mRNA engineering of allogeneic mesenchymal stem cells enables coordinated delivery of T cell engagers and immunotherapeutic cues.

Allogeneic cell therapies can enable off-the-shelf products that address limitations of autologous therapies. Mesenchymal stem cells are a robust allogeneic source, but no bioengineered mesenchymal stem cell-based therapies exist. Here we use mRNA engineering to create an off-the-shelf immunotherapy that we term DC-25. DC-25 consists of a mesenchymal stem cell armed with three designed mRNA constructs encoding CXCR4 to direct migration, a T cell engager specific for B cell maturation antigen to target B cell maturation antigen-expressing plasma cells involved in cancer and autoimmunity, and interleukin-12 to potentiate pro-immune responses. DC-25 allows tunable expression of each gene, supporting a predictable pharmacokinetic profile. In vitro, DC-25 exhibits synergistic killing of target cells, and in a preclinical in vivo myeloma model, this therapy exhibits potent efficacy that surpasses T cell engager protein infusion. In a phase 1 safety study in patients with myeloma, DC-25 appears safe and generates interleukin-12 production after each infusion. This study motivates human cell therapies that exploit mRNA to achieve efficacy through induction of secreted or surface-bound therapeutic elements.