Rotolo et al. presented an optimized protocol for the generation of CAR19 invariant NKT (iNKT) cells (which naturally target CD1d), showing higher expansion, cytotoxicity, and polyfunctionality compared to standard CAR T cells. CAR19-iNKT cells were more effective at eliminating CD19+CD1d+ lymphomas, including intracranial disease (possibly due to enhanced chemokine receptor expression); eradicating relapsed disease; and extending tumor-free and overall survival in mice. CD19-iNKT activity was enhanced by ɑGalCeramide or CD1d upregulation. Because iNKT cells do not incite GVHD, an off-the-shelf product could be developed.
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.
Author Info: (1) Centre for Haematology, Department of Medicine, Imperial College London, London, UK. (2) Centre for Haematology, Department of Medicine, Imperial College London, London, UK. (3
Author Info: (1) Centre for Haematology, Department of Medicine, Imperial College London, London, UK. (2) Centre for Haematology, Department of Medicine, Imperial College London, London, UK. (3) Centre for Haematology, Department of Medicine, Imperial College London, London, UK; Biomedical Center, Medical Faculty in Pilsen, Charles University, Alej Svobody 76, Pilsen 323 00, Czech Republic. (4) Biological Imaging Centre, Department of Medicine, Imperial College London, London, UK. (5) Biological Imaging Centre, Department of Medicine, Imperial College London, London, UK. (6) Centre for Haematology, Department of Medicine, Imperial College London, London, UK. (7) Centre for Haematology, Department of Medicine, Imperial College London, London, UK. (8) Centre for Haematology, Department of Medicine, Imperial College London, London, UK. (9) Centre for Haematology, Department of Medicine, Imperial College London, London, UK. (10) Centre for Haematology, Department of Medicine, Imperial College London, London, UK. (11) Department of Neuroradiology, Imperial College Healthcare NHS Trust, London, UK. (12) Cellular Pathology, Hammersmith Hospital, Northwest London Pathology, London, UK. (13) Centre for Haematology, Department of Medicine, Imperial College London, London, UK. (14) King's College London, School of Cancer and Pharmaceutical Sciences, Guy's Hospital, London, UK. (15) Centre for Haematology, Department of Medicine, Imperial College London, London, UK. Electronic address: a.karadimitris@imperial.ac.uk.
