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
prolekare.web.journal.doi_sk: 10.1371/journal.pone.0223258


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


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