Preclinical Evaluation of Invariant Natural Killer T Cells Modified with CD38 or BCMA Chimeric Antigen Receptors for Multiple Myeloma

• Published in: International journal of molecular sciences 2021-01, Vol.22 (3), p.1096
• Main Authors: Poels, Renée, Drent, Esther, Lameris, Roeland, Katsarou, Afroditi, Themeli, Maria, van der Vliet, Hans J, de Gruijl, Tanja D, van de Donk, Niels W C J, Mutis, Tuna
• Format: Article
• Language: English
• Subjects: adoptive immunotherapy; ADP-ribosyl Cyclase 1 - chemistry; ADP-ribosyl Cyclase 1 - metabolism; Antigens; Automobiles; B-Cell Maturation Antigen - chemistry; B-Cell Maturation Antigen - metabolism; BCMA; Bone Marrow Cells - metabolism; Cancer immunotherapy; CAR iNKT; CD1d antigen; CD38; CD38 antigen; chimeric antigen receptor; Chimeric antigen receptors; Cytokines; Cytokines - metabolism; Cytotoxicity; Cytotoxicity, Immunologic; Dendritic cells; Dendritic Cells - metabolism; Domains; Galactosylceramide; Galactosylceramides - chemistry; Glycolipids; Graft-versus-host reaction; Hematopoietic Stem Cells - cytology; Histocompatibility antigen HLA; HLA Antigens - chemistry; Humans; Immunotherapy; Immunotherapy, Adoptive; Invariants; Killer Cells, Natural - cytology; Leukocytes, Mononuclear - cytology; Lymphocytes; Lymphocytes T; Membrane Glycoproteins - chemistry; Membrane Glycoproteins - metabolism; Multiple myeloma; Multiple Myeloma - metabolism; Natural killer cells; Natural Killer T-Cells - metabolism; Patients; Protein Domains; Receptors, Antigen, T-Cell - metabolism; Receptors, Chimeric Antigen - immunology; Risk; Risk management; T cell receptors; Th1 Cells - metabolism; Tumor Necrosis Factor Receptor Superfamily, Member 9 - chemistry
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22031096

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.