title: Preclinical targeting of aggressive T-cell malignancies using anti-CD5 chimeric antigen receptor.
abstract: The outlook for T-cell malignancies remain poor due to the lack of effective therapeutic options. Chimeric antigen receptor (CAR) immunotherapy has recently shown promise in clinical trials for B-cell malignancies, however, designing CARs for T-cell based disease remain a challenge due to the shared surface antigen pool between normal and malignant T-cells. Normal T-cells express CD5 but NK (natural killer) cells do not, positioning NK cells as attractive cytotoxicity cells for CD5CAR design. Additionally, CD5 is highly expressed in T-cell acute lymphoblastic leukemia (T-ALL) and peripheral T-cell lymphomas (PTCLs). Here, we report a robust anti-CD5 CAR (CD5CAR) transduced into a human NK cell line NK-92 that can undergo stable expansion ex vivo. We found that CD5CAR NK-92 cells possessed consistent, specific, and potent anti-tumor activity against a variety of T-cell leukemia and lymphoma cell lines as well as primary tumor cells. Furthermore, we were able to demonstrate significant inhibition and control of disease progression in xenograft mouse models of T-ALL. The data suggest that CAR redirected targeting for T-cell malignancies using NK cells may be a viable method for new and complementary therapeutic approaches that could improve the current outcome for patients.
authors.affiliation: iCell Gene Therapeutics LLC, Research &Development Division, Long Island High Technology Incubator, Stony Brook, NY, USA.
authors.forename: K H
authors.initials: KH
authors.lastname: Chen
authors.affiliation: iCell Gene Therapeutics LLC, Research &Development Division, Long Island High Technology Incubator, Stony Brook, NY, USA.
authors.forename: M
authors.initials: M
authors.lastname: Wada
authors.affiliation: iCell Gene Therapeutics LLC, Research &Development Division, Long Island High Technology Incubator, Stony Brook, NY, USA.
authors.forename: K G
authors.initials: KG
authors.lastname: Pinz
authors.affiliation: Department of Pathology, Stony Brook Medicine, Stony Brook, NY, USA.
authors.forename: H
authors.initials: H
authors.lastname: Liu
authors.affiliation: iCell Gene Therapeutics LLC, Research &Development Division, Long Island High Technology Incubator, Stony Brook, NY, USA.
authors.forename: K-W
authors.initials: KW
authors.lastname: Lin
authors.affiliation: Department of Pathology, Stony Brook Medicine, Stony Brook, NY, USA.
authors.forename: A
authors.identifier: 0000-0001-8387-2362
authors.initials: A
authors.lastname: Jares
authors.affiliation: iCell Gene Therapeutics LLC, Research &Development Division, Long Island High Technology Incubator, Stony Brook, NY, USA.
authors.forename: A E
authors.initials: AE
authors.lastname: Firor
authors.affiliation: Department of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
authors.forename: X
authors.initials: X
authors.lastname: Shuai
authors.affiliation: Department of Internal Medicine, Stony Brook Medicine, Stony Brook University Medical Center, Stony Brook, NY, USA.
authors.forename: H
authors.initials: H
authors.lastname: Salman
authors.affiliation: Department of Pathology, Stony Brook Medicine, Stony Brook, NY, USA.
authors.forename: M
authors.initials: M
authors.lastname: Golightly
authors.affiliation: Department of Internal Medicine, Stony Brook Medicine, Stony Brook University Medical Center, Stony Brook, NY, USA.
authors.forename: F
authors.initials: F
authors.lastname: Lan
authors.affiliation: Department of Pathology, Stony Brook Medicine, Stony Brook, NY, USA.
authors.forename: L
authors.initials: L
authors.lastname: Senzel
authors.affiliation: Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
authors.forename: E L
authors.initials: EL
authors.lastname: Leung
authors.affiliation: iCell Gene Therapeutics LLC, Research &Development Division, Long Island High Technology Incubator, Stony Brook, NY, USA.
authors.forename: X
authors.initials: X
authors.lastname: Jiang
authors.affiliation: iCell Gene Therapeutics LLC, Research &Development Division, Long Island High Technology Incubator, Stony Brook, NY, USA.|Department of Pathology, Stony Brook Medicine, Stony Brook, NY, USA.|Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Ma
mesh_terms: D053330:4-1BB Ligand / Q000235:genetics / Q000276:immunology; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000235:genetics / Q000276:immunology; D018956:CD5 Antigens / Q000276:immunology*; D016827:CD8 Antigens / Q000276:immunology; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000637:transplantation; D016411:Lymphoma, T-Cell, Peripheral / Q000473:pathology / Q000628:therapy*; D051379:Mice; D058990:Molecular Targeted Therapy; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology / Q000628:therapy*; D011993:Recombinant Fusion Proteins / Q000276:immunology*; D016879:Salvage Therapy; D057127:Single-Chain Antibodies / Q000235:genetics / Q000276:immunology; D014161:Transduction, Genetic; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D053330:4-1BB Ligand; D000951:Antigens, Neoplasm; D018106:CD28 Antigens; D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D018956:CD5 Antigens; D016827:CD8 Antigens; D011993:Recombinant Fusion Proteins; D057127:Single-Chain Antibodies; C505714:TNFRSF9 protein, human; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9