7

Looking Toward the Future: Concluding Thoughts

Over the course of the workshop, several themes emerged, highlighting common challenges, areas of opportunity, and prospects for future innovation. In the final session of the workshop, George Daley, the director of the Stem Cell Transplantation Program at the Boston Children’s Hospital and the Dana-Farber Cancer Institute and the dean of Harvard Medical School, provided his thoughts on the state and direction of research in regenerative medicine. Daley and a panel of stakeholders then summarized their individual views of the key themes that emerged throughout the workshop and added their perspectives about the prospects for regenerative medicine and the roadblocks that must be addressed in order to move forward.

HYPE AND THE PROMISE FOR CHANGE

Daley began by proposing a paradox, prompted by a Boston Globe opinion piece by Eric Lander titled “Hype vs. Hope in Medical Research.”¹ In the article, Lander explored whether the promise of genomic medicine was overhyped, arguing that the hype surrounding genomic medicine is contradictory, because there is great potential for genomics to change the state of medicine, but it will be many years before its full potential is realized. The field of regenerative medicine faces the same issue, Daley said. In Lander’s piece he invokes Amara’s Law, which states that we tend to overestimate the effect of a technology in the short run and

___________________

¹ To read the full article from the Boston Globe, see https://www.bostonglobe.com/opinion/2016/10/12/hype-hope-medical-research/nY3hXS67HT0mQ78BGmQQfJ/story.html (accessed December 15, 2016).

underestimate the effect in the long run. Amara’s Law applies to regenerative medicine as well, Daley said, because while these exciting cell-based approaches are unlikely to drastically change medical care in the near term, the field holds great promise for transformation in the long term.

THE PATHWAY TO DEVELOPING NEW TECHNOLOGIES

Emerging medical technologies usually take 20 to 30 years to mature, Daley said, reflecting on the advent of recombinant DNA technology by Stanley Cohen and Herbert Boyer in 1973, which enables targeted, individual fragments of DNA from a donor genome to be inserted into vector DNA molecules such as plasmids, which can then be amplified in bacteria (Griffiths et al., 1999). Recombinant DNA technology allowed researchers to target DNA sequences that code for specific proteins, which could then be inserted into plasmid vectors and used to produce the desired protein in bacteria. Remarkably, the first recombinant protein product, Humulin, was brought to market by Eli Lilly in 1982, Daley said, but the broader impact of the technology was not realized until the release of Epogen in 1989, which was followed by several other protein therapeutics brought to market in the early 1990s.

Monoclonal antibodies, pioneered by Kohler and Milstein (1975), followed a similar trajectory. Orthoclone OKT3, an immunosuppressive drug used to prevent rejection in solid organ transplants and the first monoclonal antibody approved for use in humans, was approved by the Food and Drug Administration (FDA) in 1985, but again, it took more than 20 years before monoclonal antibody drugs became commonplace with the development of Rituxan, Herceptin, and others in the late 1990s, said Daley. Fire et al. (1998) successfully used RNA interference (RNAi) to manipulate gene expression in C. elegans in 1998, shared Daley, but there is still no product clinically available that uses that technology.

Stem cells and cellular therapies have followed this pattern, too, said Daley. Society is already reaping the benefits of years of research and investment in some cell-based therapies, such as hematopoietic stem cell therapy, he stated, highlighting the recent progress in applying gene editing and recombinant DNA approaches to T cell modification and other hematopoietic stem cell therapies. However, therapies that rely on other kinds of stem cells are still years away from success in the clinic. Research on embryonic stem cells, which were isolated and characterized in mice in 1997, has resulted in clinical data with indications of efficacy in

treating macular degeneration, spinal cord injury, and Parkinson’s, but has yet to result in a commercially available Food and Drug Administration (FDA)-approved product, Daley said. It has been also challenging to develop clinical therapies using induced pluripotent stem (iPS) cells, which were pioneered in 2007. They have proven invaluable as a tool for modeling disease and screening for potential drugs, but there have been few cases where patients have received iPS cell therapies in the clinic (Scullideri, 2016). The hope that accompanied the emergence of both embryonic stem cells and iPS cells as potential new regenerative approaches to treat disease has been tempered by the decades-long research and development process that has yet to yield an FDA-approved product, Daley said, but the field is on the cusp of success, with promising therapies to treat neurologic diseases currently in clinical trials and with remarkable progress having been seen in the field of in vitro gametogenesis to treat infertility.

CHALLENGES FACING THE FIELD

Deriving the medically relevant cell type is a significant challenge in the field of regenerative medicine, Daley said. Finding, characterizing, and growing the right cell is a decades-long investment, he said, as demonstrated by Lorenz Studer’s work with pluripotent stem cells and his success in “pharmaceuticalizing” a cell by understanding its identifying characteristics, potency, and developmental pathway. There is no substitute for a deep mechanistic understanding of the way cells work, Daley said. Progress is hampered by a lack of clear definitions of cell identity and cell function, which are necessary to assign sufficient confidence in a given cell type and predict its therapeutic efficacy.

Related to the challenge of defining the right cell is the challenge of identifying the right time for the clinical translation of new research. Because the research and development pathway is still unclear for the field, there is a risk of premature clinical translation, Daley said. Without clear definitions or a strong mechanistic understanding of a proposed therapy, there is an increased chance that weak clinical hypotheses will be pushed through the regulatory process, only to result in expensive failures. The field is “drowning in failures and in the expense,” he said, advocating that the solution should not be to reduce regulatory burden, but to hold the scientific community to a higher standard of understanding at the preclinical level and to bring stronger hypotheses to the clinic for testing.

INTERNATIONAL SOCIETY FOR STEM CELL RESEARCH GUIDELINES FOR STEM CELL RESEARCH AND CLINICAL TRANSLATION

Holding research to a higher standard begins with the scientific community. The International Society for Stem Cell Research (ISSCR) acts as a steward of the field of regenerative medicine by bringing together scientists and clinicians involved in stem cell research and promoting high scientific standards through communication and the development of guidelines for the responsible conduct of research, Daley said. In May 2016 the ISSCR released an updated set of guidelines for stem cell research and clinical translation.² The initial set of guidelines was meant to assist researchers in the controversial field of embryonic stem cells, but it has evolved into a broader effort to guide the clinical translation of stem cell therapies. The updated ISSCR guidelines set very high standards and aspirational goals for the scientific community rather than concrete criteria because there is so much variability between cell types and potential therapeutic applications, Daley said. The new guidelines are intended as a roadmap for the field moving forward to support the conduct of high-quality research and safe and effective clinical trials. The ISSCR’s principles, as outlined by Daley, are below:

• Clinical protocols should undergo independent, expert peer review that is free from conflicts of interest in order to set a high standard for any clinical hypotheses brought into clinical testing.
• Clinical trials should be held to a high standard of safety and efficacy, and the potential benefit of protocols should be easily and clearly weighed against well-defined risks.
• Standards for manufacturing and processing must be high to support the development of products that are consistent, safe, and effective.
• There should be high standards for efficacy and a mechanistic understanding of a therapy as a precondition for entering clinical trials and the eventual marketing of the therapy. Efforts to reduce the regulatory hurdles should be met with “healthy skepticism”

___________________

² To read the complete Guidelines for Stem Cell Research and Clinical Translation from ISSCR, please see http://www.isscr.org/docs/default-source/guidelines/isscr-guidelines-for-stem-cell-research-and-clinical-translation.pdf?sfvrsn=2 (accessed December 15, 2016).

• because lower standards will risk patients’ safety and increase the risk of failure.

• In a fledgling field, such as regenerative medicine, there is the potential for financial conflicts of interest that can corrupt the process of product development. The scientific community should consider carefully whether efforts in the regulatory or product development pathways are driven by commercial interests or patient need.

These principles must be considered in the review and implementation of new regulatory laws, Daley said. Congressional efforts such as the Reliable and Effective Growth for Regenerative Health Options that Improve Wellness (REGROW) Act pose a risk to the field by reducing the regulatory burden on cellular therapies through conditional approval on the basis of preliminary evidence of safety and efficacy, he said. The ISSCR is opposed to the REGROW Act and to any efforts that seek bring therapies to patients faster at the cost of failing to conduct sufficient research into the mechanism and safety of a new product, Daley said, emphasizing that the majority of new drugs fail, even after collecting early Phase II clinical trial data.

MOVING FORWARD

“In the 20th century, scientists learned how to turn chemistry into medicine,” Daley said. “Regenerative medicine is going to be the medicine of the 21st century.” He added that it will take decades but that scientists will learn how to transform cells into medicines. In short, he said, the path will be long and difficult, but regenerative medicine is going to transform medicine. The integrity of the research enterprise should be foremost in planning for the future. Patient welfare, respect for research subjects, transparency around the research process, and access to new regenerative therapies will be essential, he continued. The Forum on Regenerative Medicine can support this effort by continuing to convene stakeholders in the field and by illuminating opportunities and challenges of regenerative medicine in a responsible way, he suggested. By investing in the deepest scientific understanding of regenerative therapies, the field will continue to sustain support from the National Institutes of Health and from the investors who will carry promising research forward into the clinic.

PANEL DISCUSSION

Daley and a panel of presenters reflected on the workshop and shared their insights about issues that emerged over the course of the day. Panel participants identified and discussed several common themes that had emerged throughout the workshop. These themes are described below.

Understanding and Characterizing Cells

One major challenge facing research in regenerative medicine, Daley said, is deriving the medically relevant cell types and defining them in such a way that they can be assigned an identity and produced with reliable potency that can enable the development of a dose–response relationship in clinical trials. In addition to assembling a deep understanding of how cells work, Srivastava said, more research is needed on the development of cell identity in order for researchers to be able to harness the ability of endogenous cells to regenerate or convert to other cell types. It is not enough to have the right cell and understand the biology of the cell, Tsukamoto said; in order to see the biological activity that is hypothesized, “you have to have the right disease target [and] the right kind of patients for your first clinical trial.”

Another challenge with using cells in clinical therapies is understanding and manipulating the maturation process, Srivastava said. Most human cells that are generated follow the maturation timeline of human development, he said, citing Studer’s keynote talk. For example, when cardiomyocytes are made from human pluripotent cells, they take months to fully and functionally integrate. During this time, they are not providing benefit to the patient, and they may also have negative consequences such as triggering arrhythmia. In his experimental therapies for Parkinson’s, Studer said, pluripotent stem cells take between 6 and 12 months to mature, which is not optimal for patients and also makes the conduct of clinical trials more challenging. The maturation of cells is a universal problem across cell types and disease areas, Srivastava said, adding that he hopes that if the issue can be solved for one type of cell, the solution may apply to all cells. There is pressure to do in vitro cell characterization because in vivo characterizations are more challenging and take longer, Tsukamoto said, noting that with certain cells, such as human neural stem cells (HuCNS-SCs^®), in vitro characterization does not seem to be predictive of activity in vivo. The in vitro properties of the cells that ended up engrafted and survived long term were identical to the in

vitro properties of the cells that did not engraft, she said. As cells are scaled up in vitro, it will be important to ensure that bioactivity is not lost during the manufacturing process, Tsukamoto said.

Improved Model Systems

Several participants spoke about the lack of good model systems for testing regenerative cell-based therapies. While animal models are not perfect, they may be useful for some purposes. For example, as a workshop participant noted, the Royal College of Surgeons (RCS) rat is not a good model for age-related macular degeneration (AMD), but because the RCS rat has inherited retinal degeneration, it can be used to study how cellular therapies to replace retinal pigment epithelium (RPE) will operate in a host whose RPE is not functioning. Animal models have also been used with success to study therapies for other diseases, such as Parkinson’s, as evidenced the by success of Studer’s research using a mouse model. The mdx mouse model for Duchenne muscular dystrophy has not been as successful, however. The mouse has seemingly been cured many times, while the afflicted boys have not been cured, Furlong said. Moving away from animal models may be appropriate for some types of research. For example, a workshop participant said, iPS cells have the potential to be more useful as a model for AMD. Over the course of the day, many speakers emphasized that animal models are useful for answering basic questions about safety and efficacy but that ultimately the effectiveness of a therapy can only be determined by using it in humans.

Clinical Translation

Additional basic research and higher standards of evidence are needed, Temple said, noting that high-quality and rigorous science tends to propel the most promising things into the clinic. Advancing only high-quality hypotheses would use time and resources in the most effective way to bring new and effective therapies to patients. Workshop participants discussed the challenge of determining what endpoints to measure in order to assess quality, potency, and function for regenerative cellular therapies, asking the panel how the need for a deep scientific understanding of the therapy can be balanced with innovation and the role of commercial investment in clinical translation. “We need to sustain a culture of innovation,” Daley replied. Public funding in the field does not have the resources to move research beyond the discovery phase, and invest-

ment by the biotechnology field is needed for clinical translation, he said. Increasing public funding of basic science may support the development of strong clinical hypotheses.

Overcoming Challenges Associated with Immunomodulation

The issue of immunomodulation was mentioned throughout the day as a major barrier to cell-based therapies. Studer listed five avenues that regenerative medicine could pursue in the future to address this issue: autologous cells, patient matched cells, human leukocyte antigen (HLA)matched cell banks, allogeneic off-the-shelf products, and universal donor cells. Each source of cells has its benefits and drawbacks. For example, Srivastava commented, while autologous cell transplants do not risk immune rejection, they may be “too expensive and face too many regulatory hurdles to be a realistic approach.” There are efforts under way to develop iPS cell banks with multiple HLA qualities that could be used for off-the-shelf products, he noted. Participants pointed out other methods on the horizon for avoiding immune rejection, including advances in conditioning therapies and the reprogramming of endogenous cells.

Another consideration, Tsukamoto said, is whether a single stem cell treatment will be sufficient to last for a patient’s lifetime. Transplanting cells into a patient has an immunological impact, and researchers should consider what the effect would be if patients must undergo multiple transplants. If there is an immune response the first time, Tsukamoto asked, what will happen with subsequent treatments?

Navigating Regulatory Pathways

There is a great deal of regulatory uncertainty with cell-based therapies because the regulatory path is still quite undefined, Studer said in his opening remarks, noting that FDA is grappling with how to regulate novel therapies and where to draw the line on the level of safety and efficacy evidence that is required before a treatment can enter clinical trials.

Participants asked whether the current regulatory framework is sufficient for these complex areas, including cell-based therapies and gene editing. FDA has multiple accelerated approval pathways, and these pathways are malleable and responsive to new science (e.g., the use of surrogate endpoints and biomarkers), Daley said. There is no need to change or relax the regulatory framework, he said, because if the research is based on a “deep mechanistic understanding of disease,” the

efficacy of the therapy should be evident. Regenerative medicine will transform what we do in the future, but it is hard and it is going to take time, Furlong said. Strong regulatory standards are important, but it will also be important to keep the patient in mind, she said, adding that advocacy groups, researchers, and regulators should consider partnering in their efforts to move the field forward.

Rethinking Funding Models

The decision to invest in the development of cell-based therapies is fraught with potential complications: the costs of research, development, and manufacturing may be untenably high; there may be uncertainty about whether a product will be approved by regulatory bodies; insurance companies may not pay for the therapy; and there is the possibility that patient or provider demand for a therapy will be lower than expected. In order to get these therapies to the patients who need them most, a workshop participant said, it may be necessary to develop alternative funding mechanisms. For example, reducing the cost of upfront investment through government incentives or other means may encourage companies to invest in cell-based therapies, commented a workshop participant, mentioning a UK program called the Regenerative Medicine Platform in which the government funds research in several key areas and makes the resulting data available for the entire research community. This solution increases the amount of research being done and facilitates the collection and analysis of data that may support future research. A workshop participant also discussed another UK-based program that provides government funding for clinical translation and conversion to good manufacturing practices. If a biotechnology company finds a new therapy promising, it is freely given to the company to continue the development process. It is unfortunate that there are not more public funds directed toward basic science, Daley said, noting that the return on public investment in fundamental research is “amplified and multiplied many fold.”

Several participants expressed concern that once cell-based therapies do reach the clinic, they will likely be one-time therapies and likely quite expensive. Our health care system is better geared toward paying for chronic therapy over many years, rather than for one-time procedures that will not recoup costs for many years, a participant said. Insurance companies are hesitant to “take the hit” on a high payment for such a therapy because there is no guarantee that the patient will stay with the

insurance company in the future, Ratcliffe said. Advocacy from patient groups could help overcome this hurdle, Furlong suggested.

Potential Future Approaches for Cell-Based Regenerative Therapies

There will be at least two major areas of growth for regenerative medicine, Srivastava said. One will be cell-based, and therapies in that area will be applied to treat diseases such as Parkinson’s, diabetes, and spinal cord injury. For cell-based therapies, the issues of maturation and cell differentiation will be significant hurdles to overcome, Srivastava predicted. The other area of growth will be in the development of treatments for diseases that are not responsive to cellular therapies. Regenerative approaches for these conditions will focus on harnessing the regenerative capacity of endogenous cells through reprogramming, stimulating cell division, or introducing external materials such as exosomes, he said.

Refocusing on Patients

While the workshop focused primarily on the state of the science of cell-based therapies, many individual speakers urged participants to keep the needs of patients in focus. There is an inherent tension, Furlong said, between giving patients the opportunity to access potentially life-saving therapies and upholding scientific and regulatory standards in order to ensure that products entering the market are safe and effective. Furlong added that for patients who may “only have one shot” at a potentially curative therapy, the risk–benefit analysis may be different than for other patients. “We have to rigorously address and adhere to standards,” she said. “But we also must keep the patient at the center of this and recognize desperate times call for desperate [measures]. We need to really address the patient first and always.” There are unproven therapies being offered by clinics across the country, catering to patients who are desperate for new therapies, Temple said, suggesting that researchers should increase their efforts to educate the patient community. Patient organizations should speak with a unified voice and call for higher standards, so that patients are not taken advantage of by these clinics, Tsukamoto said. Expectations need to be managed for patients and families as well as for providers, Furlong added, so that everyone involved understands that the path from discovery to clinic can be a long and winding one.

CONCLUDING THOUGHTS

In her concluding comments, forum co-chair Alta Charo noted that the need for scientific rigor in the research and development process as a precursor to strong clinical hypotheses had been a common area of emphasis across all of the panels, and she said that further study on standards and quality control, as well as on finding ways to reduce the upfront costs of developing new therapies, will support efficient and useful research. Although the workshop presentations covered different tissue areas, different cell types, and different health conditions, the challenges and opportunities that each presenter discussed were quite interrelated, Charo said. The Forum on Regenerative Medicine was designed for this very type of cross-fertilization, and its continued work will encourage stakeholders in the field to look for commonalities and overlapping interests “that will fire the imagination” and inspire collaboration, she concluded.

This page intentionally left blank.