SHIELD-MM – A modular multiplex shRNA platform to enhance functional persistence of academic anti-BCMA CAR-T cells (ARI0002h) in multiple myeloma.

Description

Anti-BCMA CAR-T cell therapies achieve deep responses in relapsed/refractory multiple myeloma, yet most patients eventually relapse, largely due to limited long-term persistence and progressive dysfunction of CAR-T cells under chronic tumor antigen exposure.

SHIELD-MM addresses this critical limitation by developing a next-generation version of ARI0002h — an academic anti-BCMA CAR-T product authorized by the Spanish Agency of Medicines (AEMPS) and used to treat over 200 patients in Spain — through the integration of a modular, single-vector shRNA platform designed to reprogram CAR-T cell fate without complex gene editing.

The project is guided by strong preliminary data identifying transcriptional regulators of CAR-T differentiation and exhaustion as key determinants of long-term functional durability. By simultaneously targeting complementary axes of CAR-T dysfunction — terminal effector differentiation and exhaustion stabilization — the platform aims to preserve memory-like features and functional competence under chronic antigen exposure.

Gene silencing is achieved through RNA interference delivered via Pol III-driven shRNA cassettes integrated within the CAR vector, enabling tunable and multiplex modulation through standard lentiviral transduction, without the cellular stress or manufacturing complexity associated with CRISPR-based genome editing. Constructs will be rigorously evaluated through serial antigen rechallenge assays, 3D myeloma models, transcriptomic profiling, and in vivo xenograft validation.

The expected outcome is a manufacturable, persistence-optimized ARI0002h CAR-T candidate with a complete preclinical package supporting progression to early-phase clinical testing, as well as a reusable engineering platform applicable to future optimization strategies in multiple myeloma and other malignancies.