TRANSLATION
Emerging Translation of Regenerative Therapies JG Allickson1 This translational report on the current field of emerging cell therapy and tissue engineering therapies includes the challenges and opportunities to accelerate clinical translation in regenerative medicine. Translation of regenerative medicine refers to the transfer from bench (proof-of-concept) to bedside (clinical trials), and finally commercialization. Regenerative medicine therapies have the capacity to replace, repair, and regenerate cells, tissues, and organs to restore normal function in the body. These emerging therapies are shifting the paradigm from treatment-based to cure-based therapies.
State of regenerative medicine
Cell therapy and regenerative medicine are in a new era coupled to a rapidly aging population. It is critical to charge ahead in this rapidly evolving field that faces an abundance of challenges paired with patient rewards. There has been significant progress in the last decade in many sectors of regenerative medicine. Clinical studies in regenerative medicine already include orthobiologics, musculoskeletal, cardiology, urology, neurology, sports medicine, diabetes, and wound healing. Examples of technology being offered to patients in the area of wound healing are Dermapure/ Tissue Regenix (decellularized dermis), Apligraft/organogenesis (cell-based product), and Dermagraft/organogenesis (scaffold plus cells). In the area of mucogingival conditions, GINTUIT/ organogenesis (cells and biomaterial); for nasolabial folds in adults, Laviv/fibrocell technologies (autologous cells); and for advanced prostate cancer, Provenge/Dendreon (autologous cells) have been prescribed. These products and others were approved by US Food and Drug Administration as a biologic, which required premarket approval. Other products used for regenerative medicine are listed on an US Food and Drug Administration tissue establishment registration. In general, these are minimally manipulated, for homologous use, not combined with another article, and does not have a system effect. There are a growing number of publications (8,0001 in PubMed) with close to 200 clinical trials posted on clinicaltrials.gov for a search entitled “regenerative medicine therapy.” The Alliance for Regenerative Medicine stated in their 2016 Q2 report that there are 704 companies in the field of regenerative medicine with more than half
in the United States. The field is starting to mature as we are advancing in clinical trials and commercializing products. Present studies in regenerative therapies
Chimeric antigen receptor T-cell is an engineered receptor immunotherapy that is demonstrating promising outcome in the treatment of blood cancers. Over the last decade, significant results with (chimeric antigen receptor) T-cell and other immunotherapy has moved rapidly toward clinical application and surprisingly demonstrated a disappearance of the leukemia cells refractory to many other forms of therapy. The Children’s Hospital of Philadelphia were one of the first to begin offering the therapy in 2012 for blood cancer, such as advanced acute lymphoblastic leukemia, now many companies are moving forward with immunotherapy, including, for example, Juno Therapeutics, Kite Pharma, Bluebird Bio, Adaptimmune, and Kiadis Pharma. Currently, close to 30 clinical trials are ongoing.1 Chimeric antigen receptor technology is now being tested in the solid tumors as well. With such incredible momentum in the space, the potential of moving these therapies to market looks promising. Other technology that was cleared for clinical trial is a therapeutic genome editing using a zinc finger nuclease-mediated approach to treat mucopolysaccharidosis type II (Hunter syndrome) by Sangamo BioScience. Clustered regularly interspaced short palindromic repeats (CRISPR) technology is being proposed by the scientists at the University of Pennsylvania for the first human cancer therapy clinical trial in hopes of editing the patient’s immune cells to destroy the cancer cells at an early stage. BioMarin Pharmaceutical announced positive results of their gene therapy trial for severe hemophilia A. The latest developments in cellular therapy have the potential to accelerate progress in treatment for a wide variety of diseases that, in the past, had no hope for a cure. Patients with hemophilia A are treated with factor VIII protein to maintain hemostasis, but with gene transfer and cellular therapy we have the potential to restore the biochemical pathway to permanently eliminate the clinical manifestation. Emerging translational tissue engineering
Tissue engineering is a promising technology but not as mature as the cellular therapy sector. The significant early effort began as
1
Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston–Salem, North Carolina, USA. Correspondence: JG Allickson ([email protected]) Received 1 September 2016; accepted 27 October 2016; advance online publication 00 Month 2016. doi:10.1002/cpt.549
CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 00 NUMBER 00 | MONTH 2016
1
TRANSLATION
Figure 1 Wake Forest Institute Scientists Bio-printed Ear and Jaw Bone Fragment. This image is property of Wake Forest Institute for Regenerative Medicine and is re-used with permission.
physicians were searching for alternatives to organ transplantation, which evolved into the use of material sciences, cell biology, and bioengineering to build tissues and organs. Tissues are engineered using natural and synthetic materials coupled with cells to produce a structure to regenerate, replace, or reconstruct an organ or tissue in the body. In 2006, the first report of a tissue-engineered organ (bladder) being implanted into a patient was printed in the Lancet reported by Atala et al.2 Since then, several organs and tissues have been engineered and implanted into patients. Flat structures, such as the skin, being the most efficient to engineer and more challenging tissue-engineered organs, such as the blood vessels, urethra, trachea, esophagus, and vagina, have also been implanted in humans. There have been a growing number of publications in tissue engineering (16,999 publications in PubMed) with about 75 clinical trials posted on clinicaltrials. gov for a search entitled, “tissue engineering scaffold.” Bioprinting or advanced manufacturing is currently being used for many different applications in regenerative medicine and has been used to produce, for example, ears, bones, and cartilage (Figure 1). Wake Forest Institute for Regenerative Medicine researchers presented an integrated tissue-organ printer to perform the biofabrication of a human scale-up construct to recapitulate the native structure of an organ or tissue, including the vasculature and functionality.3 Other academicians using 3D bioprinting include the Indiana University for Dermatology, Ophthalmology, and Cancer and the Pennsylvania State University producing cartilage plates. To date, none of the 3D Bioprinted structures have been approved by the US Food and Drug Administration for human use. Regenerative medicine companies, such as Organova, are moving forward with the production of functional tissue (human liver tissue), which is mainly used for drug testing and development with the ultimate goal of producing a bioprinted organ for human transplantation. The company has efforts ongoing to release kidney and heart tissue for the same application as the liver tissue. Within the next 10 years, the medical bioprinting market is expected to reach up to $6 billion. The Mayo Clinic, in Rochester, Minnesota, is establishing a regenerative medicine hub initially focused on esophagus, 2
regenerating bronchus, and tracheal tissue. Technology developed by the Mayo Clinic, including Cellframe, which uses the patients cells seeded on a proprietary scaffolds, is in late stages of preclinical development. The Wake Forest Institute for Regenerative Medicine is leading a national effort supported by the Armed Forces Institute of Regenerative Medicine II which is a $75 million dollar effort, including 30 institutions working to develop clinical therapeutic technologies over 5 years focused on skin regeneration, restoring limb function, reconstruction of face and skull, tissue to prevent rejection of composite transplants (face and hands), and reconstruction of genital, urinary organs, and the lower abdomen. These are a few of the tissue-engineered technologies in translation in academia and industry. Challenges in acceleration of clinical translation
Clinical trials face many challenges, including trial design, accrual, and the cost of long-term follow-up studies. How do we get payers or reimbursement and when should this begin? As our goals include solving the problems of organ shortage, rejection of organ transplantation, and treating kidney disease, for example, we need to understand the pathway to efficient translation. In preclinical studies and beyond, there are numerous challenges — do animal models predict the human therapeutic value? How do we effectively translate these products into a good manufacturing practices facility? Currently, there are several barriers to be addressed in manufacturing, including the need for automation and closed systems to reduce contamination and human error. The goal is a robust process that is good manufacturing practice compliant for the different stages of manufacturing. Reagents and supplies should be a clinical grade with a backup source. Once the cell product is at the final product stage, we need to avoid entering the final bag or bioreactor and determine the best methodology for testing in a nondestructive fashion. When entering the first phase of a clinical trial, it is best practice to have a plan or start discussions with the appropriate payers. Clinical trial design is critical as well as patient recruitment. Money makes the world go around so intellectual property and freedom-to-operate are important and help to shape the investors’ opinion of the economic value of the technology. Strategy to accelerate
The path to translational regenerative medicine must embrace innovation as we strive to provide innovative cures to patients. The regulators must balance the need for innovation while safeguarding public health. We need to balance risk-vs.-benefit, understanding that there is significant risk associated with a biological therapy but balanced with patients who may have an incurable disease. Communication is key between major stakeholders and the regulators. A multidisciplinary team is critical to translate regenerative medicine products. The team must include expertise in regulatory navigation of Good Laboratory Practices (GLP), Good Tissue Practice (GTP), Good Manufacturing Practices (GMP), Good Clinical Practice (GLP), appropriate studies that mirror clinical applications, human process development of the product, and appropriate VOLUME 00 NUMBER 00 | MONTH 2016 | www.wileyonlinelibrary/cpt
TRANSLATION GMP-compliant manufacturing. Clinical trial transparency may provide safety in monitoring clinical trials and pharmacovigilance and postmarket requirements for companies. The patent process should be streamlined to provide clarity in the scope of claims prior to translation, which could allow for licensing of the therapies that will meet the needs of the payers. SUMMARY
Regenerative medicine offers unprecedented opportunities to develop technology for unmet clinical needs. Immunotherapy is quickly moving to the finish line and advanced manufacturing/ bioprinting has the potential to recapitulate the native tissue concerning vascularity and functionality. Partnership is important as industry looks to academicians for innovative therapies in health care. Early communication with regulators is important and their understanding of the product and justification of planned studies to move the product to clinic. We are observing a maturation of clinical trials in the space with a significant number of trials in phase II (>50%). The global regenerative medicine market is poised to reach $67.5 billion by 2020 according to a new research reported by Allied Market Research. This year, Tufts University published a study assessing the economics of drug development,
CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 00 NUMBER 00 | MONTH 2016
which reported $2.9 billion total compared with $2.6 billion reported in 2014. This is a huge endeavor for many regenerative medicine companies and certainly requires a heightened level of investor confidence to move the studies to mature clinical development. Regenerative medicine is a game-changer in the area of medicine with the potential to change the paradigm of healthcare economics and quality, offering solutions for patients with conditions that are currently beyond repair. CONFLICT OF INTEREST The author declared no conflict of interest. C 2016 American Society for Clinical Pharmacology and Therapeutics V
1. Chen, Y. & Liu, D. Chimeric antigen receptor (CAR)-directed adoptive immunotherapy: a new era in targeted cancer therapy. Stem Cell Investig. 1, 2 (2014). 2. Atala, A., Bauer, S.B., Soker, S., Yoo, J.J. & Retik, A.B. Tissueengineered autologous bladders for patients needing cystoplasty. Lancet 367, 1241–1246 (2006). 3. Kang, H.W., Lee, S.J., Ko, I.K., Kengla, C., Yoo, J.J. & Atala, A. A 3D bioprinting system to produce human-scale tissue constructs with structural integrity. Nat. Biotechnol. 34, 312–319 (2016).
3
Emerging Translation of Regenerative Therapies JG Allickson1 This translational report on the current field of emerging cell therapy and tissue engineering therapies includes the challenges and opportunities to accelerate clinical translation in regenerative medicine. Translation of regenerative medicine refers to the transfer from bench (proof-of-concept) to bedside (clinical trials), and finally commercialization. Regenerative medicine therapies have the capacity to replace, repair, and regenerate cells, tissues, and organs to restore normal function in the body. These emerging therapies are shifting the paradigm from treatment-based to cure-based therapies.
State of regenerative medicine
Cell therapy and regenerative medicine are in a new era coupled to a rapidly aging population. It is critical to charge ahead in this rapidly evolving field that faces an abundance of challenges paired with patient rewards. There has been significant progress in the last decade in many sectors of regenerative medicine. Clinical studies in regenerative medicine already include orthobiologics, musculoskeletal, cardiology, urology, neurology, sports medicine, diabetes, and wound healing. Examples of technology being offered to patients in the area of wound healing are Dermapure/ Tissue Regenix (decellularized dermis), Apligraft/organogenesis (cell-based product), and Dermagraft/organogenesis (scaffold plus cells). In the area of mucogingival conditions, GINTUIT/ organogenesis (cells and biomaterial); for nasolabial folds in adults, Laviv/fibrocell technologies (autologous cells); and for advanced prostate cancer, Provenge/Dendreon (autologous cells) have been prescribed. These products and others were approved by US Food and Drug Administration as a biologic, which required premarket approval. Other products used for regenerative medicine are listed on an US Food and Drug Administration tissue establishment registration. In general, these are minimally manipulated, for homologous use, not combined with another article, and does not have a system effect. There are a growing number of publications (8,0001 in PubMed) with close to 200 clinical trials posted on clinicaltrials.gov for a search entitled “regenerative medicine therapy.” The Alliance for Regenerative Medicine stated in their 2016 Q2 report that there are 704 companies in the field of regenerative medicine with more than half
in the United States. The field is starting to mature as we are advancing in clinical trials and commercializing products. Present studies in regenerative therapies
Chimeric antigen receptor T-cell is an engineered receptor immunotherapy that is demonstrating promising outcome in the treatment of blood cancers. Over the last decade, significant results with (chimeric antigen receptor) T-cell and other immunotherapy has moved rapidly toward clinical application and surprisingly demonstrated a disappearance of the leukemia cells refractory to many other forms of therapy. The Children’s Hospital of Philadelphia were one of the first to begin offering the therapy in 2012 for blood cancer, such as advanced acute lymphoblastic leukemia, now many companies are moving forward with immunotherapy, including, for example, Juno Therapeutics, Kite Pharma, Bluebird Bio, Adaptimmune, and Kiadis Pharma. Currently, close to 30 clinical trials are ongoing.1 Chimeric antigen receptor technology is now being tested in the solid tumors as well. With such incredible momentum in the space, the potential of moving these therapies to market looks promising. Other technology that was cleared for clinical trial is a therapeutic genome editing using a zinc finger nuclease-mediated approach to treat mucopolysaccharidosis type II (Hunter syndrome) by Sangamo BioScience. Clustered regularly interspaced short palindromic repeats (CRISPR) technology is being proposed by the scientists at the University of Pennsylvania for the first human cancer therapy clinical trial in hopes of editing the patient’s immune cells to destroy the cancer cells at an early stage. BioMarin Pharmaceutical announced positive results of their gene therapy trial for severe hemophilia A. The latest developments in cellular therapy have the potential to accelerate progress in treatment for a wide variety of diseases that, in the past, had no hope for a cure. Patients with hemophilia A are treated with factor VIII protein to maintain hemostasis, but with gene transfer and cellular therapy we have the potential to restore the biochemical pathway to permanently eliminate the clinical manifestation. Emerging translational tissue engineering
Tissue engineering is a promising technology but not as mature as the cellular therapy sector. The significant early effort began as
1
Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston–Salem, North Carolina, USA. Correspondence: JG Allickson ([email protected]) Received 1 September 2016; accepted 27 October 2016; advance online publication 00 Month 2016. doi:10.1002/cpt.549
CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 00 NUMBER 00 | MONTH 2016
1
TRANSLATION
Figure 1 Wake Forest Institute Scientists Bio-printed Ear and Jaw Bone Fragment. This image is property of Wake Forest Institute for Regenerative Medicine and is re-used with permission.
physicians were searching for alternatives to organ transplantation, which evolved into the use of material sciences, cell biology, and bioengineering to build tissues and organs. Tissues are engineered using natural and synthetic materials coupled with cells to produce a structure to regenerate, replace, or reconstruct an organ or tissue in the body. In 2006, the first report of a tissue-engineered organ (bladder) being implanted into a patient was printed in the Lancet reported by Atala et al.2 Since then, several organs and tissues have been engineered and implanted into patients. Flat structures, such as the skin, being the most efficient to engineer and more challenging tissue-engineered organs, such as the blood vessels, urethra, trachea, esophagus, and vagina, have also been implanted in humans. There have been a growing number of publications in tissue engineering (16,999 publications in PubMed) with about 75 clinical trials posted on clinicaltrials. gov for a search entitled, “tissue engineering scaffold.” Bioprinting or advanced manufacturing is currently being used for many different applications in regenerative medicine and has been used to produce, for example, ears, bones, and cartilage (Figure 1). Wake Forest Institute for Regenerative Medicine researchers presented an integrated tissue-organ printer to perform the biofabrication of a human scale-up construct to recapitulate the native structure of an organ or tissue, including the vasculature and functionality.3 Other academicians using 3D bioprinting include the Indiana University for Dermatology, Ophthalmology, and Cancer and the Pennsylvania State University producing cartilage plates. To date, none of the 3D Bioprinted structures have been approved by the US Food and Drug Administration for human use. Regenerative medicine companies, such as Organova, are moving forward with the production of functional tissue (human liver tissue), which is mainly used for drug testing and development with the ultimate goal of producing a bioprinted organ for human transplantation. The company has efforts ongoing to release kidney and heart tissue for the same application as the liver tissue. Within the next 10 years, the medical bioprinting market is expected to reach up to $6 billion. The Mayo Clinic, in Rochester, Minnesota, is establishing a regenerative medicine hub initially focused on esophagus, 2
regenerating bronchus, and tracheal tissue. Technology developed by the Mayo Clinic, including Cellframe, which uses the patients cells seeded on a proprietary scaffolds, is in late stages of preclinical development. The Wake Forest Institute for Regenerative Medicine is leading a national effort supported by the Armed Forces Institute of Regenerative Medicine II which is a $75 million dollar effort, including 30 institutions working to develop clinical therapeutic technologies over 5 years focused on skin regeneration, restoring limb function, reconstruction of face and skull, tissue to prevent rejection of composite transplants (face and hands), and reconstruction of genital, urinary organs, and the lower abdomen. These are a few of the tissue-engineered technologies in translation in academia and industry. Challenges in acceleration of clinical translation
Clinical trials face many challenges, including trial design, accrual, and the cost of long-term follow-up studies. How do we get payers or reimbursement and when should this begin? As our goals include solving the problems of organ shortage, rejection of organ transplantation, and treating kidney disease, for example, we need to understand the pathway to efficient translation. In preclinical studies and beyond, there are numerous challenges — do animal models predict the human therapeutic value? How do we effectively translate these products into a good manufacturing practices facility? Currently, there are several barriers to be addressed in manufacturing, including the need for automation and closed systems to reduce contamination and human error. The goal is a robust process that is good manufacturing practice compliant for the different stages of manufacturing. Reagents and supplies should be a clinical grade with a backup source. Once the cell product is at the final product stage, we need to avoid entering the final bag or bioreactor and determine the best methodology for testing in a nondestructive fashion. When entering the first phase of a clinical trial, it is best practice to have a plan or start discussions with the appropriate payers. Clinical trial design is critical as well as patient recruitment. Money makes the world go around so intellectual property and freedom-to-operate are important and help to shape the investors’ opinion of the economic value of the technology. Strategy to accelerate
The path to translational regenerative medicine must embrace innovation as we strive to provide innovative cures to patients. The regulators must balance the need for innovation while safeguarding public health. We need to balance risk-vs.-benefit, understanding that there is significant risk associated with a biological therapy but balanced with patients who may have an incurable disease. Communication is key between major stakeholders and the regulators. A multidisciplinary team is critical to translate regenerative medicine products. The team must include expertise in regulatory navigation of Good Laboratory Practices (GLP), Good Tissue Practice (GTP), Good Manufacturing Practices (GMP), Good Clinical Practice (GLP), appropriate studies that mirror clinical applications, human process development of the product, and appropriate VOLUME 00 NUMBER 00 | MONTH 2016 | www.wileyonlinelibrary/cpt
TRANSLATION GMP-compliant manufacturing. Clinical trial transparency may provide safety in monitoring clinical trials and pharmacovigilance and postmarket requirements for companies. The patent process should be streamlined to provide clarity in the scope of claims prior to translation, which could allow for licensing of the therapies that will meet the needs of the payers. SUMMARY
Regenerative medicine offers unprecedented opportunities to develop technology for unmet clinical needs. Immunotherapy is quickly moving to the finish line and advanced manufacturing/ bioprinting has the potential to recapitulate the native tissue concerning vascularity and functionality. Partnership is important as industry looks to academicians for innovative therapies in health care. Early communication with regulators is important and their understanding of the product and justification of planned studies to move the product to clinic. We are observing a maturation of clinical trials in the space with a significant number of trials in phase II (>50%). The global regenerative medicine market is poised to reach $67.5 billion by 2020 according to a new research reported by Allied Market Research. This year, Tufts University published a study assessing the economics of drug development,
CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 00 NUMBER 00 | MONTH 2016
which reported $2.9 billion total compared with $2.6 billion reported in 2014. This is a huge endeavor for many regenerative medicine companies and certainly requires a heightened level of investor confidence to move the studies to mature clinical development. Regenerative medicine is a game-changer in the area of medicine with the potential to change the paradigm of healthcare economics and quality, offering solutions for patients with conditions that are currently beyond repair. CONFLICT OF INTEREST The author declared no conflict of interest. C 2016 American Society for Clinical Pharmacology and Therapeutics V
1. Chen, Y. & Liu, D. Chimeric antigen receptor (CAR)-directed adoptive immunotherapy: a new era in targeted cancer therapy. Stem Cell Investig. 1, 2 (2014). 2. Atala, A., Bauer, S.B., Soker, S., Yoo, J.J. & Retik, A.B. Tissueengineered autologous bladders for patients needing cystoplasty. Lancet 367, 1241–1246 (2006). 3. Kang, H.W., Lee, S.J., Ko, I.K., Kengla, C., Yoo, J.J. & Atala, A. A 3D bioprinting system to produce human-scale tissue constructs with structural integrity. Nat. Biotechnol. 34, 312–319 (2016).
3
