Clinical-scale generation of multi-specific anti-fungal T cells targeting Candida,Aspergillus and mucormycetes |
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| Authors: | Lars Tramsen Stanislaw Schmidt Halvard Boenig Jean-Paul Latgé Cornelia Lass-Flörl Frauke Roeger Erhard Seifried Thomas Klingebiel Thomas Lehrnbecher |
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| Affiliation: | 1. Pediatric Hematology and Oncology, Johann Wolfgang Goethe University, Frankfurt, Germany;2. German Red Cross Blood Donor Service Baden-Wuerttemberg-Hessen and Institute for Transfusion Medicine and Immunohematology, Johann Wolfgang Goethe University, Frankfurt, Germany;3. Insitut Pasteur, Paris, France;4. Division of Hygiene and Medical Microbiology, Innsbruck Medical University, Innsbruck, Austria;1. Chemical & Biomedical Engineering, FAMU-FSU College of Engineering, The Florida State University, Tallahassee, Florida, USA;2. The National High Magnetic Field Laboratory, The Florida State University, Tallahassee, Florida, USA;1. Laboratory of Stem Cell and Tissue Engineering, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, P.R. China;2. Department of Orthopaedics and Traumatology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, P.R. China;1. Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA;2. Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA;1. Unidad de Cuidados Intensivos Cardiotorácicos, George Papanikolaou General Hospital, Tesalónica, Grecia;2. Departamento de Cirugía Cardiotorácica, George Papanikolaou General Hospital, Tesalónica, Grecia |
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| Abstract: | ![]()
Background aimsInvasive fungal infections, in particular, infections caused by Candida, Aspergillus and mucormycetes, are a major cause of morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplantation. Adoptive transfer of donor-derived anti-fungal T cells shows promise to restore immunity and to offer a cure. Because T cells recognize only specific epitopes, the low rate of patients in which the causal fungal pathogen can be identified and the considerable number of patients with co-infection with several genera or species of fungi significantly limit the application of adoptive immunotherapy.MethodsUsing the interferon-γ secretion assay, we isolated multi-specific human anti-fungal T cells after simultaneous stimulation with cellular extracts of Aspergillus fumigatus, Candida albicans and Rhizopus oryzae. Cells were phenotypically and functionally characterized by flow cytometry.ResultsOf a total of 1.1 × 109 peripheral blood mononuclear cells, a median number of 5.2 × 107 CD3+CD4+ T cells was generated within 12 days. This cell population consisted of activated memory TH1 cells and reproducibly responded to a multitude of Aspergillus spp., Candida spp. and mucormycetes with interferon-γ production. On re-stimulation, the generated T cells proliferated and enhanced anti-fungal activity of phagocytes and showed reduced alloreactivity compared with the original cell fraction.ConclusionsOur rapid and simple method of simultaneously generating functionally active multi-specific T cells that recognize a wide variety of medically relevant fungi may form the basis for future clinical trials investigating adoptive immunotherapy in allogeneic hematopoietic stem cell transplantation recipients with invasive fungal infection. |
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