title: Bioengineering T cells to target carbohydrate to treat opportunistic fungal infection.
abstract: Clinical-grade T cells are genetically modified ex vivo to express chimeric antigen receptors (CARs) to redirect their specificity to target tumor-associated antigens in vivo. We now have developed this molecular strategy to render cytotoxic T cells specific for fungi. We adapted the pattern-recognition receptor Dectin-1 to activate T cells via chimeric CD28 and CD3-ζ (designated "D-CAR") upon binding with carbohydrate in the cell wall of Aspergillus germlings. T cells genetically modified with the Sleeping Beauty system to express D-CAR stably were propagated selectively on artificial activating and propagating cells using an approach similar to that approved by the Food and Drug Administration for manufacturing CD19-specific CAR(+) T cells for clinical trials. The D-CAR(+) T cells exhibited specificity for β-glucan which led to damage and inhibition of hyphal growth of Aspergillus in vitro and in vivo. Treatment of D-CAR(+) T cells with steroids did not compromise antifungal activity significantly. These data support the targeting of carbohydrate antigens by CAR(+) T cells and provide a clinically appealing strategy to enhance immunity for opportunistic fungal infections using T-cell gene therapy.
authors.affiliation: Division of Pediatrics.
authors.forename: Pappanaicken R
authors.initials: PR
authors.lastname: Kumaresan
authors.affiliation: Division of Pediatrics.
authors.forename: Pallavi R
authors.initials: PR
authors.lastname: Manuri
authors.affiliation: Department of Infectious Diseases.
authors.forename: Nathaniel D
authors.initials: ND
authors.lastname: Albert
authors.affiliation: Division of Pediatrics.
authors.forename: Sourindra
authors.initials: S
authors.lastname: Maiti
authors.affiliation: Division of Pediatrics.
authors.forename: Harjeet
authors.initials: H
authors.lastname: Singh
authors.affiliation: Division of Pediatrics.
authors.forename: Tiejuan
authors.initials: T
authors.lastname: Mi
authors.affiliation: Division of Pediatrics.
authors.forename: Jason
authors.initials: J
authors.lastname: Roszik
authors.affiliation: Division of Pediatrics.
authors.forename: Brian
authors.initials: B
authors.lastname: Rabinovich
authors.affiliation: Division of Pediatrics.
authors.forename: Simon
authors.initials: S
authors.lastname: Olivares
authors.affiliation: Division of Pediatrics.
authors.forename: Janani
authors.initials: J
authors.lastname: Krishnamurthy
authors.affiliation: Division of Pediatrics.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Division of Diagnostic Imaging, Department of Cancer Systems Imaging.
authors.forename: Amer M
authors.initials: AM
authors.lastname: Najjar
authors.affiliation: Division of Pediatrics.
authors.forename: M Helen
authors.initials: MH
authors.lastname: Huls
authors.affiliation: Division of Pediatrics,The University of Texas Graduate School of Biomedical Sciences, and.
authors.forename: Dean A
authors.initials: DA
authors.lastname: Lee
authors.affiliation: Stem Cell Transplantation and Cell Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, 77030.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Champlin
authors.affiliation: Department of Infectious Diseases.
authors.forename: Dimitrios P
authors.initials: DP
authors.lastname: Kontoyiannis
authors.affiliation: Division of Pediatrics,The University of Texas Graduate School of Biomedical Sciences, and ljncooper@mdanderson.org.
authors.forename: Laurence J N
authors.initials: LJ
authors.lastname: Cooper
mesh_terms: D000818:Animals; D018941:Antigens, CD19 / Q000378:metabolism; D001228:Aspergillosis / Q000276:immunology* / Q000382:microbiology / Q000473:pathology / Q000628:therapy*; D001230:Aspergillus / Q000187:drug effects / Q000502:physiology; D057005:Bioengineering / Q000379:methods*; D002241:Carbohydrates / Q000037:antagonists & inhibitors*; D003907:Dexamethasone / Q000494:pharmacology; D006801:Humans; D025301:Hyphae / Q000187:drug effects / Q000502:physiology; D016130:Immunophenotyping; D037181:Lectins, C-Type / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D009894:Opportunistic Infections / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D000099181:Dectin-1
chemical_list: D018941:Antigens, CD19; D002241:Carbohydrates; D003907:Dexamethasone; D037181:Lectins, C-Type; D011948:Receptors, Antigen, T-Cell; D000099181:Dectin-1
keywords: T-cell therapy; adoptive immunotherapy; fungus; β-1,3-glucan