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

Y Xu, M Zhang, CA Ramos, A Durett… - Blood, The Journal …, 2014 - ashpublications.org
Y Xu, M Zhang, CA Ramos, A Durett, E Liu, O Dakhova, H Liu, CJ Creighton, AP Gee…
Blood, The Journal of the American Society of Hematology, 2014ashpublications.org
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 …
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.
ashpublications.org