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. 2014 Jun 12;123(24):3750-9. doi: 10.1182/blood-2014-01-552174.
Yang Xu  1 ,  Ming Zhang  2 ,  Carlos A Ramos  3 ,  April Durett  2 ,  Enli Liu  2 ,  Olga Dakhova  2 ,  Hao Liu  4 ,  Chad J Creighton  4 ,  Adrian P Gee  5 ,  Helen E Heslop  6 ,  Cliona M Rooney  7 ,  Barbara Savoldo  8 ,  Gianpietro Dotti  9
Affiliations
  • 1. Center for Cell and Gene Therapy, Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX;
  • 2. Center for Cell and Gene Therapy.
  • 3. Center for Cell and Gene Therapy, Houston Methodist Hospital, Houston, TX; Department of Medicine, Baylor College of Medicine, Houston, TX;
  • 4. Dan L. Duncan Cancer Center, Division of Biostatistics, Baylor College of Medicine, Houston, TX;
  • 5. Center for Cell and Gene Therapy, Department of Pediatrics, Baylor College of Medicine, Houston, TX; and.
  • 6. Center for Cell and Gene Therapy, Houston Methodist Hospital, Houston, TX; Department of Medicine, Baylor College of Medicine, Houston, TX; Department of Pediatrics, Baylor College of Medicine, Houston, TX; and Texas Children's Hospital, Houston, TX.
  • 7. Center for Cell and Gene Therapy, Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX; Department of Pediatrics, Baylor College of Medicine, Houston, TX; and Texas Children's Hospital, Houston, TX.
  • 8. Center for Cell and Gene Therapy, Department of Pediatrics, Baylor College of Medicine, Houston, TX; and Texas Children's Hospital, Houston, TX.
  • 9. Center for Cell and Gene Therapy, Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX; Department of Medicine, Baylor College of Medicine, Houston, TX; Texas Children's Hospital, Houston, TX.
PMID: 24782509 DOI: 10.1182/blood-2014-01-552174
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, and found 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.

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