Immunomodulation and immunogenicity of human MSC-like cells : What did we learn from in vitro and in vivo studies ?

Mesenchymal stromal cell (MSC) therapy is a promising option to support endogenous regeneration and immunomodulation. However, the clinical results are contradictory. We think that the recent studies have to major limitations: poor characterization of MSC(like) cell products which were used and the lack of adequate immune monitoring to better understand  therapy response, mode-of-action, dose-dependency etc.

Because of their high regenerative and immunomodulatory potency shown in various preclinical models and their well-defined manufactoring process in 3-D bioreactors, we focused on the characterization of placental-expanded mesenchymal like adherent cells (PLX) that are aimed to be applied as allogeneic off-the-shelf product.

Interestingly, by minor manipulation in the manufactoring process, Pluristem generated two related products PLX-PAD and PLX-RAD. Both PLX-cell types were comparable regarding their in vitro differentiation capacity and marker profile (CD73+90+105+45-31-34-) that is typical for MSC-like cells. However, the cells showed different properties in some but not all preclinical models. We hypothesized that the protective effects are mediated by the PLX-cells´ secretome which might be different between PLX-RAD and PLX-PAD cells.  In fact, conditioned medium of PLX-RAD expressed a distinct secretome and showed distinct effects in vitro and in vivo. Whole genome DNA methylation analysis and CD screen revealed significant differences between the two products.

PLX-PAD cells are supportive in different tissue regeneration models. In fact, clinical phase I/IIa studies in severe chronic limb ischemia (CLI) and muscle injury demonstrated safety but also clear hints for efficacy. Immune monitoring gave insights into immunogenicity, immune modulation, and dose-related effects which help to design ongoing studies.

In summary, extensive biomarker studies provided mechanistic insights into PLX products and highlighted the need for careful characterization of MSC-like cell products to better understand dosing, indication, mode-of-action etc.