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Mechanical sensing and reprogramming of CAR-engineered lymphocytes for next-generation ACT cancer immunotherapy

Objective

Adoptive cell transfer (ACT) with cytotoxic lymphocytes, including chimeric antigen receptor (CAR)-T cells, is a powerful immunotherapy already demonstrating remarkable success against certain blood cancers. However, its efficacy in treating solid tumors remains limited, with durable responses being rare. Current strategies to improve ACT therapy focus predominantly on biochemical interactions between immune cells and cancer cells. Yet, emerging evidence highlights the significant influence of biomechanical cues in shaping immune responses and therapeutic outcomes. For instance, the mechanical properties of cancer cells, such as cellular softness, can confer resistance to immune cell-mediated killing, while rigidifying cancer cells can sensitize them toward immune attack leading to enhanced immunotherapy.
MechanoCAR explores a novel, under-explored approach: mechanical reprogramming of cytotoxic lymphocytes, including CAR-T and CAR natural killer (NK) cells. We hypothesize that enhancing the mechano-sensitivity of the lymphocytes could overcome some of the key limitations of ACT therapies, particularly against resistant tumors. First, we aim to uncover and characterize the mechano-sensing and mechano-transduction mechanisms of CARs. Next, we will develop and test innovative mechanical reprogramming strategies to enhance the cytotoxic potential of CAR-T/NK cells in advanced tumor models and further explore the therapeutic potential using patient-derived organoids.
This ambitious and high-reward research has the potential to transform ACT cancer immunotherapy. It addresses significant gaps in current biochemical-centric approaches by introducing a new paradigm focusing on mechanical modulation. If successful, it will provide groundbreaking insights into mechano-immunology, offer a blueprint for designing the next-generation ACT immunotherapies, and ultimately improve treatment outcomes for patients with challenging cancers.

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Keywords

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Programme(s)

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Topic(s)

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HORIZON-ERC - HORIZON ERC Grants

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Call for proposal

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(opens in new window) ERC-2025-COG

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Host institution

ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 2 175 000,00
Address
BATIMENT CE 3316 STATION 1
1015 LAUSANNE
Switzerland

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Region
Schweiz/Suisse/Svizzera Région lémanique Vaud
Activity type
Higher or Secondary Education Establishments
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Total cost

The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.

€ 2 175 000,00

Beneficiaries (1)

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