lymphoblastic leukemia (B-ALL) receiving CD19-targeted chimeric antigen receptor (CAR) T cell therapy achieve remission, loss of CAR T cell functionality and subsequent relapse remains an unmet therapeutic need. We applied an integrative approach to study the immunometabolism of pre- and post-infusion CD19-CAR T cells of patients with relapsed\/refractory B-ALL. Pre-infusion CAR T cells of long-term responders (LTR) had increased oxidative phosphorylation, fatty acid oxidation, and pentose phosphate pathway activities, higher mitochondrial mass, tighter cristae, and lower mTOR expression compared to products of short-term responders. Post-infusion CAR T cells in bone marrow (BM) of LTR had high immunometabolic plasticity and mTOR-pS6 expression supported by the BM microenvironment. Transient inhibition of mTOR during manufacture induced metabolic reprogramming and enhanced anti-tumor activity of CAR T cells. Our findings provide insight into immunometabolic determinants of long-term response and suggest a therapeutic strategy to improve long-term remission.<\/jats:p>","DOI":"10.1101\/2025.10.23.684261","type":"posted-content","created":{"date-parts":[[2025,10,25]],"date-time":"2025-10-25T04:00:15Z","timestamp":1761364815000},"source":"Crossref","is-referenced-by-count":0,"title":["Immunometabolic determinants of long-term response in leukemia patients receiving CD19 CAR T cell therapy"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1643-7616","authenticated-orcid":false,"given":"Lior","family":"Goldberg","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric R.","family":"Haas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqi","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan","family":"Garcia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5289-5000","authenticated-orcid":false,"given":"Ryan","family":"Urak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vibhuti","family":"Vyas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruby","family":"Espinosa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamara","family":"Munoz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shirley","family":"Bierkatz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khyatiben V.","family":"Pathak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathaniel P.","family":"Hansen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Pirrotte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jyotsana","family":"Singhal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James L.","family":"Figarola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo Zerda","family":"Noriega","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuo","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dasol","family":"Wi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin","family":"Tanaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramon","family":"Klein Geltink","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min-Hsuan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiwei","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamie R.","family":"Wagner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinny","family":"Paul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1672-2684","authenticated-orcid":false,"given":"Mary C.","family":"Clark","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dat","family":"Ngo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ibrahim","family":"Aldoss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen J.","family":"Forman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuli","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025102901534726000_2025.10.23.684261v1.1","doi-asserted-by":"crossref","first-page":"2182","DOI":"10.1182\/bloodadvances.2024012885","article-title":"Reinfusion of CD19 CAR T cells for relapse prevention and treatment in children with acute lymphoblastic leukemia","volume":"8","year":"2024","journal-title":"Blood Adv"},{"key":"2025102901534726000_2025.10.23.684261v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-019-0203-y"},{"key":"2025102901534726000_2025.10.23.684261v1.3","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1158\/1078-0432.CCR-22-2038","article-title":"Favorable Activity and Safety Profile of Memory-Enriched CD19-Targeted Chimeric Antigen Receptor T-Cell Therapy in Adults with High-Risk Relapsed\/Refractory ALL","volume":"29","year":"2023","journal-title":"Clin Cancer Res"},{"key":"2025102901534726000_2025.10.23.684261v1.4","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1158\/0008-5472.CAN-23-2299","article-title":"Immunometabolic Adaptation of CD19-Targeted CAR T Cells in the Central Nervous System Microenvironment of Patients Promotes Memory Development","volume":"84","year":"2024","journal-title":"Cancer Res"},{"key":"2025102901534726000_2025.10.23.684261v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.05.035"},{"key":"2025102901534726000_2025.10.23.684261v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.08.018"},{"key":"2025102901534726000_2025.10.23.684261v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2011.12.007"},{"key":"2025102901534726000_2025.10.23.684261v1.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.08.029"},{"key":"2025102901534726000_2025.10.23.684261v1.9","doi-asserted-by":"crossref","first-page":"e2655","DOI":"10.1038\/cddis.2016.222","article-title":"Amino-acid transporters in T-cell activation and differentiation","volume":"8","year":"2017","journal-title":"Cell Death Dis"},{"key":"2025102901534726000_2025.10.23.684261v1.10","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-022-01301-3"},{"key":"2025102901534726000_2025.10.23.684261v1.11","doi-asserted-by":"publisher","DOI":"10.1002\/cyto.a.23724"},{"key":"2025102901534726000_2025.10.23.684261v1.12","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-020-0651-8"},{"key":"2025102901534726000_2025.10.23.684261v1.13","doi-asserted-by":"crossref","first-page":"653605","DOI":"10.3389\/fimmu.2021.653605","article-title":"Control of T Cell Metabolism by Cytokines and Hormones","volume":"12","year":"2021","journal-title":"Front Immunol"},{"key":"2025102901534726000_2025.10.23.684261v1.14","first-page":"1","article-title":"Nutrients: Signal 4 in T cell immunity","volume":"22","year":"2024","journal-title":"J Exp Med"},{"key":"2025102901534726000_2025.10.23.684261v1.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2017.01.014"},{"key":"2025102901534726000_2025.10.23.684261v1.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2024.01.002"},{"key":"2025102901534726000_2025.10.23.684261v1.17","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1038\/s42255-022-00730-6","article-title":"Extracellular acidosis restricts one-carbon metabolism and preserves T cell stemness","volume":"5","year":"2023","journal-title":"Nat Metab"},{"key":"2025102901534726000_2025.10.23.684261v1.18","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2015.11.002"},{"key":"2025102901534726000_2025.10.23.684261v1.19","doi-asserted-by":"crossref","first-page":"2120","DOI":"10.1056\/NEJMe2405538","article-title":"T-Cell Cancer after CAR T-Cell Therapy","volume":"390","year":"2024","journal-title":"N Engl J Med"},{"key":"2025102901534726000_2025.10.23.684261v1.20","doi-asserted-by":"crossref","first-page":"1884","DOI":"10.1038\/s41590-024-01963-1","article-title":"Deficiency of metabolic regulator PKM2 activates the pentose phosphate pathway and generates TCF1(+) progenitor CD8(+) T cells to improve immunotherapy","volume":"25","year":"2024","journal-title":"Nat Immunol"},{"key":"2025102901534726000_2025.10.23.684261v1.21","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1038\/s43018-024-00768-3","article-title":"Identification of a clinically efficacious CAR T cell subset in diffuse large B cell lymphoma by dynamic multidimensional single-cell profiling","volume":"5","year":"2024","journal-title":"Nat Cancer"},{"key":"2025102901534726000_2025.10.23.684261v1.22","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07762-w"},{"key":"2025102901534726000_2025.10.23.684261v1.23","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-04390-6"},{"key":"2025102901534726000_2025.10.23.684261v1.24","doi-asserted-by":"crossref","first-page":"1635","DOI":"10.1007\/s00262-020-02804-4","article-title":"BRAF and MEK inhibition in melanoma patients enables reprogramming of tumor infiltrating lymphocytes","volume":"70","year":"2021","journal-title":"Cancer Immunol Immunother"},{"key":"2025102901534726000_2025.10.23.684261v1.25","doi-asserted-by":"crossref","unstructured":"Weber, E.W. , et al. Transient rest restores functionality in exhausted CAR-T cells through epigenetic remodeling. Science 372(2021).","DOI":"10.1126\/science.aba1786"},{"key":"2025102901534726000_2025.10.23.684261v1.26","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-023-01791-5"},{"key":"2025102901534726000_2025.10.23.684261v1.27","doi-asserted-by":"crossref","unstructured":"Aldoss, I. , et al. Favorable Activity and Safety Profile of Memory-Enriched CD19-Targeted Chimeric Antigen Receptor T Cell Therapy in Adults with high-risk Relapsed\/Refractory ALL. Clin Cancer Res (2022).","DOI":"10.1158\/1078-0432.c.6533177.v1"},{"key":"2025102901534726000_2025.10.23.684261v1.28","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-41167-z"},{"key":"2025102901534726000_2025.10.23.684261v1.29","doi-asserted-by":"publisher","DOI":"10.1021\/acs.analchem.8b05592"},{"key":"2025102901534726000_2025.10.23.684261v1.30","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-59745-294-6_2"},{"key":"2025102901534726000_2025.10.23.684261v1.31","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2089"},{"key":"2025102901534726000_2025.10.23.684261v1.32","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu170"},{"key":"2025102901534726000_2025.10.23.684261v1.33","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bty560"},{"key":"2025102901534726000_2025.10.23.684261v1.34","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts635"},{"key":"2025102901534726000_2025.10.23.684261v1.35","doi-asserted-by":"crossref","unstructured":"Anders, S. & Huber, W . Differential expression analysis for sequence count data. Genome Biol 11, R106 (2010).","DOI":"10.1186\/gb-2010-11-10-r106"},{"key":"2025102901534726000_2025.10.23.684261v1.36","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp616"},{"key":"2025102901534726000_2025.10.23.684261v1.37","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2011.0118"},{"key":"2025102901534726000_2025.10.23.684261v1.38","first-page":"100722","article-title":"Thirteen years of clusterProfiler","volume":"5","year":"2024","journal-title":"Innovation (Camb"},{"key":"2025102901534726000_2025.10.23.684261v1.39","doi-asserted-by":"publisher","DOI":"10.1038\/s41596-024-01020-z"},{"key":"2025102901534726000_2025.10.23.684261v1.40","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv1042"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.10.23.684261","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T05:07:41Z","timestamp":1782277661000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.10.23.684261"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,24]]},"references-count":40,"URL":"https:\/\/doi.org\/10.1101\/2025.10.23.684261","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1038\/s41467-026-69857-4","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2025,10,24]]},"subtype":"preprint"}}