Development of CAR T Cells Expressing a Suicide Gene Plus a Chimeric Antigen Receptor Targeting Signaling Lymphocytic-Activation Molecule F7

Mol Ther. 2021 Feb 3;29(2):702-717. doi: 10.1016/j.ymthe.2020.10.008. Epub 2020 Oct 14.

Abstract

Chimeric antigen receptors (CARs) are fusion proteins that contain antigen-recognition domains and T cell signaling domains. Signaling lymphocytic-activation molecule F7 (SLAMF7) is a promising target for CAR T cell therapies of the plasma cell malignancy multiple myeloma (MM) because SLAMF7 is expressed by MM but not normal nonhematopoietic cells. We designed CARs targeting SLAMF7. We transduced human T cells with anti-SLAMF7 CARs containing either CD28 or 4-1BB costimulatory domains. T cells expressing CD28-containing CARs or 4-1BB-containing CARs recognized SLAMF7 in vitro. SLAMF7-specific cytokine release was higher for T cells expressing CARs with CD28 versus 4-1BB domains. In murine solid tumor and disseminated tumor models, anti-tumor activity of T cells was superior with CD28-containing CARs versus 4-1BB-containing CARs. Because of SLAMF7 expression on some normal leukocytes, especially natural killer cells that control certain viral infections, the inclusion of a suicide gene with an anti-SLAMF7 CAR is prudent. We designed a construct with a CD28-containing anti-SLAMF7 CAR and a suicide gene. The suicide gene encoded a dimerization domain fused to a caspase-9 domain. T cells expressing the anti-SLAMF7 CAR plus suicide-gene construct specifically recognized SLAMF7 in vitro and eliminated tumors from mice. T cells expressing this construct were eliminated on demand by administering the dimerizing agent AP1903 (rimiducid).

Keywords: 4-1BB; CAR; CAR T cells; CD28; CD319; SLAMF7; T cell therapy; immunotherapy; multiple myeloma; suicide gene.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Disease Models, Animal
  • Gene Expression*
  • Genes, Transgenic, Suicide / genetics*
  • Humans
  • Immunotherapy, Adoptive* / methods
  • Mice
  • Multiple Myeloma / immunology
  • Multiple Myeloma / therapy
  • Receptors, Chimeric Antigen / genetics
  • Receptors, Chimeric Antigen / immunology*
  • Signaling Lymphocytic Activation Molecule Family / antagonists & inhibitors*
  • Signaling Lymphocytic Activation Molecule Family / immunology
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism*
  • Xenograft Model Antitumor Assays

Substances

  • Receptors, Chimeric Antigen
  • SLAMF7 protein, human
  • Signaling Lymphocytic Activation Molecule Family