Targeted in-vitro-stimulation reveals highly proliferative multi-virus-specific human central memory T cells as candidates for prophylactic T cell therapy
Autoři:
Benjamin Faist aff001; Fabian Schlott aff001; Christian Stemberger aff003; Kevin M. Dennehy aff004; Angela Krackhardt aff006; Mareike Verbeek aff006; Götz U. Grigoleit aff007; Matthias Schiemann aff001; Dieter Hoffmann aff002; Andrea Dick aff009; Klaus Martin aff010; Martin Hildebrandt aff011; Dirk H. Busch aff001; Michael Neuenhahn aff001
Působiště autorů:
Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, Munich, Germany
aff001; German Center for Infection Research (DZIF), partner site Munich, Munich, Germany
aff002; Juno Therapeutics, Munich, Germany
aff003; German Center for Infection Research (DZIF), partner site Tübingen, Tübingen, Germany
aff004; Institute for Medical Virology, University Hospital Tübingen, Tübingen, Germany
aff005; Department of Medicine III, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany
aff006; Department of Internal Medicine II, University of Würzburg, Wuerzburg, Germany
aff007; Institute for Virology, Technische Universität München, Munich, Germany
aff008; Department of Transfusion Medicine and Haemostaseology, Ludwig-Maximilians-Universität München, Munich, Germany
aff009; Institute of Anaesthesiology, Deutsches Herzzentrum München, Klinik an der Technischen Universität München, Munich, Germany
aff010; TUM Cells Interdisciplinary Center for Cellular Therapies, Munich, Germany
aff011
Vyšlo v časopise:
PLoS ONE 14(9)
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pone.0223258
Souhrn
Adoptive T cell therapy (ACT) has become a treatment option for viral reactivations in patients undergoing allogeneic hematopoietic stem cell transplantation (alloHSCT). Animal models have shown that pathogen-specific central memory T cells (TCM) are protective even at low numbers and show long-term survival, extensive proliferation and high plasticity after adoptive transfer. Concomitantly, our own recent clinical data demonstrate that minimal doses of purified (not in-vitro- expanded) human CMV epitope-specific T cells can be sufficient to clear viremia. However, it remains to be determined if human virus-specific TCM show the same promising features for ACT as their murine counterparts. Using a peptide specific proliferation assay (PSPA) we studied the human Adenovirus- (AdV), Cytomegalovirus- (CMV) and Epstein-Barr virus- (EBV) specific TCM repertoires and determined their functional and proliferative capacities in vitro. TCM products were generated from buffy coats, as well as from non-mobilized and mobilized apheresis products either by flow cytometry-based cell sorting or magnetic cell enrichment using reversible Fab-Streptamers. Adjusted to virus serology and human leukocyte antigen (HLA)-typing, donor samples were analyzed with MHC multimer- and intracellular cytokine staining (ICS) before and after PSPA. TCM cultures showed strong proliferation of a plethora of functional virus-specific T cells. Using PSPA, we could unveil tiniest virus epitope-specific TCM populations, which had remained undetectable in conventional ex-vivo-staining. Furthermore, we could confirm these characteristics for mobilized apheresis- and GMP-grade Fab-Streptamer-purified TCM products. Consequently, we conclude that TCM bare high potential for prophylactic low-dose ACT. In addition, use of Fab-Streptamer-purified TCM allows circumventing regulatory restrictions typically found in conventional ACT product generation. These GMP-compatible TCM can now be used as a broad-spectrum antiviral T cell prophylaxis in alloHSCT patients and PSPA is going to be an indispensable tool for advanced TCM characterization during concomitant immune monitoring.
Klíčová slova:
Cell differentiation – Cell staining – Cytotoxic T cells – Prophylaxis – Stem cells – T cells – Leukapheresis – Memory T cells
Zdroje
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