Distinct cellular dynamics associated with response to CAR-T therapy for refractory B cell lymphoma

Nat Med. 2022 Sep;28(9):1848-1859. doi: 10.1038/s41591-022-01959-0. Epub 2022 Sep 12.


Chimeric antigen receptor (CAR)-T cell therapy has revolutionized the treatment of hematologic malignancies. Approximately half of patients with refractory large B cell lymphomas achieve durable responses from CD19-targeting CAR-T treatment; however, failure mechanisms are identified in only a fraction of cases. To gain new insights into the basis of clinical response, we performed single-cell transcriptome sequencing of 105 pretreatment and post-treatment peripheral blood mononuclear cell samples, and infusion products collected from 32 individuals with large B cell lymphoma treated with either of two CD19 CAR-T products: axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel). Expansion of proliferative memory-like CD8 clones was a hallmark of tisa-cel response, whereas axi-cel responders displayed more heterogeneous populations. Elevations in CAR-T regulatory cells among nonresponders to axi-cel were detected, and these populations were capable of suppressing conventional CAR-T cell expansion and driving late relapses in an in vivo model. Our analyses reveal the temporal dynamics of effective responses to CAR-T therapy, the distinct molecular phenotypes of CAR-T cells with differing designs, and the capacity for even small increases in CAR-T regulatory cells to drive relapse.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Antigens, CD19
  • Biological Products*
  • Humans
  • Immunotherapy, Adoptive / adverse effects
  • Leukocytes, Mononuclear
  • Lymphoma, Large B-Cell, Diffuse* / pathology
  • Neoplasm Recurrence, Local / drug therapy
  • Receptors, Chimeric Antigen* / genetics


  • Antigens, CD19
  • Biological Products
  • Receptors, Chimeric Antigen