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 (EVs)

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.

Tumor-Derived EVs

Even though they can transfer tumor antigens which potentially activate T cells, tumor-derived EVs (TEX) have mainly been associated with immunosuppressive functions.

Recent Findings

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.

Objectives of IMMUNO-TEX

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 designing combinations with isTEX to allow responsiveness in patients with poorly immunogenic tumors.