AUG 30, 2016 08:00 AM PDT

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

  • Chairman, Institute for Med. Immunology & Berlin-Brandenburg Center for Regenerative Therapies (BCRT) & Dept. Immunology, Labor Berlin Vivantes, Charité GmbH Charité-Universitätsmedizin, Berl
      Hans-Dieter Volk, MD, is Professor of Immunology and head of the both the Institute of Medical Immunology, Charité Berlin and Berlin-Brandenburg Center for Regenerative Therapies (BCRT) as well as deputy spokesman of the Berlin-Brandenburg School for Regenerative Therapies (BSRT) (all Berlin, Germany). In addition, he is scientific head of the Division of Immunology of the Labor Berlin Charité Vivantes GmbH, Berlin. His focus lies in implementation of new concepts in diagnosis and therapy of immunological diseases. Dr. Volk is an expert in coordinating and conducting clinical trials by biomarker development, monitoring new cell therapies, performing proof-of-concept and investigator-initiated trials (all phase I/II). He has been co-editor/editorial board member of several high-impact journals and board member of several scientific medicine societies (e.g., German Society Immunology, German Society Sepsis).

    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.

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