Immunological Synapse Predicts Effectiveness of Chimeric Antigen Receptor Cells

Mol Ther. 2018 Apr 4;26(4):963-975. doi: 10.1016/j.ymthe.2018.01.020. Epub 2018 Mar 2.

Abstract

Chimeric antigen receptor (CAR)-modified T cell therapy has the potential to improve the overall survival of patients with malignancies by enhancing the effectiveness of CAR T cells. Precisely predicting the effectiveness of various CAR T cells represents one of today's key unsolved problems in immunotherapy. Here, we predict the effectiveness of CAR-modified cells by evaluating the quality of the CAR-mediated immunological synapse (IS) by quantitation of F-actin, clustering of tumor antigen, polarization of lytic granules (LGs), and distribution of key signaling molecules within the IS. Long-term killing capability, but not secretion of conventional cytokines or standard 4-hr cytotoxicity, correlates positively with the quality of the IS in two different CAR T cells that share identical antigen specificity. Xenograft model data confirm that the quality of the IS in vitro correlates positively with performance of CAR-modified immune cells in vivo. Therefore, we propose that the quality of the IS predicts the effectiveness of CAR-modified immune cells, which provides a novel strategy to guide CAR therapy.

Keywords: 4-1BB; CD19; Kappa; T cell; chimeric antigen receptor; immunological synapse; immunotherapy.

Publication types

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

MeSH terms

  • Animals
  • Antigens, CD19 / immunology
  • Antigens, Neoplasm / immunology
  • Biomarkers
  • Cell Line
  • Cytokines / metabolism
  • Cytotoxicity, Immunologic
  • Disease Models, Animal
  • Gene Expression
  • Gene Order
  • Genes, Reporter
  • Genetic Vectors / genetics
  • Humans
  • Immunological Synapses / immunology*
  • Immunological Synapses / metabolism*
  • Immunotherapy, Adoptive* / methods
  • Mice
  • Microscopy, Confocal
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / metabolism*
  • Receptors, Chimeric Antigen / genetics
  • Receptors, Chimeric Antigen / metabolism*
  • Retroviridae / genetics
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism*
  • Transduction, Genetic
  • Xenograft Model Antitumor Assays

Substances

  • Antigens, CD19
  • Antigens, Neoplasm
  • Biomarkers
  • Cytokines
  • Receptors, Antigen, T-Cell
  • Receptors, Chimeric Antigen