Engineering B cells to fight cancer

Introduction

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.

Mechanisms of Action

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.

Proposed Approach

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.

Anti-Tumor Effects

The B cells will exert multiple anti-tumor effects:

• Secreted antibodies will induce ADCC, CDC, and ADCP.
• A polyclonal T cell response with epitope spreading will be facilitated by engineered B cells acting as APCs.
• Antibodies will form immune complexes to be taken up by dendritic cells and macrophages for cross-presentation.

Co-Engineering Strategies

The B cells will be co-engineered to locally secrete additional immune effectors upon activation. These include:

1. Stimulatory cytokines
2. BiTEs
3. Checkpoint inhibitors
4. CD40/27 agonists
5. Cell-penetrating nanobodies

Localized secretion is predicted to increase efficacy while reducing systemic toxicities.

Targeting Self-Antigens

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.

Safety and Scalability

We will further demonstrate in vivo B cell engineering for increased scalability and ensure safety using a suicide cassette for inducible B cell elimination.

Conclusion

B cell engineering is thus a flexible and robust platform technology that may revolutionize cancer immunotherapy.