Designer-T-Zellen: Können T-Zellen mit definierter Spezifität die adoptive Immuntherapie zum Erfolg führen?

Zusammenfassung

Die adoptive Zelltherapie mit modifizierten T-Zellen hat kürzlich spektakuläre Erfolge in der Behandlung refraktärer Leukämien erzielt. Die Strategie beruht darauf, dass Patienten-T-Zellen durch einen chimären Antigenrezeptor (CAR) definierte Spezifität verliehen wird, sodass sie Zielzellen im Patienten gezielt aufspüren können. Der CAR erkennt mithilfe einer antikörperabgeleiteten Bindedomäne seine Zielstruktur unabhängig vom Histokompatibilitätskomplex und aktiviert die T-Zelle, was zur Zytokinfreisetzung und Lyse der Zielzelle führt. In der klinischen Anwendung werden die T-Zellen aus dem peripheren Blut des Patienten isoliert, ex vivo mit einem viralen Vektor zur Expression des CAR modifiziert, zu therapeutischen Zellzahlen amplifiziert und dem Patienten transfundiert. Die CAR-T-Zellen akkumulieren in Geweben mit der CAR-Zielstruktur, eliminieren die erkannten Tumorzellen und bilden ein spezifisches immunologisches Gedächtnis aus. Aufgrund dieser Eigenschaften hat die CAR-T-Zell-Strategie besonderes Interesse in der Onkologie erlangt. Jüngste Phase-I-Studien unterstreichen die Hoffnung, dass patienteneigene T-Zellen mit einem tumorspezifischen CAR eine Remission erzielen und den Tumor langfristig kontrollieren können.

Abstract

Adoptive cell therapy with modified T cells has recently gained spectacular success in the treatment of refractory leukemia. The strategy is based on the engraftment of defined specificity to patientʼs T cells by a chimeric antigen receptor (CAR) in order to specifically retrieve targeted cells. The CAR recognizes its target by an antibody-derived binding domain independently of the major histocompatibility complex and activates the T cell resulting in cytokine release and lysis of target cells. For clinical application T cells are isolated from patientʼs blood, modified ex vivo by a viral vector to express the CAR, amplified to therapeutic cell numbers and administered to the patient. CAR T cells accumulate in tissues with the CAR target, eliminate targeted tumor cells and build up an immunologic memory. Based on these properties the CAR T cell strategy has gained particular interest in oncology. Recent phase I trials sustain hope that patientʼs T cells engineered with a tumor-specific CAR induce remission and control tumors in the long term.

Schlüsselwörter

Immuntherapie - adoptive T-Zell-Therapie - rekombinanter T-Zell-Rezeptor - chimärer Antigenrezeptor - CAR

Key words

immune therapy - adoptive cell therapy - recombinant T cell receptor - chimeric antigen receptor - CAR

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