Enhanced Anti-lymphoma Activity of CAR19-iNKT Cells Underpinned by Dual CD19 and CD1d Targeting

Cancer Cell. 2018 Oct 8;34(4):596-610.e11. doi: 10.1016/j.ccell.2018.08.017.

Abstract

Chimeric antigen receptor anti-CD19 (CAR19)-T cell immunotherapy-induced clinical remissions in CD19+ B cell lymphomas are often short lived. We tested whether CAR19-engineering of the CD1d-restricted invariant natural killer T (iNKT) cells would result in enhanced anti-lymphoma activity. CAR19-iNKT cells co-operatively activated by CD1d- and CAR19-CD19-dependent interactions are more effective than CAR19-T cells against CD1d-expressing lymphomas in vitro and in vivo. The swifter in vivo anti-lymphoma activity of CAR19-iNKT cells and their enhanced ability to eradicate brain lymphomas underpinned an improved tumor-free and overall survival. CD1D transcriptional de-repression by all-trans retinoic acid results in further enhanced cytotoxicity of CAR19-iNKT cells against CD19+ chronic lymphocytic leukemia cells. Thus, iNKT cells are a highly efficient platform for CAR-based immunotherapy of lymphomas and possibly other CD1d-expressing cancers.

Keywords: B cell malignancies; CAR immunotherapy; iNKT.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD19 / genetics
  • Antigens, CD19 / immunology
  • Antigens, CD1d / genetics*
  • Antigens, CD1d / immunology
  • Cell- and Tissue-Based Therapy*
  • Humans
  • Immunotherapy / methods
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics
  • Leukemia, Lymphocytic, Chronic, B-Cell / immunology
  • Lymphoma / drug therapy*
  • Lymphoma / immunology
  • Mice
  • Natural Killer T-Cells / cytology*
  • Natural Killer T-Cells / immunology

Substances

  • Antigens, CD19
  • Antigens, CD1d
  • CD1D protein, human