Establishment of a GMP-compliant mesenchymal stromal cell bank from pooled bone marrow mononuclear cells of eight “third-party” healthy donors: clinical evidence of safety and efficacy

Kuçi, Zyrafete; Bönig, Halvard; Kreyenberg, Hermann; Bunos, Milica; Jauch, Anna; Janssen, Johannes W.G.; Škifić, Marijana; Michel, Kristina; Eising, Ben; Lucchini, Giovanna; Jarisch, Andrea; Soerensen, Jan; Seifried, Erhard; Klingebiel, Thomas; Bader, Peter; Kuçi, Selim

doi:10.1016/j.jcyt.2015.03.325

Cited by 2 publications

(3 citation statements)

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“…Donor-to-donor variability and extensive in vitro expansion are major drivers of inconsistent results from clinical trials, particularly when hMSCs batches are manufactured from single donors (3,56). Pooling single donations, a concept implemented for platelet concentrates for many years (57), has been introduced recently for both hMSC and hPL products (13,16,19,20,25,58). To balance the needs for scale-up and low-level expansion of a pooled hMSC product, our concept starts with MCBs from single donor hMSCs.…”

Section: Discussionmentioning

confidence: 99%

“…To address this, hMSC pooling concepts were developed. As one example, the product "MSC-FFM" was manufactured from pooled bone marrow (BM) mononuclear cells (MNCs), containing hMSC precursors as well as alloreactive immune cells of eight healthy 3rd-party donors (16). Besides reducing donor variability, an allogeneic immune reaction was intended to produce immunologically primed hMSCs with higher immunosuppressive strength.…”

Section: Introductionmentioning

confidence: 99%

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Pooled human bone marrow-derived mesenchymal stromal cells with defined trophic factors cargo promote dermal wound healing in diabetic rats by improved vascularization and dynamic recruitment of M2-like macrophages

et al. 2022

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Human Mesenchymal Stromal Cells (hMSCs) are a promising source for cell-based therapies. Yet, transition to phase III and IV clinical trials is remarkably slow. To mitigate donor variabilities and to obtain robust and valid clinical data, we aimed first to develop a manufacturing concept balancing large-scale production of pooled hMSCs in a minimal expansion period, and second to test them for key manufacture and efficacy indicators in the clinically highly relevant indication wound healing. Our novel clinical-scale manufacturing concept is comprised of six single donor hMSCs master cell banks that are pooled to a working cell bank from which an extrapolated number of 70,000 clinical doses of 1x106 hMSCs/cm2 wound size can be manufactured within only three passages. The pooled hMSC batches showed high stability of key manufacture indicators such as morphology, immune phenotype, proliferation, scratch wound healing, chemotactic migration and angiogenic support. Repeated topical hMSCs administration significantly accelerated the wound healing in a diabetic rat model by delivering a defined growth factor cargo (specifically BDNF, EGF, G-CSF, HGF, IL-1α, IL-6, LIF, osteopontin, VEGF-A, FGF-2, TGF-β, PGE-2 and IDO after priming) at the specific stages of wound repair, namely inflammation, proliferation and remodeling. Specifically, the hMSCs mediated epidermal and dermal maturation and collagen formation, improved vascularization, and promoted cell infiltration. Kinetic analyses revealed transient presence of hMSCs until day (d)4, and the dynamic recruitment of macrophages infiltrating from the wound edges (d3) and basis (d9), eventually progressing to the apical wound on d11. In the wounds, the hMSCs mediated M2-like macrophage polarization starting at d4, peaking at d9 and then decreasing to d11. Our study establishes a standardized, scalable and pooled hMSC therapeutic, delivering a defined cargo of trophic factors, which is efficacious in diabetic wound healing by improving vascularization and dynamic recruitment of M2-like macrophages. This decision-making study now enables the validation of pooled hMSCs as treatment for impaired wound healing in large randomized clinical trials.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pooled human bone marrow-derived mesenchymal stromal cells with defined trophic factors cargo promote dermal wound healing in diabetic rats by improved vascularization and dynamic recruitment of M2-like macrophages

et al. 2022

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“…One Phase 3 study of MC0518 (Medac GmBH, Germany) is currently recruiting adult and adolescent subjects with SR-aGVHD in 34 centers across Europe. MC0518 (other names: MSC-FFM, Obnitix) is an allogeneic MSC treatment product for SR-aGVHD, created by pooling the BM mononuclear cells of eight unrelated, healthy donors (128,129). The manufacturing protocol of MC0518 is characterized by high potency and near-identical individual doses.…”

Section: Mesenchymal Stromal Cellsmentioning

confidence: 99%

Novel therapies for graft versus host disease with a focus on cell therapies

Zeiser,

Ringden,

Sadeghi

et al. 2023

Front. Immunol.

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Graft versus host disease (GVHD) can occur at any period post allogeneic hematopoietic stem cell transplantation as a common clinical complication contributing to significant morbidity and mortality. Acute GVHD develops in approximately 30-50% of patients receiving transplants from matched related donors. High doses of steroids are used as first-line treatment, but are unsuccessful in around 40% of patients, resulting in the diagnosis of steroid-refractory acute GVHD. Consensus has yet to develop for the management of steroid-refractory acute GVHD, and prognosis at six months has been estimated at around 50%. Thus, it is critical to find effective treatments that increase survival of steroid-refractory acute GVHD. This article describes the currently known characteristics, pathophysiology, and treatments for GVHD, with a special focus on recent advances in cell therapies. In particular, a novel cell therapy using decidua stromal cells (DSCs) was recently shown to have promising results for acute GVHD, with improved effectiveness over previous treatments including mesenchymal stromal cells. At the Karolinska Institute, severe acute GVHD patients treated with placenta-derived DSCs supplemented with either 5% albumin or 10% AB plasma displayed a one-year survival rate of 76% and 47% respectively. Furthermore, patients with steroid-refractory acute GVHD, displayed survival rates of 73% with albumin and 31% with AB plasma-supplemented DSCs, compared to the 20% survival rate in the mesenchymal stromal cell control group. Adverse events and deaths were found to be attributed only to complications of hematopoietic stem cell transplant and GVHD, not to the study intervention. ASC Therapeutics, Inc, in collaboration with the Karolinska Institute, will soon initiate a phase 2 multicenter, open-label study to further assess the efficacy and safety of intravenous DSC treatment in sixty patients with Grade II-IV steroid-refractory acute GVHD. This novel cell therapy represents a promising treatment to combat the poor prognosis that steroid-refractory acute GVHD patients currently face.

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Establishment of a GMP-compliant mesenchymal stromal cell bank from pooled bone marrow mononuclear cells of eight “third-party” healthy donors: clinical evidence of safety and efficacy

Cited by 2 publications

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Pooled human bone marrow-derived mesenchymal stromal cells with defined trophic factors cargo promote dermal wound healing in diabetic rats by improved vascularization and dynamic recruitment of M2-like macrophages

Pooled human bone marrow-derived mesenchymal stromal cells with defined trophic factors cargo promote dermal wound healing in diabetic rats by improved vascularization and dynamic recruitment of M2-like macrophages

Novel therapies for graft versus host disease with a focus on cell therapies

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