A BCMA-mRNA vaccine is a promising therapeutic for multiple myeloma

Abstract

Abstract Cancer vaccines are emerging as promising therapies to not only prevent cancer but to treat cancer. Here, we developed a therapeutic vaccine for multiple myeloma (MM) using B-cell maturation antigen (BCMA) protein as a target. Given the remarkable efficacy of COVID-19 messenger RNA (mRNA) vaccines, we first packaged sequence- and base-optimized BCMA mRNA into lipid nanoparticles (LNPs) using next-generation ionizable lipid, enhancing their accumulation in the spleen. A toll-like receptor 3 agonist, polyinosinic:polycytidylic acid [poly(I:C)], was also encapsulated in LNPs to further elicit BCMA-specific immune response. BCMA-mRNA LNPs were internalized by dendritic cells (DCs) in vitro, triggering proliferation and activation of BCMA-specific CD8+ cytolytic T cells (CTLs). Importantly, these CTLs lysed BCMA+ U266 MM cells and CD138+ patient MM cells, without affecting BCMA-knockout U266 or CD138− patient–derived bone marrow cells. Vaccination of C57BL/6J mice with BCMA-mRNA LNPs activated splenic DCs and induced BCMA-specific CTLs, assessed by tetramer staining, which selectively killed murine 5TGM1 BCMA overexpressing MM cells. Finally, vaccination of C57BL/KaLwRijHsd mice bearing BCMA-overexpressing 5TGM1 cells inhibited tumor growth associated with BCMA-specific CD8+ T-cell responses. The combination treatment with poly(I:C) further triggered the immune response induced by BCMA-mRNA LNPs in all instances. Our findings provide the framework for clinical evaluation of BCMA-mRNA LNP vaccines to improve patient outcome in MM.