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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-? (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 ?-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.

SUBMITTER: Kumaresan PR

PROVIDER: S-EPMC4115509 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Bioengineering T cells to target carbohydrate to treat opportunistic fungal infection.

Kumaresan Pappanaicken R PR Manuri Pallavi R PR Albert Nathaniel D ND Maiti Sourindra S Singh Harjeet H Mi Tiejuan T Roszik Jason J Rabinovich Brian B Olivares Simon S Krishnamurthy Janani J Zhang Ling L Najjar Amer M AM Huls M Helen MH Lee Dean A DA Champlin Richard E RE Kontoyiannis Dimitrios P DP Cooper Laurence J N LJ

Proceedings of the National Academy of Sciences of the United States of America 20140707 29

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 ...[more]

PMID: 25002471

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Project description:UnlabelledRapidly fatal cases of invasive fungal infections due to a fungus later identified as Saprochaete clavata were reported in France in May 2012. The objectives of this study were to determine the clonal relatedness of the isolates and to investigate possible sources of contamination. A nationwide alert was launched to collect cases. Molecular identification methods, whole-genome sequencing (WGS), and clone-specific genotyping were used to analyze recent and historical isolates, and a case-case study was performed. Isolates from thirty cases (26 fungemias, 22 associated deaths at day 30) were collected between September 2011 and October 2012. Eighteen cases occurred within 8 weeks (outbreak) in 10 health care facilities, suggesting a common source of contamination, with potential secondary cases. Phylogenetic analysis identified one clade (clade A), which accounted for 16/18 outbreak cases. Results of microbiological investigations of environmental, drug, or food sources were negative. Analysis of exposures pointed to a medical device used for storage and infusion of blood products, but no fungal contamination was detected in the unused devices. Molecular identification of isolates from previous studies demonstrated that S. clavata can be found in dairy products and has already been involved in monocentric outbreaks in hematology wards. The possibility that S. clavata may transmit through contaminated medical devices or can be associated with dairy products as seen in previous European outbreaks is highly relevant for the management of future outbreaks due to this newly recognized pathogen. This report also underlines further the potential of WGS for investigation of outbreaks due to uncommon fungal pathogens.ImportanceSeveral cases of rapidly fatal infections due to the fungus Saprochaete clavata were reported in France within a short period of time in three health care facilities, suggesting a common source of contamination. A nationwide alert collected 30 cases over 1 year, including an outbreak of 18 cases over 8 weeks. Whole-genome sequencing (WGS) was used to analyze recent and historical isolates and to design a clade-specific genotyping method that uncovered a clone associated with the outbreak, thus allowing a case-case study to analyze the risk factors associated with infection by the clone. The possibility that S. clavata may transmit through contaminated medical devices or can be associated with dairy products as seen in previous European outbreaks is highly relevant for the management of future outbreaks due to this newly recognized pathogen.

Dataset Information

Bioengineering T cells to target carbohydrate to treat opportunistic fungal infection.

Publications

Bioengineering T cells to target carbohydrate to treat opportunistic fungal infection.

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