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SMART-SMAPs: a new paradigm of cell-free cytotoxic immunotherapy for resistant CLL

Objective

Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia, with ~32,000 new cases annually in Europe and a disease burden that has more than doubled over the past three decades. Despite significant advances with BTK and BCL-2 inhibitors, CLL remains incurable. Acquired resistance driven by the immunosuppressive tumour microenvironment (TME) leads to inevitable relapse in most patients. This challenge is shared across B-cell neoplasias, including non-Hodgkin lymphoma, diffuse large B-cell lymphoma and acute lymphoblastic leukemia, which together affect over 100,000 patients annually in Europe and are treated with overlapping immunotherapeutic strategies. Supramolecular attack particles (SMAPs) are stable, acellular glycoprotein nanostructures released by cytotoxic T and NK cells that encapsulate toxic molecules and induce cell death autonomously. Lacking a lipid membrane, SMAPs evade TME suppression, resist immune rejection, and have a long shelf life, properties that position them as promising off-the-shelf cytotoxic agents. However, as isolated nanoparticles, SMAPs lack tumour-targeting capacity, causing non-specific toxicity and preventing clinical translation. We have engineered the SMAP glycoprotein shell to confer tumour specificity. Preliminary data confirm that the chimeric SMAPs have full cytotoxic potency and the ability to selectively kill CLL cells. This ERC PoC project will translate these findings through three objectives: (1) optimising the engineered SMAPs for stable production and yield; (2) engineering a scalable cytotoxic cell line as a SMAP bioreactor; and (3) establishing a purification pipeline for preclinical testing. Success will lay the foundation for a cell free,off-the-shelf immunotherapy for CLL and the broader B-cell neoplasias.

Fields of science (EuroSciVoc)

Keywords

Programme(s)

Topic(s)

Funding Scheme

HORIZON-ERC-POC - HORIZON ERC Proof of Concept Grants

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Call for proposal

(opens in new window) ERC-2026-POC

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Host institution

UNIVERSITA DEGLI STUDI DI SIENA
Net EU contribution
€ 150 000,00
Address
VIA BANCHI DI SOTTO 55
53100 Siena
Italy
Region
Centro (IT) Toscana Siena
Activity type
Higher or Secondary Education Establishments
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Total cost
No data

Beneficiaries (1)

Partners (1)