Ensuring the safety of cell therapy: a quality control pipeline for cell purification and validation

Ensuring the safety of cell therapy: a quality control pipeline for cell purification and validation

Funding Type: 
Early Translational I
Grant Number: 
TR1-01250
Award Value: 
$5,830,771
Collaborative Funder: 
Victoria, Australia
Stem Cell Use: 
Embryonic Stem Cell
iPS Cell
Status: 
Closed
Public Abstract: 
The clinical application of cell replacement therapy in the US is dependent on the FDA's approval, and the primary objective of the FDA is to protect patients from unsafe drugs and procedures. The FDA has a specific mandate for human gene and cell therapy and since the unexpected deaths in early trials of gene therapy trials the bar for safety in these areas is unusually high. This is a summary of the key findings from the FDA's report on human embryonic stem cell therapy (April 2008): "From the perspective of toxicology, the proliferative potential of undifferentiated human embryonic and embryonic germ cells evokes the greatest level of concern. A characteristic of hESCs is their capacity to generate teratomas when transplanted into immunologically incompetent strains of mice. Undifferentiated hESCs are not considered as suitable for transplantation due to the risk of unregulated growth. Before clinical trials are begun in humans, the issue of unregulated growth potential and its relationship to stem cell differentiation must be evaluated". In order to overcome the concerns about the safety of pluripotent stem cell therapy, we have designed a pipeline of quality control measures that can be applied to any cell type that is being considered for Investigational New Drug (IND) approval by the FDA. The technologies that we will develop under this award will allow rigorous selection and characterization of cells before they are tested as transplants. By reducing the possibility that stem cell therapies will be toxic or cause cancer in patients, we will remove the major barriers to advancement of these therapies to the clinic.
Statement of Benefit to California: 
Californians are a large and diverse population that poses unique challenges for the future of medical care. Fortunately, California has a tradition of taking the lead in technology and medical breakthroughs and following through from the first idea to the final product. Almost 20,000 Californians await organ transplants, and more than a million suffer from progressive degenerative diseases and injuries such as Alzheimer disease, Parkinson’s disease, nerve-muscle disease such as amyotrophic lateral sclerosis (ALS) and muscular dystrophy, liver disease, diabetes, and spinal cord injury. The possibility of applying cell replacement therapy to these problems could drastically improve the outlook for treatment for the victims. A major goal for California's supporters of stem cell research is development of stem cell-based products that have medical use, and the mandate for the research community is to provide the best possible fundamental information to help guide clinical applications to make these cells as safe as is possible for cell therapy, by ensuring that they retain normal, noncancerous qualities. California scientists have taken the first steps to clinical applications of pluripotent stem cells through their cutting edge research in developing new ways to derive these cells and to differentiate them into cell types that can be used to replace damaged tissues. We propose to take this research to the next step, to prepare the cells for clinical trials. We propose to develop a comprehensive pipeline of quality control technologies that will ensure the safety and purity of cells used first for preclinical testing and later for obtaining IND approval from the FDA for initiating human trials. These technologies can be used for any cell therapy, and will considerably reduce the barriers to development of safe, effective new treatments for incurable disease. This will have a positive effect on the health care of all Californians, reduce the cost of development of cell therapies, and create new opportunities for jobs and industry in the state.
Progress Report: 

Year 1

One of the chief concerns about the clinical application of stem cells to cell therapy is the safety of the cells after they are transplanted. This research program addresses safety bottlenecks that are common to all stem cell-based therapies. We have two general goals. The first goal is to generate a set of methods that can be used to rid populations of cells to be transplanted of any contaminating stem cells that might be capable of forming tumors. The second goal is to develop methods to identify and purify the cell type that is most likely to be therapeutic. Over the first year of this joint California/Victoria partnership, the research work has progressed according to the plans described in the grant application, and all milestones have been met.

Year 2

One of the chief concerns about the clinical application of stem cells to cell therapy is the safety of the cells after they are transplanted. This research program addresses safety bottlenecks that are common to all stem cell-based therapies. We have two general goals. The first goal is to generate a set of methods that can be used to rid populations of cells to be transplanted of any contaminating stem cells that might be capable of forming tumors. The second goal is to develop methods to identify and purify the cell type that is most likely to be therapeutic. Over the second year of this joint California/Victoria partnership the research has progressed according to the plans described in the grant application and all millestones have been met.

Year 3

The goal of this project is to develop methods for improving the safety of human pluripotent stem cell-based therapies. The methods we have developed are based on in-depth molecular analysis of stem cells and their derivatives. We have developed the largest, most comprehensive database of molecular profiles of undifferentiated profiles, which includes gene expression, genomic integrity, and epigenetic analysis of thousands of stem cell lines and adult and human tissues. This has allowed us to benchmark our progress toward producing quality-controlled cells for clinical use. Among our accomplishments beyond the database are new methods for purging cultures of potentially dangerous undifferentiated cells, capturing single circulating tumor cells from the bloodstreams of melanoma patients, and the first successful full RNA sequencing of single cells. These new tools will improve the quality of research and clinical development throughout the stem cell community. We have accomplished all of our original milestones and are extending the work to include new methods.

Year 4

The goal of this project is to develop methods for improving the safety of human pluripotent stem cell-based therapies. The methods we have developed are based on in-depth molecular analysis of stem cells and their derivatives. We have developed the largest, most comprehensive database of molecular profiles of thousands of stem cell lines as well as adult stem cell lines and primary human tissues. This has allowed us to benchmark our progress toward producing quality-controlled cells for clinical use. Among our accomplishments beyond the database are new methods for purging cultures of potentially dangerous undifferentiated cells, capturing single circulating tumor cells from the bloodstreams of melanoma patients, and the first successful full RNA sequencing of single cells. These new tools will improve the quality of research and clinical development throughout the stem cell community. We have accomplished all of our original milestones and are extending the work to include new methods.

© 2013 California Institute for Regenerative Medicine