Closely related T-memory stem cells correlate with in vivo expansion of CAR.CD19-T cells and are preserved by IL-7 and IL-15

Yang Xu, Ming Zhang, Carlos A. Ramos, April Durett, Enli Liu, Olga Dakhova, Hao Liu, Chad J. Creighton, Adrian P. Gee, Helen E. Heslop, Cliona M. Rooney, Barbara Savoldo, Gianpietro Dotti

Research output: Contribution to journalArticle

230 Scopus citations

Abstract

Adoptive transfer of T lymphocytes expressing a CD19-specific chimeric antigen receptor (CAR.CD19) induces complete tumor regression in patients with lymphoid malignancies. Although in vivo persistence of CAR-T cells correlates with clinical responses, it remains unknown whether specific cell subsets within the CAR-T-cell product correlate with their subsequent in vivo expansion and persistence. We analyzed 14 patients with B-cell malignancies infused with autologous CAR.CD19-redirected T cells expanded ex vivo using IL-2,andfound that their in vivo expansion only correlated with the frequency within the infused product of a CD8+CD45RA+CCR7+ subset, whose phenotype is closest to "T-memory stem cells." Preclinical models showed that increasing the frequency of CD8+ CD45RA +CCR7+ CAR-T cells in the infused line by culturing the cells with IL-7 and IL-15 produced greater antitumor activity of CAR-T cells mediated by increased resistance to cell death, following repetitive encounters with the antigen, while preserving their migration to secondary lymphoid organs. This trial was registered at www.clinicaltrials.gov as #NCT00586391 and #NCT00709033.

Original languageEnglish (US)
Pages (from-to)3750-3759
Number of pages10
JournalBlood
Volume123
Issue number24
DOIs
StatePublished - Jun 12 2014

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Xu, Y., Zhang, M., Ramos, C. A., Durett, A., Liu, E., Dakhova, O., Liu, H., Creighton, C. J., Gee, A. P., Heslop, H. E., Rooney, C. M., Savoldo, B., & Dotti, G. (2014). Closely related T-memory stem cells correlate with in vivo expansion of CAR.CD19-T cells and are preserved by IL-7 and IL-15. Blood, 123(24), 3750-3759. https://doi.org/10.1182/blood-2014-01-552174