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ABSTRACT In vivo persistence of chimeric antigen receptor (CAR)-modified T cells correlates with therapeutic efficacy, yet CAR-specific factors that support persistence are not well

resolved. Using a CD33-specific CAR in an acute myeloid leukemia (AML) model, we show how CAR expression alters T cell differentiation in a ligand independent manner. Ex vivo expanded CAR-T

cells demonstrated decreased naïve and stem memory populations and increased effector subsets relative to vector-transduced control cells. This was associated with reduced in vivo

persistence. Decreased persistence was not due to specificity or tumor presence, but to pre-transfer tonic signaling through the CAR CD3ζ ITAMs. We identified activation of the PI3K pathway

in CD33 CAR-T cells as responsible. Treatment with a PI3K inhibitor modulated the differentiation program of CAR-T cells, preserved a less differentiated state without affecting T cell

expansion, and improved in vivo persistence and reduced tumor burden. These results resolve mechanisms by which tonic signaling of CAR-T cells modulates their fate, and identifies a novel

pharmacologic approach to enhance the durability of CAR-T cells for immunotherapy. Access through your institution Buy or subscribe This is a preview of subscription content, access via your

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* Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS ANTIGEN EXPERIENCE HISTORY DIRECTS DISTINCT FUNCTIONAL STATES OF

CD8+ CAR T CELLS DURING THE ANTILEUKEMIA RESPONSE Article Open access 02 January 2025 COUNTERACTING CAR T CELL DYSFUNCTION Article Open access 14 January 2021 DECADE-LONG LEUKAEMIA

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phosphatidylinositol 3-kinase inhibitors. Curr Med Chem. 2009;16:2839–54. Article  CAS  Google Scholar  Download references ACKNOWLEDGEMENTS This research was supported by ALSAC/SJCRH, The

Assissi Foundation of Memphis, NCI Cancer Center Support Grant CA021765, and the Howard Hughes Medical Institute (JHB). The authors thank Richard Cross, Grieg Lennon, Parker Ingle, Tammar

Williams, and the SJCRH Blood Donor Center for assistance. AUTHOR INFORMATION Author notes * Carol E. O’Hear Present address: Genentech, Inc., South San Francisco, CA, USA AUTHORS AND

AFFILIATIONS * Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN, 38105, USA Wenting Zheng, Carol E. O’Hear, Rajshekhar Alli, Jacob H. Basham, Lindsay L. Jones 

& Terrence L. Geiger * Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN, 38105, USA Hossam A. Abdelsamed & Ben Youngblood * Department of Computational

Biology, St. Jude Children’s Research Hospital, Memphis, TN, 38105, USA Lance E. Palmer Authors * Wenting Zheng View author publications You can also search for this author inPubMed Google

Scholar * Carol E. O’Hear View author publications You can also search for this author inPubMed Google Scholar * Rajshekhar Alli View author publications You can also search for this author

inPubMed Google Scholar * Jacob H. Basham View author publications You can also search for this author inPubMed Google Scholar * Hossam A. Abdelsamed View author publications You can also

search for this author inPubMed Google Scholar * Lance E. Palmer View author publications You can also search for this author inPubMed Google Scholar * Lindsay L. Jones View author

publications You can also search for this author inPubMed Google Scholar * Ben Youngblood View author publications You can also search for this author inPubMed Google Scholar * Terrence L.

Geiger View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Terrence L. Geiger. ETHICS DECLARATIONS CONFLICT OF

INTEREST The authors declare that they have no conflict of interest. ELECTRONIC SUPPLEMENTARY MATERIAL SUPPLEMENTARY MATERIALS RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS

ARTICLE CITE THIS ARTICLE Zheng, W., O’Hear, C., Alli, R. _et al._ PI3K orchestration of the in vivo persistence of chimeric antigen receptor-modified T cells. _Leukemia_ 32, 1157–1167

(2018). https://doi.org/10.1038/s41375-017-0008-6 Download citation * Received: 02 August 2017 * Revised: 07 December 2017 * Accepted: 13 December 2017 * Published: 02 February 2018 * Issue

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