Descrizione del progetto
L’immunoterapia con cellule B ingegnerizzate nel trattamento del cancro
L’ingegnerizzazione delle cellule B in vivo per esprimere antibiotici terapeutici rappresenta un metodo sicuro ed efficiente per il trattamento di molte condizioni, tra cui il cancro. La presenza delle cellule B tumore-specifiche e degli anticorpi anitumorali nel plasma è correlata a una prognosi favorevole e a una risposta al trattamento con inibitori dei checkpoint nei sarcomi e nei carcinomi. Il progetto EngineerBcells, finanziato dall’UE, svilupperà un’innovativa immunoterapia tumorale basata su cellule B ingegnerizzate attraverso CRISPR/Cas9 e i vettori virali adeno-associati per integrare i geni degli anticorpi antitumorali all’interno del locus IgH. L’attivazione localizzata delle cellule B ingegnerizzate sarà dimostrata e valutata in diversi modelli tumorali. Le cellule B saranno co-ingegnerizzate per secernere effettori immunitari aggiuntivi all’attivazione.
Obiettivo
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.
Campo scientifico
Programma(i)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Argomento(i)
Meccanismo di finanziamento
HORIZON-AG - HORIZON Action Grant Budget-BasedIstituzione ospitante
69978 Tel Aviv
Israele