Synergistic Antitumor Activity of Microbiome and OMV-based in situ Vaccination

Introduction

ISV is a promising immunotherapy strategy which envisages the direct injection of immunostimulatory reagents into the tumor mass. ISV offers the advantage of reducing off-target toxicity and inducing potent inflammation where cancer antigens have the maximal concentration.

Substances Used in ISV

Different substances are being exploited in ISV, including:

• Adjuvants
• Lytic viruses
• Cytokines/chemokines
• Antibodies

The rationale is to recruit antigen-presenting cells, T cells, NK cells, and macrophages, thus promoting a strong anti-tumor immunity.

Current ISV Products

Two ISV products are available, and others are expected to come in the near future. Similarly to other cancer therapies, the current ISV strategies need to be optimized to improve their efficacy.

Proposed Optimization Strategies

In this proposal, we wish to demonstrate the strength of a novel approach to ISV optimization based on two main innovative solutions:

1. Coupling ISV to Probiotics: We plan to couple ISV to the oral administration of Bifidobacterium, a probiotic that, in the context of the Advanced ERC Grant “Vaccibiome”, we have shown to promote the remodeling of the gut microbiome and the tumor infiltration of T cells.

2. Engineered Bacterial Outer Membrane Vesicles (OMVs): We propose to treat tumors with engineered bacterial Outer Membrane Vesicles (OMVs). OMVs are naturally decorated with a number of immunostimulatory molecules, and we have already demonstrated the effectiveness of E. coli OMVs in different tumor mouse models.

OMV Engineering Strategies

We plan to exploit our proprietary OMV engineering strategies to further potentiate OMV adjuvanticity by decorating them with Flt3L, a chemokine known to recruit immune cells.

Expected Outcomes

The combination of Bifidobacterium and Flt3L-OMVs will create a “perfect immunological storm” at the tumor site capable of eliminating both primary and metastatic tumors.

Conclusion

Considering its simplicity and low production costs, our Microbiome-ISV therapy has the potential to become a broadly applicable neoadjuvant therapy to be performed before surgery in a large panel of solid tumors.