Natural killer T (NKT) cells as a novel platform for cancer immunotherapy with chimeric antigen receptors


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Leonid S Metelitsa1
1Baylor College of Medicine, Houston, USA

Abstract

Advances in the design of chimeric antigen receptors (CARs) improved antitumour efficacy of redirected T cells in early-phase cancer clinical trials. However, high heterogeneity of CAR T cells limits their therapeutic potential. We proposed that CAR expression in Vα24-invariant NKT cells (NKTs) could build upon natural antitumour properties of these cells. Primary human NKTs were engineered to express a CAR against GD2 ganglioside (CAR.GD2), which is highly expressed in neuroblastoma and other solid tumours. We compared CAR.GD2 constructs that encoded CD3ζ chain alone (Gz), with CD28 (G28z), 4-1BB (GBBz), or CD28 and 4-1BB (G28BBz) co-stimulatory endodomains. CAR.GD2 expression rendered NKTs highly cytotoxic against neuroblastoma cells without affecting their native CD1d-restricted reactivity and ability to kill M2 macrophages. We also observed a striking Th1-like NKT-cell polarisation by 4-1BB-containing constructs that was dependent on EGR1 transcription factor. Compared with T and CAR.GD2 T cells, NKTs and CAR.GD2 NKTs better infiltrated neuroblastoma xenografts after adoptive transfer in humanised NOD/SCID/IL2Rγ(null) mice. Although CAR.GD2 NKTs and CAR.GD2 T cells had similar antitumour activity in this model, only the former spared recipients from graft-versus-host disease. These results establish the potential of NKTs to serve as a safe and effective cellular platform for antitumour CAR therapy either in autologous or allogeneic settings.

Participants will learn: i) the rationale for using NKT cells as a platform for CARs; ii) dual-specific cytotoxicity of CAR.GD2 NKT cells against neuroblasts and tumour-associated macrophages; iii) Th1-polarising properties of CAR.GD2 constructs with a 4-1BB co-stimulatory endodomain; iv) the advantage of using NKT cells in allogeneic settings; v) current limitations of the NKT-based cellular platform.