CAR T cell manufacturing from naive/stem memory T lymphocytes enhances antitumor responses while curtailing cytokine release syndrome

J Clin Invest. 2022 Jun 15;132(12):e150807. doi: 10.1172/JCI150807.


Chimeric antigen receptor (CAR) T cell expansion and persistence represent key factors to achieve complete responses and prevent relapses. These features are typical of early memory T cells, which can be highly enriched through optimized manufacturing protocols. Here, we investigated the efficacy and safety profiles of CAR T cell products generated from preselected naive/stem memory T cells (TN/SCM), as compared with unselected T cells (TBULK). Notwithstanding their reduced effector signature in vitro, limiting CAR TN/SCM doses showed superior antitumor activity and the unique ability to counteract leukemia rechallenge in hematopoietic stem/precursor cell-humanized mice, featuring increased expansion rates and persistence together with an ameliorated exhaustion and memory phenotype. Most relevantly, CAR TN/SCM proved to be intrinsically less prone to inducing severe cytokine release syndrome, independently of the costimulatory endodomain employed. This safer profile was associated with milder T cell activation, which translated into reduced monocyte activation and cytokine release. These data suggest that CAR TN/SCM are endowed with a wider therapeutic index compared with CAR TBULK.

Keywords: Cancer immunotherapy; Immunology; Immunotherapy; T cells; Therapeutics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytokine Release Syndrome
  • Immunotherapy, Adoptive / methods
  • Interleukin-15
  • Memory T Cells
  • Mice
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Chimeric Antigen* / genetics


  • Interleukin-15
  • Receptors, Antigen, T-Cell
  • Receptors, Chimeric Antigen

Grants and funding

N. 667980 (CARAT to M.C.), N. 754658 (CARAMBA to M.C. and F.C.)