International Society for Cellular Therapy perspective on immune functional assays for mesenchymal stromal cells as potency release criterion for advanced phase clinical trials

Jacques Galipeau,David F Stroncek,John Barrett,Peiman Hematti,Ivan Martin,Willem E Fibbe,Katarina Leblanc,Francesco Dazzi,Mauro Krampera,Daniel J Weiss,Donald G Phinney,Sowmya Viswanathan,Michael Mendicino,Mickey B.C Koh,Adrian P Gee,Joost Debruijn,Yufang Shi,Massimo Dominici,J M Gimble ,Valérie Planat ,Steve Kah‐Weng Oh ,Luis A Ortiz ,Robert Deans ,Ian Mcniece ,Luc Sensebé

doi:10.1016/j.jcyt.2015.11.008

Abstract

Mesenchymal stromal cells (MSCs) as a pharmaceutical for ailments characterized by pathogenic autoimmune, alloimmune and inflammatory processes now cover the spectrum of early- to late-phase clinical trials in both industry and academic sponsored studies. There is a broad consensus that despite different tissue sourcing and varied culture expansion protocols, human MSC-like cell products likely share fundamental mechanisms of action mediating their anti-inflammatory and tissue repair functionalities. Identification of functional markers of potency and reduction to practice of standardized, easily deployable methods of measurements of such would benefit the field. This would satisfy both mechanistic research as well as development of release potency assays to meet Regulatory Authority requirements for conduct of advanced clinical studies and their eventual registration. In response to this unmet need, the International Society for Cellular Therapy (ISCT) addressed the issue at an international workshop in May 2015 as part of the 21st ISCT annual meeting in Las Vegas. The scope of the workshop was focused on discussing potency assays germane to immunomodulation by MSC-like products in clinical indications targeting immune disorders. We here provide consensus perspective arising from this forum. We propose that focused analysis of selected MSC markers robustly deployed by in vitro licensing and metricized with a matrix of assays should be responsive to requirements from Regulatory Authorities. Workshop participants identified three preferred analytic methods that could inform a matrix assay approach: quantitative RNA analysis of selected gene products; flow cytometry analysis of functionally relevant surface markers and protein-based assay of secretome. We also advocate that potency assays acceptable to the Regulatory Authorities be rendered publicly accessible in an “open-access” manner, such as through publication or database collection.

Highlights

The Food & Drug Administration (FDA) has published guidance with recommendations for developing tests to measure potency for cellular and gene therapy (CGT) products.3 These recommendations are intended to clarify the potency information that could support an Investigational New Drug Application (IND) or a Biologics License Application
Similar guidance has been published by European Medicines Agency (EMA), which defines potency as the quantitative measure of biological activity based on the attribute of the product, which is linked to the relevant biological properties
This guidance is focused on release potency assays, these remain tightly coupled to companion identity assays that themselves likely require refinement from the original 2006 International Society for Cellular Therapy (ISCT) position paper [1] as new knowledge on Mesenchymal stromal cells (MSCs)-like cells from various tissue sources is gained by the field at large

Summary

Introduction

The FDA has published guidance with recommendations for developing tests to measure potency for CGT products. These recommendations are intended to clarify the potency information that could support an IND or a Biologics License Application. FDA guidance defines potency (strength is synonymously used) as the therapeutic activity of the drug product as indicated by appropriate laboratory tests or by adequately developed and controlled clinical data. There is no single test that can adequately measure product attributes that predict clinical efficacy Taking into consideration this limitation, the potency assay should represent the product’s mechanism of action (i.e., relevant therapeutic activity or intended biological effect). The traditional approach for assessing the potency of biological products is to develop a quantitative biological assay (bioassay) that measures the activity of the product related to its specific ability to affect a given result and that meets the criteria required by Regulatory Authorities (Table II)

Methods

Conclusion