Chimäre Antigenrezeptor-T-Zellen – Die Evolution zellulärer Immuntherapie von malignen zu nicht-malignen Erkrankungen

Zusammenfassung

Immunonkologische Therapien wie Immuncheckpoint-Inhibitoren (ICIs) und bispezifische Antikörper haben die Behandlung von soliden und hämatologischen Tumorentitäten mit einem neuen Arsenal an Möglichkeiten ausgestattet. Dabei spielen T-Zellen eine zentrale Rolle bei der Bekämpfung entarteter Zellen. Moderne Gen-Transfer- und -Engineering-Methoden haben im letzten Jahrzehnt die Kombination von synthetischer Biologie und adoptiver, zellulärer Immuntherapie ermöglicht und somit die Ausstattung von Patienten-T-Zellen mit chimären Antigenrezeptoren (CAR). Diese vereinen die Antigen-bindenden Eigenschaften von Antikörpern mit den Signal-gebenden Domänen des T-Zell-Rezeptors und erlauben den so entstehenden CAR-T-Zellen die Zerstörung von Tumorzellen in Antigen-spezifischer Art und Weise. Diese „living drugs“ haben insbesondere die Behandlung B-Zell-vermittelter, hämatologischer Erkrankungen revolutioniert und zeigen neben hohen Ansprech- ebenso langjährige Remissionsraten. Die Möglichkeit CAR gegen neue Zielantigene zu generieren und auch die Eigenschaften von T-Zellen über Genom-Editierung zu steuern führt das Feld nicht nur immer weiter in den Bereich der soliden Tumore, sondern gleichsam in das Feld nicht-maligner Erkrankungen. Insbesondere die tiefe B-Zell-Depletion über CD19-CAR-T-Zellen hat bei ersten Patienten mit Systemischem Lupus erythematosus (SLE) und anderen Kollagenosen zu beachtlichen Erfolgen geführt. Dabei beschränkt sich die bisher publizierte Erfahrung auf kleine Fallserien und Fallberichte. Auf Basis dieser Daten ist ebenso der Einsatz von CAR-T-Zellen in anderen B-Zell-vermittelten Autoimmunitäten denkbar und wird die Rheumatologie in Zukunft gewiss beschäftigen. Mehrere Phase 1- und 2-Studien zu CAR-T-Zell-Therapien bei Autoimmunerkrankung werden aktuell entwickelt oder schon initiiert. Der vorliegende Artikel soll die Grundzüge der CAR-T-Zell-Technologie erläutern sowie ihre Perspektiven für die Verwendung im Bereich nicht-maligner Erkrankungen beleuchten.

Abstract

Immunotherapies such as immune checkpoint inhibitors (ICIs) and bispecific antibodies have brought a new arsenal of possibilities to the treatment of solid and haematological tumour entities. T cells play a central role in the fight against malignant cells. In the past decade, modern gene transfer and engineering methods have made it possible to combine synthetic biology and adoptive cellular immunotherapy and thus to equip patient T cells with chimeric antigen receptors (CARs). Combining the antigen-binding properties of antibodies with the signalling domains of the T cell receptor, CARs allow the generated CAR T cells to destroy tumour cells in an antigen-specific manner. In particular, these “living drugs” have revolutionised the treatment of B cell-mediated haematological diseases, and they show high response and long-term remission rates. The ability to generate CARs against new target antigens and to control the properties of T cells via genome editing is moving the field further into the area of solid tumours as well as into applications for non-malignant diseases. In particular, deep B cell depletion via CD19 CAR T cells has led to considerable success in the first patients with systemic lupus erythematosus (SLE) and other collagenoses. The experience published to date is limited to small case series and case reports. Based on these data, the use of CAR T cells in other B cell-mediated autoimmunities is also conceivable and will certainly be a focus in the field of rheumatology in the future. Several phase 1 and 2 studies on CAR T cell therapies for autoimmune diseases are currently being developed or have already been initiated. This article intends to explain the main features of CAR T cell technology and highlight its prospects for use in the field of non-malignant diseases.

Schlüsselwörter

CAR-T-Zellen - Zelltherapie - Nicht-maligne Erkrankungen

Keywords

CAR T cells - cellular therapy - non-malignant diseases

Publication History

Article published online:
07 August 2024

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