Rapid and sustained T cell-based immunotherapy against invasive fungal disease via a combined two step procedure

Frontiers in Immunology

Immunology

Britta Maecker-Kolhoff¹  Volker Witt²  Sabine Tischer-Zimmermann³  Rainer Blasczyk³  Britta Eiz-Vesper⁴  Gerhard Fritsch⁵  Wolfgang Paster⁵  Christine Hoffmann-Freimüller⁵  Tamires Bitencourt⁵  Thomas Lion⁵  Julia Stemberger⁵  Nelli Frank⁵  René Geyeregger⁶  Elisabeth Salzer⁷ 

[1]Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany

[2]German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Hannover, Germany

[3]Department of Pediatrics, St. Anna Children’s Hospital, Medical University of Vienna, Vienna, Austria

[4]Department of Pediatrics, Medical University of Vienna, Vienna, Austria

[5]Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany

[6]Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany

[7]German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Hannover, Germany

[8]St. Anna Children’s Cancer Research Institute (CCRI), Vienna, Austria

[9]St. Anna Children’s Cancer Research Institute (CCRI), Vienna, Austria

[10]Department of Pediatrics, St. Anna Children’s Hospital, Medical University of Vienna, Vienna, Austria

[11]St. Anna Children’s Cancer Research Institute (CCRI), Vienna, Austria

[12]Department of Pediatrics, St. Anna Children’s Hospital, Medical University of Vienna, Vienna, Austria

[13]Department of Pediatrics, Laboratory for Pediatric Immunology, Willem-Alexander Children’s Hospital, Leiden University Medical Center, Leiden, Netherlands

关键词: HSCT;    Aspergillus;    T-cell immunotherapy;    Aspergillus;    T-cell expansion;    cytokine secretion;   

DOI  :  10.3389/fimmu.2023.988947

 received in 2022-07-13, accepted in 2023-03-09,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionAspergillus fumigatus (Asp) infections constitute a major cause of morbidity and mortality in patients following allogeneic hematopoietic stem cell transplantation (HSCT). In the context of insufficient host immunity, antifungal drugs show only limited efficacy. Faster and increased T-cell reconstitution correlated with a favorable outcome and a cell-based therapy approach strongly indicated successful clearance of fungal infections. Nevertheless, complex and cost- or time-intensive protocols hampered their implementation into clinical application.MethodsTo facilitate the clinical-scale manufacturing process of Aspergillus fumigatus-specific T cells (ATCs) and to enable immediate (within 24 hours) and sustained (12 days later) treatment of patients with invasive aspergillosis (IA), we adapted and combined two complementary good manufacturing practice (GMP)-compliant approaches, i) the direct magnetic enrichment of Interferon-gamma (IFN-γ) secreting ATCs using the small-scale Cytokine Secretion Assay (CSA) and ii) a short-term in vitro T-cell culture expansion (STE), respectively. We further compared stimulation with two standardized and commercially available products: Asp-lysate and a pool of overlapping peptides derived from different Asp-proteins (PepMix).ResultsFor the fast CSA-based approach we detected IFN-γ+ ATCs after Asp-lysate- as well as PepMix-stimulation but with a significantly higher enrichment efficiency for stimulation with the Asp-lysate when compared to the PepMix. In contrast, the STE approach resulted in comparably high ATC expansion rates by using Asp-lysate or PepMix. Independent of the stimulus, predominantly CD4+ helper T cells with a central-memory phenotype were expanded while CD8+ T cells mainly showed an effector-memory phenotype. ATCs were highly functional and cytotoxic as determined by secretion of granzyme-B and IFN-γ.DiscussionFor patients with IA, the immediate adoptive transfer of IFN-γ+ ATCs followed by the administration of short-term in vitro expanded ATCs from the same donor, might be a promising therapeutic option to improve the clinical outcome.

【 授权许可】

Unknown   
Copyright © 2023 Tischer-Zimmermann, Salzer, Bitencourt, Frank, Hoffmann-Freimüller, Stemberger, Maecker-Kolhoff, Blasczyk, Witt, Fritsch, Paster, Lion, Eiz-Vesper and Geyeregger