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

• We developed a therapeutic cancer vaccine for multiple myeloma against B cell maturation antigen (BCMA).

• Our findings revealed BCMA-specific immune response, providing the framework for its clinical evaluation to improve patient outcome.

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 BCMA protein as a target. Given the remarkable efficacy of COVID 19 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 TLR3 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 (KO) 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 (5TGM1-BCMA-OE) 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.