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Immunotherapy

PI3K orchestration of the in vivo persistence of chimeric antigen receptor-modified T cells

Leukemia volume 32, pages 1157–1167 (2018)Cite this article

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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.

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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.

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Author notes

  1. Carol E. O’Hear

    Present address: Genentech, Inc., South San Francisco, CA, USA

Authors and Affiliations

  1. 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

  2. Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN, 38105, USA

    Hossam A. Abdelsamed & Ben Youngblood

  3. Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, TN, 38105, USA

    Lance E. Palmer

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Correspondence to Terrence L. Geiger.

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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

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