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Redirection of genetically engineered CAR-T cells using bifunctional small molecules

Academic Article
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Overview

authors

  • Kim, M. S.
  • Ma, J. S. Y.
  • Yun, H.
  • Cao, Y.
  • Kim, J. Y.
  • Chi, V.
  • Wang, D.
  • Woods, A.
  • Sherwood, L.
  • Caballero, D.
  • Gonzalez, J.
  • Schultz, Peter
  • Young, Travis Scott
  • Kim, C. H.

publication date

  • 2015

journal

  • Journal of the American Chemical Society  Journal

abstract

  • Chimeric antigen receptor (CAR)-engineered T cells (CAR-Ts) provide a potent antitumor response and have become a promising treatment option for cancer. However, despite their efficacy, CAR-T cells are associated with significant safety challenges related to the inability to control their activation and expansion and terminate their response. Herein, we demonstrate that a bifunctional small molecule "switch" consisting of folate conjugated to fluorescein isothiocyanate (folate-FITC) can redirect and regulate FITC-specific CAR-T cell activity toward folate receptor (FR)-overexpressing tumor cells. This system was shown to be highly cytotoxic to FR-positive cells with no activity against FR-negative cells, demonstrating the specificity of redirection by folate-FITC. Anti-FITC-CAR-T cell activation and proliferation was strictly dependent on the presence of both folate-FITC and FR-positive cells and was dose titratable with folate-FITC switch. This novel treatment paradigm may ultimately lead to increased safety for CAR-T cell immunotherapy.

subject areas

  • Cell Engineering
  • Fluorescein-5-isothiocyanate
  • Folic Acid
  • Folic Acid Transporters
  • HEK293 Cells
  • Humans
  • KB Cells
  • Receptors, Antigen, T-Cell
  • T-Lymphocytes
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Identity

International Standard Serial Number (ISSN)

  • 0002-7863

Digital Object Identifier (DOI)

  • 10.1021/jacs.5b00106

PubMed ID

  • 25692571
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Additional Document Info

start page

  • 2832

end page

  • 2835

volume

  • 137

issue

  • 8

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