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.
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.
Center for Cell and Gene Therapy, Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX;
Yang
Y
Xu
Center for Cell and Gene Therapy.
Ming
M
Zhang
Center for Cell and Gene Therapy, Houston Methodist Hospital, Houston, TX; Department of Medicine, Baylor College of Medicine, Houston, TX;
Carlos A
CA
Ramos
Center for Cell and Gene Therapy.
April
A
Durett
Center for Cell and Gene Therapy.
Enli
E
Liu
Center for Cell and Gene Therapy.
Olga
O
Dakhova
Dan L. Duncan Cancer Center, Division of Biostatistics, Baylor College of Medicine, Houston, TX;
Hao
H
Liu
Dan L. Duncan Cancer Center, Division of Biostatistics, Baylor College of Medicine, Houston, TX;
Chad J
CJ
Creighton
Center for Cell and Gene Therapy, Department of Pediatrics, Baylor College of Medicine, Houston, TX; and.
Adrian P
AP
Gee
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.
Helen E
HE
Heslop
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.
Cliona M
CM
Rooney
Center for Cell and Gene Therapy, Department of Pediatrics, Baylor College of Medicine, Houston, TX; and Texas Children's Hospital, Houston, TX.
Barbara
B
Savoldo
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.
Gianpietro
G
Dotti
D019264:Adoptive Transfer / Q000379:methods; D053687:Adult Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology* / Q000637:transplantation; D000818:Animals; D018941:Antigens, CD19 / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D007156:Immunologic Memory; D019409:Interleukin-15 / Q000494:pharmacology*; D015851:Interleukin-7 / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects; D008223:Lymphoma / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D011946:Receptors, Antigen / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology* / Q000637:transplantation
D018941:Antigens, CD19; D019409:Interleukin-15; D015851:Interleukin-7; D011946:Receptors, Antigen; D011993:Recombinant Fusion Proteins