Clonal expansion of T memory stem cells determines early anti-leukemic responses and long-term CAR T cell persistence in patients

Nat Cancer. 2021 Jun;2(6):629-642. doi: 10.1038/s43018-021-00207-7. Epub 2021 May 24.

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 (>3yr) 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD19
  • Humans
  • Immunotherapy, Adoptive / adverse effects
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Chimeric Antigen* / genetics
  • Stem Cells

Substances

  • Antigens, CD19
  • Receptors, Antigen, T-Cell
  • Receptors, Chimeric Antigen