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CORDIS

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

Project description

Cell-free tumour-derived immunotherapy

Extracellular vesicles (EVs) are cell-secreted particles employed for cell-to-cell communication and delivery metabolites, proteins, lipids, and nucleic acids. Although tumour-derived EVs (TEX) are known for their immunosuppressive function, emerging evidence suggests that cancer cells can modulate the biogenesis and content of TEX, potentially altering their impact on the immune system. Funded by the European Research Council, the IMMUNO-TEX project proposes to generate TEX as cell-free anticancer agents to stimulate anti-cancer immunity. Researchers will investigate the mechanisms by which TEX are loaded with specific cargo and exploit the cellular machinery to produce immunostimulatory TEX. The proposed work will overcome the limited effectiveness and resistance linked to certain immunotherapies.

Objective

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. With a vast and bioactive cargo (proteins, lipids, nucleic acids), extracellular vesicles (EVs) have 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. 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. 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. 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. The ability to harness the vast potential of isTEX is directly interwoven with a more detailed mechanistic understanding how tumor-specific cargo packaging in EVs occurs and how they alter immune cell function. Therefore, IMMUNO-TEX will identify and exploit the intracellular machinery in tumor cells for optimal isTEX generation, investigate how isTEX enable an immune-supportive tumor microenvironment, and validate isTEX to overcome ICI resistance in relevant murine and human model systems. 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.

Host institution

KLINIKUM RECHTS DER ISAR DER TECHNISCHEN UNIVERSITAT MUNCHEN
Net EU contribution
€ 1 650 778,00
Address
ISMANINGER STRASSE 22
81675 Muenchen
Germany

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Region
Bayern Oberbayern München, Kreisfreie Stadt
Activity type
Higher or Secondary Education Establishments
Links
Total cost
€ 1 650 778,00

Beneficiaries (1)