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 »