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Author Notes:

Correspondence: Edmund K. Waller, Winship Cancer Institute, Emory University School of Medicine, 1365B Clifton Rd NE, Room B519, Atlanta, GA 30322; e-mail: ewaller@emory.edu.

Contribution: C.T.P. designed and performed research, analyzed data, and wrote the manuscript

M.H. performed research and analyzed data

A.B.M. designed and performed research and analyzed data

J.J. performed research and analyzed data

K.L. analyzed data

N.J. analyzed data

A.D.S. analyzed data and helped obtain samples

S.S.R. designed and performed research and analyzed data

H.T.S. designed research

T.S. helped fund the study and reviewed the data

C.R.F. helped obtain samples and edited the manuscript

E.K.W. designed research and wrote the manuscript.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

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Research Funding:

This study was supported by the Coulter Foundation (project 60934), the Katz Foundation (Principal Investigator, E.K.W.), and the National Institutes of Health, National Institute of General Medical Sciences (MARC program T34GM105550).

Improving T-cell expansion and function for adoptive T-cell therapy using ex vivo treatment with PI3Kδ inhibitors and VIP antagonists.

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Journal Title:

Blood Advances

Volume:

Volume 2, Number 3

Publisher:

, Pages 210-223

Type of Work:

Article | Final Publisher PDF

Abstract:

Adoptive therapy with ex vivo-expanded genetically modified antigen-specific T cells can induce remissions in patients with relapsed/refractory cancer. The clinical success of this therapy depends upon efficient transduction and expansion of T cells ex vivo and their homing, persistence and cytotoxicity following reinfusion. Lower rates of ex vivo expansion and clinical response using anti-CD19 chimeric antigen receptor (CAR) T cells have been seen in heavily pretreated lymphoma patients compared with B-cell acute lymphoblastic leukemia patients and motivate the development of novel strategies to enhance ex vivo T cell expansion and their persistence in vivo. We demonstrate that inhibition of phosphatidylinositol 3-kinase δ (PI3Kδ) and antagonism of vasoactive intestinal peptide (VIP) signaling partially inhibits the terminal differentiation of T cells during anti-CD3/CD28 bead-mediated expansion (mean, 54.4% CD27+CD28+T cells vs 27.4% in control cultures;P< .05). This strategy results in a mean of 83.7% more T cells cultured from lymphoma patients in the presence of PI3Kδ and VIP antagonists, increased survival of human T cells from a lymphoma patient in a murine xenograft model, enhanced cytotoxic activity of antigen-specific human CAR T cells and murine T cells against lymphoma, and increased transduction and expansion of anti-CD5 human CAR T cells. PI3Kδ and VIP antagonist-expanded T cells from lymphoma patients show reduced terminal differentiation, enhanced polyfunctional cytokine expression, and preservation of costimulatory molecule expression. Taken together, synergistic blockade of these pathways is an attractive strategy to enhance the expansion and functional capacity of ex vivo-expanded cancer-specific T cells.

Copyright information:

© 2018 by The American Society of Hematology

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