title: Invariant NKT cells with chimeric antigen receptor provide a novel platform for safe and effective cancer immunotherapy.
abstract: Advances in the design of chimeric antigen receptors (CARs) have improved the antitumor efficacy of redirected T cells. However, functional heterogeneity of CAR T cells limits their therapeutic potential and is associated with toxicity. We proposed that CAR expression in Vα24-invariant natural killer T (NKT) cells can build on the natural antitumor properties of these cells while their restriction by monomorphic CD1d limits toxicity. Primary human NKT cells were engineered to express a CAR against the GD2 ganglioside (CAR.GD2), which is highly expressed by neuroblastoma (NB). We compared CAR.GD2 constructs that encoded the CD3ζ chain alone, with CD28, 4-1BB, or CD28 and 4-1BB costimulatory endodomains. CAR.GD2 expression rendered NKT cells highly cytotoxic against NB cells without affecting their CD1d-dependent reactivity. We observed a striking T helper 1-like polarization of NKT cells by 4-1BB-containing CARs. Importantly, expression of both CD28 and 4-1BB endodomains in the CAR.GD2 enhanced in vivo persistence of NKT cells. These CAR.GD2 NKT cells effectively localized to the tumor site had potent antitumor activity, and repeat injections significantly improved the long-term survival of mice with metastatic NB. Unlike T cells, CAR.GD2 NKT cells did not induce graft-versus-host disease. These results establish the potential of NKT cells to serve as a safe and effective platform for CAR-directed cancer immunotherapy.
authors: Texas Children's Cancer Center, Department of Pediatrics.
authors: Andras
authors: A
authors: Heczey
authors: Texas Children's Cancer Center, Department of Pediatrics.
authors: Daofeng
authors: D
authors: Liu
authors: Department of Pathology and Immunology.
authors: Gengwen
authors: G
authors: Tian
authors: Texas Children's Cancer Center, Department of Pediatrics.
authors: Amy N
authors: AN
authors: Courtney
authors: Texas Children's Cancer Center, Department of Pediatrics.
authors: Jie
authors: J
authors: Wei
authors: Texas Children's Cancer Center, Department of Pediatrics.
authors: Ekaterina
authors: E
authors: Marinova
authors: Texas Children's Cancer Center, Department of Pediatrics.
authors: Xiuhua
authors: X
authors: Gao
authors: Texas Children's Cancer Center, Department of Pediatrics.
authors: Linjie
authors: L
authors: Guo
authors: Center for Cell and Gene Therapy, and.
authors: Eric
authors: E
authors: Yvon
authors: Department of Pathology and Immunology.
authors: John
authors: J
authors: Hicks
authors: Division of Biostatistics, Dan L. Duncan Cancer Center, Department of Medicine, Baylor College of Medicine, Houston, TX.
authors: Hao
authors: H
authors: Liu
authors: Department of Pathology and Immunology, Center for Cell and Gene Therapy, and.
authors: Gianpietro
authors: G
authors: Dotti
authors: Texas Children's Cancer Center, Department of Pediatrics, Department of Pathology and Immunology, Center for Cell and Gene Therapy, and.
authors: Leonid S
authors: LS
authors: Metelitsa
mesh_terms: D053330:4-1BB Ligand / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D055610:Antigens, CD1d / Q000378:metabolism; D018106:CD28 Antigens / Q000378:metabolism; D019496:Cancer Vaccines / Q000276:immunology*; D002460:Cell Line; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D005732:Gangliosides; D006086:Graft vs Host Disease / Q000276:immunology; D006801:Humans; D007167:Immunotherapy; D008213:Lymphocyte Activation / Q000276:immunology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D055611:Natural Killer T-Cells / Q000276:immunology*; D009362:Neoplasm Metastasis; D009447:Neuroblastoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D017434:Protein Structure, Tertiary; D011946:Receptors, Antigen / Q000276:immunology*; D012190:Retroviridae / Q000235:genetics; D014161:Transduction, Genetic; D016896:Treatment Outcome
chemical_list: D053330:4-1BB Ligand; D055610:Antigens, CD1d; D018106:CD28 Antigens; D019496:Cancer Vaccines; D016207:Cytokines; D005732:Gangliosides; D011946:Receptors, Antigen; C019403:ganglioside, GD2