Stewart et al. used mRNA engineering to generate DC-25 – an allogeneic, off-the-shelf, mesenchymal stem cell (MSC)-based therapy for cancer immunotherapy and autoimmunity. Derived from umbilical cord MSCs, DC-25 transiently expressed CXCR4 for bone marrow migration, humanized anti-BCMA/anti-CD3 bispecific mAb to target malignant and autoimmune B cells, and IL-12 to potentiate immune responses. DC-25 demonstrated tunable expression, predictable pharmacodynamics, synergistic killing of target cells in vitro, and superior efficacy in a myeloma model. In a phase 1 trial in MM patients, DC-25 was well tolerated.
Contributed by Katherine Turner
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.
Author Info: (1) Cartesian Therapeutics, Frederick, MD, USA. andy.stewart@cartesiantx.com. (2) Cartesian Therapeutics, Frederick, MD, USA. (3) Cartesian Therapeutics, Frederick, MD, USA. (4) Ca
Author Info: (1) Cartesian Therapeutics, Frederick, MD, USA. andy.stewart@cartesiantx.com. (2) Cartesian Therapeutics, Frederick, MD, USA. (3) Cartesian Therapeutics, Frederick, MD, USA. (4) Cartesian Therapeutics, Frederick, MD, USA. (5) Cartesian Therapeutics, Frederick, MD, USA. (6) Cartesian Therapeutics, Frederick, MD, USA. (7) Cartesian Therapeutics, Frederick, MD, USA. (8) Cartesian Therapeutics, Frederick, MD, USA. (9) Cartesian Therapeutics, Frederick, MD, USA. (10) Cartesian Therapeutics, Frederick, MD, USA. (11) Cartesian Therapeutics, Frederick, MD, USA. (12) Cartesian Therapeutics, Frederick, MD, USA. (13) Cartesian Therapeutics, Frederick, MD, USA. (14) Cartesian Therapeutics, Frederick, MD, USA. (15) Cartesian Therapeutics, Frederick, MD, USA. (16) Cartesian Therapeutics, Frederick, MD, USA. (17) Cartesian Therapeutics, Frederick, MD, USA. (18) University of Health Sciences, Dr. Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital, Ankara, Turkey. (19) University of Health Sciences, Dr. Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital, Ankara, Turkey. (20) Center for Cancer and Blood Disorders, Bethesda, USA, MD. (21) Sarah Cannon Research Institute and Tennessee Oncology, Nashville, TN, USA. (22) Louisiana State University Health-Shreveport, Shreveport, LA, USA. (23) Cartesian Therapeutics, Frederick, MD, USA. (24) Cartesian Therapeutics, Frederick, MD, USA. (25) Cartesian Therapeutics, Frederick, MD, USA. (26) Cartesian Therapeutics, Frederick, MD, USA. (27) Cartesian Therapeutics, Frederick, MD, USA. (28) Cartesian Therapeutics, Frederick, MD, USA. (29) Cartesian Therapeutics, Frederick, MD, USA. (30) Cartesian Therapeutics, Frederick, MD, USA. chris.jewell@cartesiantx.com.
