Third-Party-T-Zell-Spender: eine alternative Quelle virusspezifischer T-Zellen für die adoptive Immuntherapie

Zusammenfassung

Nach Stammzell- (SZT) und solider Organtransplantation (SOT) kommt es aufgrund der damit einhergehenden Immunsuppression zum Verlust oder zur funktionellen Störung virusspezifischer T-Zellen (VST), einem essenziellen Element in der zellulären Immunabwehr. Dabei können insbesondere Infektionen oder Reaktivierungen durch persistierende Viren (z. B. humanes Zytomegalievirus [HCMV], Epstein-Barr-Virus [EBV], humanes Herpesvirus 6 [HHV-6]) und lytische Viren (z. B. humanes Adenovirus [hAdV]) zu lebensgefährlichen Komplikationen führen, deren Ausmaß entscheidend von der Geschwindigkeit der Rekonstitution des Immunsystems abhängt. Der adoptive Transfer von VST eines geeigneten Spenders ist ein aussichtsreicher Therapieansatz zur gezielten Unterstützung und beschleunigten Rekonstitution der zellulären Immunität. Dabei sind schon geringste Dosen der VST für einen therapeutisch nachweisbaren Effekt ausreichend, während das Risiko der Graft-versus-Host-Erkrankung (engl. Graft-versus-Host Disease, GvHD) gering ist. Wenn der Stammzellspender nicht zur Verfügung steht oder die entsprechenden Zellen nicht in ausreichender Frequenz vorhanden sind, stellen sowohl HLA-teilkompatible Familienspender als auch Fremdspender als Third-Party-T-Zell-Spender (engl. Third-Party Donor, TPD) eine geeignete alternative Quelle virusspezifischer T-Zellen dar. Der Aufbau und die Etablierung von TPD-Registern und TPD-Zellbanken ermöglichen die schnelle Bereitstellung der spezifischen T-Zellen zur umgehenden, individuell auf den Patienten abgestimmten Behandlung. Um die klinische Anwendung von VST zu verbessern, werden etablierte Verfahren zur Herstellung der VST unter den Gesichtspunkten Sensitivität, Reproduzierbarkeit, Reinheit, Funktionalität und Persistenz angereicherter T-Zellen ständig optimiert und weiterentwickelt.

Abstract

Antiviral T cells play a major role in the cellular immunity against viral pathogens. After stem cell (SCT) or solid organ transplantation (SOT) viral infections or reactivations of human cytomegalovirus (HCMV), Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), and adenovirus (hAdV) are major complications and remain a leading cause of morbidity and mortality in immunocompromised recipients. The treatment with immunosuppressive drugs results in a delayed T-cell recovery, which is a key requirement for the effective elimination and control of viral infections following transplantation. The adoptive transfer of virus-specific T cells (VST) derived from a suitable donor is an effective strategy to rapidly restore the antiviral T-cell immunity of the recipient with no acute toxicity or increased risk of developing Graft-versus-Host disease (GvHD). Only low numbers of adoptively transferred antiviral T cells are required to improve clinical outcome. Partially HLA-matched related and unrelated donors can serve as third-party T-cell donors (TPD) and represent an appropriate alternative T-cell source, in particular for patients whose stem cells donors are either lacking virus-reactive T cells or are unavailable for further donations. The development and implementation of TPD registries and TPD T-cell line banks provide a rapid donor search and identification followed by the immediate T-cell allocation. To improve the clinical application for adoptive T-cell therapy, enhancement of established strategies for antiviral T-cell manufacturing considering sensitivity, reproducibility, purity, functionality and persistence of enriched T cells is still ongoing.

Schlüsselwörter

Third-Party-T-Zell-Spender - adoptive T-Zell-Therapie - Stammzell- und Organtransplantation - virusspezifische T-Zellen

Key words

third-party T-cell donor - adoptive T-cell therapy - stem cell and organ transplantation - virus-specific T cells

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