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My Translational View
6th International Symposium on Stem Cell Therapy& Cardiovascular Innovations
Madrid, April 23-24, 2009
Cardiac Cell Therapy : The Translational Leap
Bench
To
Bedside
Models
Translation
Trial design
Concept
Regulation
Bench
The Gatekeepers
Cell Therapy : The Translational Leap
Key Steps of the Process CMC package Preclinical testing Delivery system evaluation
Cell Therapy : The Translational Leap
The CMC Package : Chemistry Traceability of starting and raw materials, including cells if allogeneic Preferential use of xeno-free products Clinical upgrade of antibodies used for yielding a cell population enriched for a specific surface antigen
Cell Therapy : The Translational Leap
The CMC Package : Manufacturing Cell processing and scale-up in GMP-approved facilities Detailed description of storage/shipping/labeling conditions Implementation of quality-approved processes for ensuring product consistency until release
Cell Therapy : The Translational Leap
The CMC Package : Controls Sterility Oncogenicity (whenever relevant) Safety/quality of the selection system Detailed description of release criteria :
Phenotypic characterization StabilityPurity PotencyViability
Cell Therapy : The Translational Leap
Key Steps of the Process CMC package Preclinical testing Delivery system evaluation
Cell Therapy : The Translational Leap
Preclinical Testing In vitro data (i.e., immunophenotype, functional assays) Small animal models (comparative screening of cell types, cell survival and differentiation, potential safety issues) Large animal models
Nature Methods 2009;6:257-61.
*P = 0.016
Cell Therapy : The Translational Leap
Why Large Animal Models Are Mandatory They yield functional data which are more reliable than those generated in rodents They allow a closer simulation of clinical settings They provide the only possiblity of testing clinically relevant cell delivery route and systems
Klocke et al. Cardiovasc Res 2007;74:29-38.
Limitations of Small Animal ModelsComparative duration of action potentials and resting EKGs
between rodent and human
The G-CSF Saga
Harada et al. Nature Medicine 2005;11:305-11.
G-CSF prevents cardiac remodeling after myocardial infarction by activating the Jak-Stat pathway in cardiomyocytes
Influence of mobilized stem cells on myocardial infarct repair in a nonhuman primate model
Norol et al. Blood 2003;102:4361-8.
Abdel-Latif et al. Am Heart J 2008;156:216-26.
Meta-analysis of RCTs
Cell Therapy : The Translational Leap
Why Large Animal Models Are Mandatory They yield functional data which are more reliable than those generated in rodents They allow a closer simulation of clinical settings They provide the only possiblity of testing clinically relevant cell delivery routes and systems
Markkanen et al. Cardiovasc Res 2005;65:656-64.
Cell Therapy : The Translational Leap
Dosing Scalability Distribution
Cell Therapy : The Translational Leap
Why Large Animal Models Are Mandatory They yield functional data which are more reliable than those generated in rodents They allow a closer simulation of clinical settings They provide the only possiblity of testing clinically relevant cell delivery routes and systems
Eur J Cardio-thorac Surg 2003;24:393-8.
Effect of Delivery Technique on MSC Engraftment
Freyman et al. Eur Heart J 2006;27:1114-22.
Pig model of MI; Tx of iridium-loaded male MSCs (50 million) ; Ex vivo measurement of the iridium nanoparticle concentration in the infarct
Hofmann et al. Circulation 2005;111:2198-2202.
Myocardial Homing of Unselected Bone Marrow CellsFollowing Intravenous/Intracoronary Transfer
Cell Therapy : The Translational Leap
Key Steps of the Process CMC package Preclinical testing Delivery system evaluation
Cell Therapy : The Translational Leap
Delivery System Evaluation In vitro testing of mechanical performance (i.e., burst pressure, flow rate, tensile/bending and torsional strength) Delivery system/patient biocompatibility Delivery system/product biocompatibility (i.e., cell viability, activity, adhesion to the device)
Bekarta et al. Acad Emerg Med 2003;10:684-7.
Animal studies that do not utilize randomization and blindingare 5 times more likely to be outcome-positive than studies that use either
or both of these methods
Impact of Randomization and Blinding on the Outcome of Animal Studies
Wylan et al. Nature Biotechnology 2005;23:807-15.
Cardiac Cell Therapy ; The « Reverse » Translational Leap
Cell Therapy : The Translational Leap
Keys to a Successful Bench to Bedside Process
■ Upfront interactions with the regulatory authorities and regular update of the guidance documents to incorporate new knowledge
■ Tight cooperation between the clinical and basic scientist project managers to try achieving a reasonable trade-off between preclinical data, regulatory constraints and practicality of clinical implementation
■ Acceptance that « zero risk does not exist »
Cell Therapy : The Translational Leap
Keys to a Successful Bench to Bedside Process
■ Upfront interactions with the regulatory authorities and regular update of the guidance documents to incorporate new knowledge
■ Tight cooperation between the clinical and basic scientist project managers to try achieving a reasonable trade-off between preclinical data, regulatory constraints and practicality of clinical implementation
■ Acceptance that « zero risk does not exist »
Cell Therapy : The Translational Leap
Keys to a Successful Bench to Bedside Process
■ Upfront interactions with the regulatory authorities and regular update of the guidance documents to incorporate new knowledge
■ Tight cooperation between the clinical and basic scientist project managers to try achieving a reasonable trade-off between preclinical data, regulatory constraints and practicality of clinical implementation
■ Acceptance that « zero risk does not exist »