{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T08:13:27Z","timestamp":1790842407560,"version":"4.1.0"},"reference-count":57,"publisher":"BMJ","issue":"9","license":[{"start":{"date-parts":[[2023,9,11]],"date-time":"2023-09-11T00:00:00Z","timestamp":1694390400000},"content-version":"unspecified","delay-in-days":10,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"NIHR Blood and Transplant Research Unit","award":["IS-BTU-0214-10074"],"award-info":[{"award-number":["IS-BTU-0214-10074"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2023,7,27]]},"published-print":{"date-parts":[[2023,9]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>AUTO1 is a fast off-rate CD19-targeting chimeric antigen receptor (CAR), which has been successfully tested in adult lymphoblastic leukemia. Tscm\/Tcm-enriched CAR-T populations confer the best expansion and persistence, but Tscm\/Tcm numbers are poor in heavily pretreated adult patients. To improve this, we evaluate the use of AKT inhibitor (VIII) with the aim of uncoupling T-cell expansion from differentiation, to enrich Tscm\/Tcm subsets.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>VIII was incorporated into the AUTO1 manufacturing process based on the semiautomated the CliniMACS Prodigy platform at both small and cGMP scale.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>AUTO1 manufactured with VIII showed Tscm\/Tcm enrichment, improved expansion and cytotoxicity in vitro and superior antitumor activity in vivo. Further, VIII induced AUTO1 Th1\/Th17 skewing, increased polyfunctionality, and conferred a unique metabolic profile and a novel signature for autophagy to support enhanced expansion and cytotoxicity. We show that VIII-cultured AUTO1 products from B-ALL patients on the ALLCAR19 study possess superior phenotype, metabolism, and function than parallel control products and that VIII-based manufacture is scalable to cGMP.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Ultimately, AUTO1 generated with VIII may begin to overcome the product specific factors contributing to CD19+relapse.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2023-007002","type":"journal-article","created":{"date-parts":[[2023,9,14]],"date-time":"2023-09-14T01:00:15Z","timestamp":1694653215000},"page":"e007002","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":29,"title":["AKT inhibition generates potent polyfunctional clinical grade AUTO1 CAR T-cells, enhancing function and 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