Cancer Cell
Volume 34, Issue 4, 8 October 2018, Pages 596-610.e11
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Article
Enhanced Anti-lymphoma Activity of CAR19-iNKT Cells Underpinned by Dual CD19 and CD1d Targeting

https://doi.org/10.1016/j.ccell.2018.08.017Get rights and content
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Highlights

  • Bespoke protocol for CAR19-iNKT cell transduction and clinical scale expansion

  • Higher CAR19-iNKT than CAR19-T cell expandability and killing of CD19+CD1d+ targets

  • CAR19-iNKT cell reactivity potentiation by αGalCer and ATRA

  • Prolonged survival and brain lymphoma eradication of CAR19-iNKT cell-treated mice

Summary

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

iNKT
CAR immunotherapy
B cell malignancies

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