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Mesenchymal stromal cells (MSCs) are a promising therapy candidate for the treatment of graft-versus-host disease (GvHD). Although MSCs are well-tolerated in patients with GvHD, their insufficient immunosuppression at the sites of inflammation remains a challenge.1,2 To address this limitation, Sirpilla et al. introduced chimeric antigen receptor (CAR) technology to MSCs to enhance their immunosuppressive efficacy at inflammation sites.1,2
In GvHD, the host epithelial tissues are susceptible to donor immune cell attack through the interaction of T-cell integrins with E-cadherin (Ecad) expressed on epithelia. Thus, Sirpilla et al.1 hypothesized that an anti-Ecad CAR-MSC (EcCAR-MSC) with Ecad+ (human, mouse, and canine) cross-reactivity and a CD28ζ intracellular signaling domain would induce antigen-specific immunosuppression at these inflammatory target tissue sites.1,2 The possible mechanism of action of EcCAR-MSCs is shown in Figure 1.
Figure 1. Mechanism of CAR-MSCs for the treatment of GvHD*
CAR, chimeric antigen receptor; GvHD, graft-versus-host disease; MSC, mesenchymal stromal cells; ScFv, single-chain variable fragment.
*Adapted from Sirpilla, et al.1 Created with BioRender.com
Here, we summarize the key findings of a study investigating immunosuppressive efficacy and safety of EcCAR-MSCs in GvHD preclinical models, presented was given at the 2023 Tandem Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR.
EcCAR-MSCs were developed by transducing CAR into adipose-derived MSCs via lentiviral vector enhancement. CD28 signal was selected for its ability to activate downstream immunosuppressive factors.
To test T-cell immunosuppression in vitro, MSCs were cocultured for 24 hours with activated donor T cells with or without antigen-specific Ecad stimulation.
The in vivo testing was done using GvHD xenograft models. GvHD was induced in NOD-SCID-γ-/- mice via intravenous injection of human peripheral blood mononuclear cells. Mice were then treated with intraperitoneal injections of CAR-MSC, untransduced MSCs (UTD-MSC), or vehicle control to monitor weight loss, clinical GvHD score, human T cell suppression, and survival outcomes.
Figure 2. Serum cytokine assays and immunophenotype analyses*
EcCAR-MSC, E-cadherin targeted chimeric antigen receptor–mesenchymal stromal cells; Gal, galectin; G-CSF, granulocyte colony-stimulating factor; IL, interleukin; PD, programmed death; TNF, tumor necrosis factor; UTD-MSC, untransduced mesenchymal stromal cells.
*Adapted from Sirpilla, et al.1,2
The findings demonstrate EcCAR-MSCs as a novel therapeutic platform to enhance MSC antigen-specific immunosuppression in GvHD with no toxicity. EcCAR-MSCs will next be employed in a phase I clinical trial for patients with steroid-refractory acute GvHD, with alternative CAR-MSC designs also in progress for other autoimmune disease treatments.
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