An anti-CD19/CTLA-4 switch improves efficacy and selectivity of CAR T cells targeting CD80/86-upregulated DLBCL

Cell Rep Med. 2024 Feb 20;5(2):101421. doi: 10.1016/j.xcrm.2024.101421. Epub 2024 Feb 9.

Abstract

Chimeric antigen receptor T cell (CAR T) therapy is a potent treatment for relapsed/refractory (r/r) B cell lymphomas but provides lasting remissions in only ∼40% of patients and is associated with serious adverse events. We identify an upregulation of CD80 and/or CD86 in tumor tissue of (r/r) diffuse large B cell lymphoma (DLBCL) patients treated with tisagenlecleucel. This finding leads to the development of the CAR/CCR (chimeric checkpoint receptor) design, which consists of a CD19-specific first-generation CAR co-expressed with a recombinant CTLA-4-linked receptor with a 4-1BB co-stimulatory domain. CAR/CCR T cells demonstrate superior efficacy in xenograft mouse models compared with CAR T cells, superior long-term activity, and superior selectivity in in vitro assays with non-malignant CD19+ cells. In addition, immunocompetent mice show an intact CD80-CD19+ B cell population after CAR/CCR T cell treatment. The results reveal the CAR/CCR design as a promising strategy for further translational study.

Keywords: CAR T cells; CD19; CD80; CD86; DLBCL; FL; checkpoint ligand; chimeric checkpoint receptor; lymphoma; neurotoxicity.

MeSH terms

  • Animals
  • Antigens, CD19 / genetics
  • B-Lymphocytes
  • CTLA-4 Antigen
  • Humans
  • Immunotherapy, Adoptive / methods
  • Lymphoma, Large B-Cell, Diffuse* / etiology
  • Lymphoma, Large B-Cell, Diffuse* / therapy
  • Mice
  • T-Lymphocytes*

Substances

  • CTLA-4 Antigen
  • Antigens, CD19