[en] Multiple myeloma (MM) is an incurable hematologic malignancy characterized by the
accumulation of monoclonal plasma cells in the bone marrow. Although therapeutic
strategies have significantly improved, relapse remains inevitable. Chimeric antigen
receptor T-cell (CAR-T) therapy has demonstrated strong clinical efficacy, and the use of
single-domain antibodies (sdAbs) offers a promising alternative to conventional scFvbased
CARs by improving stability and reducing tonic signaling.
This thesis comprises three projects. The primary project compares a newly developed
anti-BCMA nanoCAR-T with the clinical CT103a CAR-T. Both constructs display potent
and specific cytotoxic activity against BCMA-expressing MM cells in vitro and show
comparable antitumor efficacy in vivo. They exhibit similar activation profiles, cytokine
production, memory differentiation, and CD4/CD8 ratios, while nanoCAR-T cells
demonstrate enhanced proliferation and reduced exhaustion upon repeated antigen
exposure.
The second project compares bead-based and bead-free T-cell activation. While both
methods support robust expansion, they induce distinct activation and differentiation
kinetics, converging upon restimulation, highlighting the importance of activation
strategies in CAR-T manufacturing.
The third project investigates Fc receptor-like 5 (FCRL5) as a novel MM – B lymphoma
antigen. Two scFv-based CARs and one nanoCAR targeting FCRL5 were generated.
Among them, the F2 CAR shows strong and antigen-specific cytotoxicity, supporting its
potential for MM and B-cell lymphomas, consistent with high FCRL5 expression
observed in several lymphoma subtypes.
