Safety Profile of Good Manufacturing Practice Manufactured Interferon γ-Primed Mesenchymal Stem/Stromal Cells for Clinical Trials

Author:

Guess Adam J.1,Daneault Beth2,Wang Rongzhang2,Bradbury Hillary2,La Perle Krista M. D.3,Fitch James1,Hedrick Sheri L.1,Hamelberg Elizabeth1,Astbury Caroline4,White Peter15,Overolt Kathleen15,Rangarajan Hemalatha15,Abu-Arja Rolla15,Devine Steven M.2,Otsuru Satoru1,Dominici Massimo6,O'Donnell Lynn2,Horwitz Edwin M.125

Affiliation:

1. a Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio, USA

2. b Departments of Medicine, The Ohio State University, Columbus, Ohio, USA

3. c Comparative Pathology & Mouse Phenotyping Shared Resource, The Ohio State University, Columbus, Ohio, USA

4. d Departments of Pathology and Laboratory Medicine, Cleveland Clinic, Cleveland Ohio, USA

5. e Department of Medical and Surgical Sciences for Children & Adults, Pediatrics, College of Medicine, The Ohio State University, Columbus, Ohio, USA

6. f Laboratory of Cellular Therapy, University-Hospital of Modena and Reggio Emilia, Modena, Italy

Abstract

Abstract Mesenchymal stem/stromal cells (MSCs) are widely studied by both academia and industry for a broad array of clinical indications. The collective body of data provides compelling evidence of the clinical safety of MSC therapy. However, generally accepted proof of therapeutic efficacy has not yet been reported. In an effort to generate a more effective therapeutic cell product, investigators are focused on modifying MSC processing protocols to enhance the intrinsic biologic activity. Here, we report a Good Manufacturing Practice-compliant two-step MSC manufacturing protocol to generate MSCs or interferon γ (IFNγ) primed MSCs which allows freshly expanded cells to be infused in patients on a predetermined schedule. This protocol eliminates the need to infuse cryopreserved, just thawed cells which may reduce the immune modulatory activity. Moreover, using (IFNγ) as a prototypic cytokine, we demonstrate the feasibility of priming the cells with any biologic agent. We then characterized MSCs and IFNγ primed MSCs prepared with our protocol, by karyotype, in vitro potential for malignant transformation, biodistribution, effect on engraftment of transplanted hematopoietic cells, and in vivo toxicity in immune deficient mice including a complete post-mortem examination. We found no evidence of toxicity attributable to the MSC or IFNγ primed MSCs. Our data suggest that the clinical risk of infusing MSCs or IFNγ primed MSCs produced by our two-step protocol is not greater than MSCs currently in practice. While actual proof of safety requires phase I clinical trials, our data support the use of either cell product in new clinical studies.

Publisher

Oxford University Press (OUP)

Subject

Cell Biology,Developmental Biology,General Medicine

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