Projektbeschreibung
B-Zell-Immuntherapie in der Krebsbehandlung
Die In-vivo-Entwicklung von B-Zellen zur Expression therapeutischer Antikörper ist eine sichere und effiziente Methode für die Behandlung vieler Krankheiten, einschließlich Krebs. Das Vorhandensein von tumorspezifischen B-Zellen und Antikörpern gegen Tumore im Plasma korreliert mit einer günstigen Prognose und dem Ansprechen auf eine Behandlung mit Checkpoint-Inhibitoren bei Sarkomen und Karzinomen. Im Rahmen des EU-finanzierten Projekts EngineerBcells wird eine neuartige, auf B-Zellen basierende Krebsimmuntherapie konzipiert, bei der CRISPR/Cas9- und Adeno-assoziierte virale Vektoren eingesetzt werden, um die Antikörpergene gegen Tumore in den IgH-Locus zu integrieren. Die lokalisierte Aktivierung der manipulierten B-Zellen wird in verschiedenen Tumormodellen demonstriert und bewertet. Die B-Zellen werden so bearbeitet, dass sie bei Aktivierung zusätzliche Immuneffektoren absondern.
Ziel
B cells have an important role in the immune response against cancer. Tumor specific B cells in tertiary lymphoid structures and anti-tumor antibodies in the plasma are associated with a favorable prognosis and with an improved response to checkpoint inhibition in different sarcomas and carcinomas. Antigen specific B cells home to tumors and prolong survival in mice, while B cell based vaccines allow durable anti-tumor activity in cervical cancer patients. We have recently demonstrated both ex vivo and in vivo B cell engineering for the expression of anti-HIV antibodies. Here, we propose a novel cancer immunotherapy approach based on engineered B cells. In particular, we use CRISPR/Cas9 and AAV to target the integration of anti-tumor antibody genes into the IgH locus. In diverse tumor models, we plan to demonstrate localized B cell activation upon antigen engagement. The B cells will exert multiple anti-tumor effects. Secreted antibodies will induce ADCC, CDC and ADCP. In addition, a polyclonal T cell response with epitope spreading will be facilitated by engineered B cells acting as APCs as well as by antibodies forming immune complexes to be taken up by dendritic cells and macrophages for cross-presentation. The B cell will be co-engineered to locally secrete additional immune effectors upon activation. These include: stimulatory cytokines, BiTEs, checkpoint inhibitors, CD40/27 agonists and cell penetrating nanobodies. Localized secretion is predicted to increase efficacy while reducing systemic toxicities. When targeting self-antigens, B cells will be engineered to co-express a CAR, relaying CD40 or TLR signals for T cell independent B cell activation and allowing allogeneic therapy. We will further demonstrate in vivo B cell engineering for increased scalability, and ensure safety using a suicide cassette for inducible B cell elimination. B cell engineering is thus a flexible and robust platform technology that may revolutionize cancer immunotherapy.
Wissenschaftliches Gebiet
Programm/Programme
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Thema/Themen
Finanzierungsplan
HORIZON-AG - HORIZON Action Grant Budget-BasedGastgebende Einrichtung
69978 Tel Aviv
Israel