Abstract
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.
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Data availability
All raw data used to generate the figures are provided as Source Data, excluding patient-specific data. Access to anonymized, individual and trial-level data (analysis datasets) and/or the study protocol will be provided by request from qualified researchers performing independent, rigorous research, after review and approval of a research proposal and statistical analysis plan and execution of a data sharing agreement. Data requests can be submitted at any time, and the data will be accessible for 12 months. Requests can be submitted to trials@cartesiantx.com. Source data are provided with this paper.
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Acknowledgements
We acknowledge A. Filev for technical assistance and clinical support staff from Medex. We thank M. Jamal, S. Cherukuri and A. Ghosh for expert assistance and direction of animal experiments at Noble Life Sciences. We thank U. Yerramalla and J. Hayashi of Precision Antibody for expert assistance with analysis of protein affinity. This work was supported by Cartesian Therapeutics.
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C.A.S., S.D., E.J.C., Y.Z., H.K., Y.L., M.T., M.T.D., Y.S., M.S.S., M.V.K., M. Kurtoglu, E.P.E., L.H.T., M.D.M. and C.M.J. conceptualized and designed the work. C.A.S., S.D., E.J.C., Y.Z., H.K., K.S., M.N.C., A.C., H.X., Y.L., M.T., M.T.D., Y.S., M.D., M. Kireeva, J.L.B., T.G., F.A., T.N.Y., R.B., J.B., T.W., M.S.S., M.V.K., M. Kurtoglu, A.B., E.P.E., L.H.T., M.D.M. and C.M.J. contributed to the acquisition, analysis and interpretation of the data. C.A.S., E.J.C., M.V.K., M. Kurtoglu, L.H.T., M.D.M. and C.M.J. drafted the paper. All authors reviewed, provided feedback and approved the submitted version of the work.
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C.A.S., S.D., E.J.C., Y.Z., H.K., K.S., M.N.C., A.C., H.X., Y.L., M.T., M.T.D., Y.S., M.D., M.K., J.L.B., T.G., M.S.S., M.V.K., M.K., A.B., E.P.E., L.H.T., M.D.M. and C.M.J. are employees of and/or hold equity in Cartesian Therapeutics. C.M.J. is appointed as a professor at the University of Maryland and a research health scientist at the VA Maryland Health Care System. The views in this paper do not reflect the views of the state of Maryland or the United States Government. C.M.J. is founder of Nodal Therapeutics and holds equity positions with Nodal Therapeutics and Barinthus Biotherapeutics. J.B.’s institution receives research funds in their name from AstraZeneca, BMS, C4 Therapeutics, Caribou Biosciences, CARsgen, Cartesian Therapeutics, Genentech, GSK, Gracell, Ichnos Sciences, J&J, Juno Therapeutics, K36 Therapeutics, Karyopharm, Kite, Moderna, Pfizer, Regeneron, Roche and Sanofi. J.B. is a consultant for AstraZeneca, BMS, Galapagos, Genentech, J&J, Karyopharm, Kite Pharma, Kyowa Kirin, Pfizer, Regeneron, Roche and Sebia. J.B. has received a speaker honorarium from Janssen. No other conflicts are declared.
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Extended data
Extended Data Fig. 1 Repeated administration of high-dose soluble TCE restricts MM.1S tumor cell growth in vivo.
A: Timeline indicating model of myeloma-bearing mice carrying human Pan-T cells and 6-day dosing regimen. Figure partially created in BioRender. Jewell, CM. (2025) https://BioRender.com/deuj2vw. B: Quantitation of bioluminescence signal over time (mean ± SD, n = 3 mice). C: Day 14 bioluminescence images show strong tumor control in the high-dose soluble TCE administered mice.
Extended Data Fig. 2 Repeated administration of high or low doses of DC-25 restrains MM.1S tumor cell growth and drives dose-dependent expression of IL-12.
A: Bioluminescence imaging of myeloma-bearing mice carrying human Pan-T cells. Animals were randomized into treatment groups on Day 5 following evaluation of MM.1S-fluc tumor burden by bioluminescence. This was followed by treatment with vehicle, 0.25 M DC-25, or 0.75 M DC-25 on Day 7 and Day 14. B: Post-treatment comparisons of quantitation of bioluminescence signal at indicated individual timepoints (mean and all data points shown, n = 4 mice/group). C: Quantitation of bioluminescence signal over time, including pre- and post-treatment. Arrows indicate treatment administration (mean ± SD, n = 4 mice/group). D: Expression of IL-12 in the serum of mice treated with DC-25 measured by ELISA one day post-administration (dotted line indicates LOQ; mean and all data points shown, n = 4-8 mice; statistical significance was determined by an unpaired Mann-Whitney test).
Extended Data Fig. 3 IL-12 in serum of human MM patients.
Data show IL-12 for all dose levels at all analyzed timepoints. Arrows indicate days of DC-25 infusion (light grey = DL1, grey = DL2, green = DL3).
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Stewart, C.A., Daniel, S., Curvino, E.J. et al. mRNA engineering of allogeneic mesenchymal stem cells enables coordinated delivery of T cell engagers and immunotherapeutic cues. Nat. Biomed. Eng 10, 647–659 (2026). https://doi.org/10.1038/s41551-025-01552-z
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DOI: https://doi.org/10.1038/s41551-025-01552-z
