title: Preclinical targeting of human T-cell malignancies using CD4-specific chimeric antigen receptor (CAR)-engineered T cells.
abstract: Peripheral T-cell lymphomas (PTCLs) are aggressive lymphomas with no effective upfront standard treatment and ineffective options in relapsed disease, resulting in poorer clinical outcomes as compared with B-cell lymphomas. The adoptive transfer of T cells engineered to express chimeric antigen receptors (CARs) is a promising new approach for treatment of hematological malignancies. However, preclinical reports of targeting T-cell lymphoma with CARs are almost non-existent. Here we have designed a CAR, CD4CAR, which redirects the antigen specificity of CD8+ cytotoxic T cells to CD4-expressing cells. CD4CAR T cells derived from human peripheral blood mononuclear cells and cord blood effectively redirected T-cell specificity against CD4+ cells in vitro. CD4CAR T cells efficiently eliminated a CD4+ leukemic cell line and primary CD4+ PTCL patient samples in co-culture assays. Notably, CD4CAR T cells maintained a central memory stem cell-like phenotype (CD8+CD45RO+CD62L+) under standard culture conditions. Furthermore, in aggressive orthotropic T-cell lymphoma models, CD4CAR T cells efficiently suppressed the growth of lymphoma cells while also significantly prolonging mouse survival. Combined, these studies demonstrate that CD4CAR-expressing CD8+ T cells are efficacious in ablating malignant CD4+ populations, with potential use as a bridge to transplant or stand-alone therapy for the treatment of PTCLs.
authors.affiliation: R and D, iCell Gene Therapeutics LLC, Long Island High Technology Incubator, Stony Brook, NY, USA.
authors.forename: K
authors.initials: K
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: Department of Pathology, Stony Brook Medicine, Stony Brook, NY, USA.
authors.forename: M
authors.initials: M
authors.lastname: Golightly
authors.affiliation: Department of Pathology, Stony Brook Medicine, Stony Brook, NY, USA.
authors.forename: A
authors.initials: A
authors.lastname: Jares
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: R and D, iCell Gene Therapeutics LLC, Long Island High Technology Incubator, Stony Brook, NY, USA.
authors.forename: G W
authors.initials: GW
authors.lastname: Zieve
authors.affiliation: Department of Internal Medicine, Stony Brook Medicine, Stony Brook University Medical Center, Stony Brook, NY, USA.
authors.forename: N
authors.initials: N
authors.lastname: Hagag
authors.affiliation: Department of Internal Medicine, Stony Brook Medicine, Stony Brook University Medical Center, Stony Brook, NY, USA.
authors.forename: M
authors.initials: M
authors.lastname: Schuster
authors.affiliation: R and D, iCell Gene Therapeutics LLC, Long Island High Technology Incubator, Stony Brook, NY, USA.
authors.forename: A E
authors.initials: AE
authors.lastname: Firor
authors.affiliation: R and D, iCell Gene Therapeutics LLC, Long Island High Technology Incubator, Stony Brook, NY, USA.
authors.forename: X
authors.initials: X
authors.lastname: Jiang
authors.affiliation: R and D, iCell Gene Therapeutics LLC, Long Island High Technology Incubator, Stony Brook, NY, USA.|Department of Pathology, Stony Brook Medicine, Stony Brook, NY, USA.|The Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Ma
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000637:transplantation; D060846:Cell Engineering; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic; D015870:Gene Expression; D006801:Humans; D007938:Leukemia / Q000235:genetics / Q000276:immunology / Q000473:pathology; D016411:Lymphoma, T-Cell, Peripheral / Q000235:genetics / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D050506:Mutant Chimeric Proteins / Q000235:genetics* / Q000276:immunology; D009368:Neoplasm Transplantation; D061251:Primary Cell Culture; D062165:Receptors, Artificial / Q000235:genetics* / Q000276:immunology; D016019:Survival Analysis
chemical_list: D050506:Mutant Chimeric Proteins; D062165:Receptors, Artificial