Descripción del proyecto
Inmunoterapia con linfocitos B genomodificados para el tratamiento antineoplásico
La genomodificación de linfocitos B «in vivo» para que expresen anticuerpos terapéuticos es un método seguro y eficaz para el tratamiento de muchas enfermedades, incluido el cáncer. La presencia de linfocitos B específicos del tumor y de anticuerpos antitumorales en el plasma está correlacionada con un pronóstico y una respuesta favorables al tratamiento con inhibidores de puntos de control en sarcomas y carcinomas. En el proyecto EngineerBcells, financiado con fondos europeos, se desarrollará una nueva inmunoterapia antineoplásica basada en linfocitos B diseñada con CRISPR/Cas9 y vectores víricos adenoasociados para integrar los genes de anticuerpos antitumorales en el locus de inmunoglobulina humana. La activación localizada de los linfocitos B genomodificados se demostrará y evaluará en diversos modelos tumorales. Los linfocitos B se diseñarán conjuntamente para secretar efectores inmunitarios adicionales tras la activación.
Objetivo
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.
Ámbito científico
Programa(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Régimen de financiación
HORIZON-AG - HORIZON Action Grant Budget-BasedInstitución de acogida
69978 Tel Aviv
Israel