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<p>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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年11月28日

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  • C. Andrew Stewart,
  • Shaji Daniel,
  • Elizabeth J. Curvino,
  • Yi Zhang,
  • Hafsa Kamboh,
  • Kirill Sergueev,
  • Minhtran N. Casi,
  • Adam Chowdhury,
  • Heng Xu,
  • Youqiang Li,
  • Mehmet Tosun,
  • Matthew T. Duvernay,
  • Yufei Shan,
  • Mame Djigal,
  • Maria Kireeva,
  • Jennifer L. Biaksangi,
  • Taylor Glassband,
  • Fevzi Altuntas,
  • Tuğçe Nur Yiğenoğlu,
  • Ralph Boccia,
  • Jesus Bardeja,
  • Tamna Wangjam,
  • Michael S. Singer,
  • Murat V. Kalayoglu,
  • Metin Kurtoglu,
  • Albina Benson,
  • Emily P. English,
  • Lisa H. Tostanoski,
  • Milos D. Miljkovic,
  • Christopher M. Jewell

摘要

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.