Biasco, L;
Izotova, N;
Rivat, C;
Ghorashian, S;
Richardson, R;
Guvenel, A;
Hough, R;
... Amrolia, PJ; + view all
(2021)
Clonal expansion of T memory stem cells determines early anti-leukemic responses and long-term CAR T cell persistence in patients.
Nature Cancer
, 2
pp. 629-64.
10.1038/s43018-021-00207-7.
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Abstract
Low-affinity CD19 chimeric antigen receptor (CAR) T cells display enhanced expansion and persistence, enabling fate tracking through integration site analysis. Here we show that integration sites from early (1 month) and late (>3 yr) timepoints cluster separately, suggesting different clonal contribution to early responses and prolonged anti-leukemic surveillance. CAR T central and effector memory cells in patients with long-term persistence remained highly polyclonal, whereas diversity dropped rapidly in patients with limited CAR T persistence. Analysis of shared integrants between the CAR T cell product and post-infusion demonstrated that, despite their low frequency, T memory stem cell clones in the product contributed substantially to the circulating CAR T cell pools, during both early expansion and long-term persistence. Our data may help identify patients at risk of early loss of CAR T cells and highlight the critical role of T memory stem cells both in mediating early anti-leukemic responses and in long-term surveillance by CAR T cells.
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