Exploring Sources of Variability Related to the Clinical Translation of Regenerative Engineering Products Proceedings of a Workshop (2019) / Chapter Skim
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3 Factors Contributing to Patient Variability
3 Factors Contributing to Patient Variability
Pages 23-40
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From page 23... ...
• There is a need to collect more immunologic data from clinical trials in order to learn about patient variability and the role that variability plays in disease. (Badylak, Elisseeff, Roy)
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Joseph Wu, the director of the Stanford Cardiovascular Institute, described the factors that contribute to variability in patient outcomes in cardiovascular stem cell clinical trials. Steve Badylak, a professor of surgery at the McGowan Institute for Regenerative Medicine at the University of Pittsburgh, showed how unacceptable variability can result in acceptable outcomes.
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Biomaterials are broadly classified as either biological or synthetic. Biological materials, such as the scaffolds derived from the extracellular matrix of tissues, can promote tissue repair.1 Synthetic materials can provide greater physical control over their properties, but they can also elicit a foreign body response when implanted, leading to tissue fibrosis (the formation of excess tissue)
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Immune cells and the immune environment set the stage for later regenerative processes (e.g., vascularization, stem cell mobilization, tissue matrix growth)
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The study is assessing cell migration over time and the biological activity of the scaffold and its impact on the immune environment. A participant asked Elisseeff to expand on the potential impact of the immune response in clinical trials, such as in the response to sham controls or to off-target injection of cells that might be stimulating the immune system and the wound-healing response.
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OUTCOME VARIABILITY IN CARDIOVASCULAR STEM CELL TRIALS To date, Wu said, more than 7,000 cardiovascular patients have been treated with adult stem cells as participants in a wide range of randomized clinical trials of regenerative medicine products (Fernández-Avilés et al., 2017)
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• Dosing. Clinical trials of cardiac stem cell therapies generally administer a one-time dose of 20 million to 200 million cells (Nguyen et al., 2016)
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In particular, Wu said, the challenge is to determine how the particular pathway that is being targeted remains activated. Wu briefly described several examples of how investigators are working to bring cardiovascular stem cell therapies to clinical trials.
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In cardiology, many investigational products fail in clinical trials, he said, and, as a result, cardiology clinical trials are generally very large to allow the determination of the effect of the product in light of high rates of placebo effects. Still, Wu said, the efforts should be continued because valuable knowledge is being gained from these clinical trials.
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This demonstrates the importance of immunomodulation in regenerative medicine approaches, he said. Badylak added that he and Elisseeff had recently launched a new journal, Journal of Immunology and Regenerative Medicine, to address some of these issues.5 More immunological data should be collected in clinical trials because they would provide an opportunity to learn about the role of the immune system, Badylak said, agreeing with Elisseeff and Wu.
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He said that pre clinical tudies in animals had helped to uncover how the implanta s tion of bio aterial had led to the development of tendon, cartilage, or m muscle rather than scar tissue. Echoing Elisseeff, he said that the immune response plays an important role in how the biomaterial is received by
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Stem cells that were recruited to the site differentiated into muscle cells. Patient functional performance was also assessed, and, on average, patients showed at least 25 percent improvement in strength and function.
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Badylak described a regenerative medicine study performed in patients with advanced esophageal conditions, all with non-operative comorbidities. Badylak and colleagues developed an endoscopic technique to remove the esophageal mucosa, completely denuding the inside of the esophagus.
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ALLOGENEIC CELL THERAPY FOR DEGENERATIVE DISC DISEASE DiscGenics is a clinical-stage biotechnology company developing cell therapies for patients with degenerative disc disease, Flanagan said. Low back pain is a global health problem and a leading cause of disability worldwide, affecting about one-quarter of the population.
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Flanagan described the two-part cell manufacturing process in this way: in the first part, donor tissue is collected, and intermediate cells are generated, analyzed for purity and potency, and cryopreserved, while the second stage of manufacturing involves culturing the intermediate cells, generating the discogenic cells, finalizing the formulation of the product, and cryopreserving the final allogeneic cell therapy product. These cells must pass a second checkpoint for potency, safety, identity, and purity.
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In addition, a clinical trial notification has been filed with the Japanese regulatory authority to begin a clinical trial there.8 Patients enrolled in the U.S. study have painful, single-level lumbar degenerative disc disease (3 to 7 on a Modified Pfirrmann scale; pain for 6 months; unresponsive to conservative care for 3 months)
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Injecting cells therapeutically, even if a large percentage of those cells die, can still induce healing and clearance of senescent cells if some cells survive. She reiterated the need to be open to the possibility of different mechanisms when analyzing the results of clinical trials, even if preclinical studies show the growth of the tissue.
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