Abstract
Due to the CD1d restricted recognition of altered glycolipids, Vα24-invariant natural killer T (iNKT) cells are excellent tools for cancer immunotherapy with a significantly reduced risk for graft-versus-host disease when applied as off-the shelf-therapeutics across Human Leukocyte Antigen (HLA) barriers. To maximally harness their therapeutic potential for multiple myeloma (MM) treatment, we here armed iNKT cells with chimeric antigen receptors (CAR) directed against the MM-associated antigen CD38 and the plasma cell specific B cell maturation antigen (BCMA). We demonstrate that both CD38- and BCMA-CAR iNKT cells effectively eliminated MM cells in a CAR-dependent manner, without losing their T cell receptor (TCR)-mediated cytotoxic activity. Importantly, iNKT cells expressing either BCMA-CARs or affinity-optimized CD38-CARs spared normal hematopoietic cells and displayed a Th1-like cytokine profile, indicating their therapeutic utility. While the costimulatory domain of CD38-CARs had no influence on the cytotoxic functions of iNKT cells, CARs containing the 4-1BB domain showed a better expansion capacity. Interestingly, when stimulated only via CD1d+ dendritic cells (DCs) loaded with α-galactosylceramide (α-GalCer), both CD38- and BCMA-CAR iNKT cells expanded well, without losing their CAR- or TCR-dependent cytotoxic activities. This suggests the possibility of developing an off-the-shelf therapy with CAR iNKT cells, which might even be boostable in vivo by administration α-GalCer pulsed DCs.
Highlights
We evaluated whether the chimeric antigen receptors (CAR) invariant natural killer T (iNKT) cells could be stimulated and expanded by mature monocyte dendritic cells loaded with α-GalCer
INKT cells are very low in frequency in human peripheral blood, the discovery that they can be exponentially expanded ex vivo or in vivo through stimulation with α-GalCer loaded dendritic cells (DCs) prompted the design of several strategies to utilize iNKT cells in cancer treatment
In MM, CD1d expression, which is high in premalignant and early disease, may be reduced and in some cases lost in the advanced stages [52], posing a potential drawback for iNKT-based immunotherapies
Summary
An alternative is to introduce CARs into another subset of innate-like, but antigen-specific immune cells that can sustain a long-term memory, such as the invariant natural killer T (iNKT) cells [22]. In clinical studies, stimulation of iNKT cells with α-GalCer loaded antigen presenting cells enhanced their activity and decreased patients’ tumor load [37,38,39]. This TCR-specific expansion property makes iNKT cells appealing tools as CAR-carriers with low toxicity profiles. We analyzed CAR iNKT cells for the possibility to expand through the endogenous TCR via stimulation with α-GalCer pulsed dendritic cells (DCs)
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