Overcoming resistance to immunotherapy: Immunostimulatory tumor-derived extracellular vesicles as multifunctional anticancer agents

Introduction

Tumor immunotherapy with immune checkpoint inhibitors (ICI) has unprecedented therapeutic potential, but its success is limited to a minority of patients with preexisting antitumor T-cell immunity. For patients with poorly-immunogenic tumors, combinatorial immunotherapies are urgently needed.

Extracellular Vesicles

With a vast and bioactive cargo (proteins, lipids, nucleic acids), extracellular vesicles (EVs) have the intrinsic property to regulate complex pathways in distant target cells. Even though they can transfer tumor antigens which potentially activate T cells, tumor-derived EVs (TEX) have mainly been associated with immunosuppressive function.

Recent Discoveries

I have recently identified innate immune pathways within tumor cells that regulate TEX biogenesis and immunogenicity. This allows for the first time to “force” tumor cells to release a defined immunostimulatory (is)TEX product.

Project Objective

The unconventional objective of IMMUNO-TEX is to generate a platform for the pioneering therapeutic use of tumor-derived isTEX as multifunctional cell-free anticancer agents.

Characteristics of isTEX

isTEX combine a cargo of a plethora of patient-specific tumor (neo-) antigens and immunostimulatory constituents within a single, non-toxic delivery vehicle, that allows for efficient priming of tumor antigen-specific T cells.

Mechanistic Understanding

The ability to harness the vast potential of isTEX is directly interwoven with a more detailed mechanistic understanding of how tumor-specific cargo packaging in EVs occurs and how they alter immune cell function.

Research Goals

Therefore, IMMUNO-TEX will:

1. Identify and exploit the intracellular machinery in tumor cells for optimal isTEX generation.
2. Investigate how isTEX enable an immune-supportive tumor microenvironment.
3. Validate isTEX to overcome ICI resistance in relevant murine and human model systems.

Conclusion

Hereby, IMMUNO-TEX will eliminate current limitations of ICI immunotherapy by rationally designed combination with isTEX to allow responsiveness in patients with poorly immunogenic tumors.