Over the last 25 years, gene and cell therapy has made enormous progress. In the early 2000s, clinical gene therapy experienced setbacks due to adverse events experienced by patients. Since then, dedicated translational research work performed at academic facilities laid out the path toward safe and efficacious gene therapy applications, and particularly stem cell gene therapies (1). The best example for this would be the successful translation of stem cell gene therapy for ADA deficiency from basic to clinical research, and then into a marketed product. A first clinical trial of stem cell gene therapy for ADA deficiency was performed in 1994, 23 years later, the approved product is called “Strimvelis”, and is marketed by Glaxo Smith Kline (2).
In order to align an advanced therapy medicinal product (ATMP) with market expectations and also commercial success, an affordable and reimbursable product is needed. Therefore, optimisation of product costs (3) and the early discussions with relevant authorities on reimbursement strategies (4) play a key role in transforming these products into standard of care therapeutics (5). ATMPs that include autologous products, such as the recently FDA approved CAR T cell therapies Kymriah (Novartis) and Yescarta (Gilead), are a particular challenge. The use of the patient's own cells limits the scope for scaling up manufacturing. Rather, efficient product manufacturing for each individual autologous product is required (6). Since lentiviral vectors have become important tools for gene therapy, particularly for clinical applications of gene therapy, is has also become necessary to manufacture affordable and high quality lentiviral vector while minimising reagent use and personnel time required. Automation and closed system manufacturing will become of great importance in these applications (7). In contrast, for allogeneic products, early on, greater emphasis needs to be put into developing systems to appropriately scale up product manufacturing, while retaining product efficacy. The enormous challenge here is to achieve all of that under conditions that will lower cost and speed up production (6).
Figure 1: Successful translational research fosters multidirectional and multidisciplinary integration of various elements along the discovery-translation-adoption continuum in order to accelerates laboratory discoveries into treatments for patients
Once a product has been translated into a clinical product and has gone through all necessary testing, it is important that providers of such therapies are appropriately trained to safely and effectively apply them (8). The required infrastructure and training for physicians and their support personnel will be required (2). This can most likely be achieved in specialised centres that are already set up to provide educational programs (2). In this training it should also be emphasised that physicians communicate with patients clearly the risks and benefits of these novel therapies (5).
The role of regulators and regulations should not be underestimated in the process of gene and cell therapy development. During the short history of this evolving field, regulators have already played a major role in keeping these new therapies safe (9). Enlightening examples are an in vivo gene therapy application for ornithine transcarbamylase deficiency, and a stem cell gene therapy application for X linked SCID (10). After adverse effects of the treatments during clinical trials, regulators suspended the trials and asked the research community to get to the bottom of the issue. Only several years later could clinical trials be resumed with much stricter regulations in place, and with valuable knowledge gained for both researchers and regulators. However, as research evolves and new safety and efficacy data is generated, regulations will also have to continue to evolve (11). Currently, a strong focus is being put on harmonising regulations between countries (12), accelerating therapeutic development (13), and sharing of data from pre-clinical and clinical research with the public (12).
As already pointed out, CAR T cell therapies are currently among the most prominent and most therapeutically useful ATMP applications. The technology was first developed in academic settings, but the creation of a successful academic / industrial partnership has led to 2 commercially approved CAR T cell products on the US market (14). Clinical investigations for new indications using this therapeutic platform continue, and large pool of data is being generated. It will be important to utilise such “big data” to continue building a strong safety and efficacy profile for these novel therapies.
It is vital that any modern research application is also aligned with ethical requirements. For instance, genome editing used for germline modification is highly debated; however, something even more pressing is the unauthorised and unregulated use of stem cell applications (15). People are lured into unregulated stem cell clinics, and are asked to pay large amounts of money to receive unproven and perhaps even dangerous “stem cell therapies”. Patient advocacy is highly needed to curb such practices, and raising awareness among patients and members of the public should be an important priority (16).
In summary, the field of ATMPs has clearly evolved over the last few years with the availability of efficient gene and cell therapy products on the market. Academic research has been the driving force in this field, contributing with the inception of novel technologies and early development of promising products (17). With the current focus of academic centers on implementing multidirectional and multidisciplinary translational research capabilities (Figure 1), it is anticipated that several more ATMPs currently in the clinical development pipeline will receive marketing approval in the near future. The next big challenge will be the large scale manufacturing of gene and cell therapy products, their affordability and accessibility in not just wealthy countries, but throughout the entire world (4, 6). At the same time, unauthorised applications of products such as stem cell therapies need to be curbed. Collaboration among researchers from academia and industry, patient advocates and regulators will be required, on both national and international stages. Only with such collaboration can novel products reach their full potential to reduce suffering and facilitate cures for debilitating diseases.
For further reading please refer to the full bibliography.
1. Bauer, G., and M. Abou-El-Enein. 2016. Clinical translation of viral vectors for gene therapies and beyond. Cell Gene Ther. Insights 2: 507–511.
2. Abou-El-Enein, M., A. Elsanhoury, and P. Reinke. 2016. Overcoming Challenges Facing Advanced Therapies in the EU Market. Cell Stem Cell 19: 293–297.
3. Abou-El-Enein, M., A. Römhild, D. Kaiser, C. Beier, G. Bauer, H.-D. Volk, and P. Reinke. 2013. Good Manufacturing Practices (GMP) manufacturing of advanced therapy medicinal products: a novel tailored model for optimizing performance and estimating costs. Cytotherapy 15: 362–83.
4. Abou-El-Enein, M., G. Bauer, and P. Reinke. 2014. The business case for cell and gene therapies. Nat. Biotechnol. 32: 1192–1193.
5. Abou-El-Enein, M., G. Bauer, and P. Reinke. 2015. Gene therapy: A possible future standard for HIV care. Trends Biotechnol. 33: 374–376.
6. Abou-El-Enein, M., G. Bauer, N. Medcalf, H.-D. Volk, and P. Reinke. 2016. Putting a price tag on novel autologous cellular therapies. Cytotherapy 18.
7. Mock, U., L. Nickolay, B. Philip, G. W.-K. Cheung, H. Zhan, I. C. D. Johnston, A. D. Kaiser, K. Peggs, M. Pule, A. J. Thrasher, and W. Qasim. 2016. Automated manufacturing of chimeric antigen receptor T cells for adoptive immunotherapy using CliniMACS Prodigy. Cytotherapy 18: 1002–1011.
8. Abou-El-Enein, M., G. N. Duda, E. A. Gruskin, and D. W. Grainger. 2017. Strategies for Derisking Translational Processes for Biomedical Technologies. Trends Biotechnol. 35: 100–108.
9. Abou-El-Enein, M., G. Bauer, P. Reinke, M. Renner, and C. K. Schneider. 2014. A roadmap toward clinical translation of genetically-modified stem cells for treatment of HIV. Trends Mol. Med. 20: 632–642.
10. Kohn, D. B., M. Sadelain, and J. C. Glorioso. 2003. Occurrence of leukaemia following gene therapy of X-linked SCID. Nat. Rev. Cancer 3: 477–488.
11. Abou-El-Enein, M., T. Cathomen, Z. Ivics, C. H. June, M. Renner, C. K. Schneider, and G. Bauer. 2017. Human Genome Editing in the Clinic: New Challenges in Regulatory Benefit-Risk Assessment. Cell Stem Cell 21.
12. Abou-El-Enein, M., and C. K. Schneider. 2016. Deciphering the EU clinical trials regulation. Nat. Biotechnol. 34.
13. Elsanhoury, A., R. Sanzenbacher, P. Reinke, and M. Abou-El-Enein. 2017. Accelerating Patients’ Access to Advanced Therapies in the EU. Mol. Ther. - Methods Clin. Dev. 7: 15–19.
14. June, C. H., S. R. Riddell, and T. N. Schumacher. 2015. Adoptive cellular therapy: A race to the finish line. Sci. Transl. Med. 7: 280ps7–280ps7.
15. Sipp, D., T. Caulfield, J. Kaye, J. Barfoot, C. Blackburn, S. Chan, M. De Luca, A. Kent, C. McCabe, M. Munsie, M. Sleeboom-Faulkner, J. Sugarman, E. van Zimmeren, A. Zarzeczny, and J. E. J. Rasko. 2017. Marketing of unproven stem cell–based interventions: A call to action. Sci. Transl. Med. 9: eaag0426.
16. Bauer, G., M. Abou-El-Enein, A. Kent, B. Poole, and M. Forte. 2017. The path to successful commercialization of cell and gene therapies: empowering patient advocates. Cytotherapy 19: 293–298.
17. Abou-El-Enein, M., H.-D. Volk, and P. Reinke. 2017. Clinical Development of Cell Therapies: Setting the Stage for Academic Success. Clin. Pharmacol. Ther. 101.