SECTION
Stem Cell Therapy
21
170
C H A P T E R
Vinod K Shah, Kavita K Shalia
Potential of Stem Cell Banking in India
INTRODUCTION
India has not only made great progress along with the world in stem cell basic research but has also made advances in understanding on how to use these cells for treating various diseases. Here, the requirement of stem cell bank with guidelines from regulatory bodies becomes an essential to provide standard material for research and good manufacturing practice (GMP)/ good laboratory practice (GLP) compliant cell-based product for therapy. The upcoming feature in this area is umbilical cord blood (UCB) banks. UCB banking has improved with time largely due to involvement of professional organizations and their published standards. However, accreditation of these organizations remains voluntary, and in India three of ten banks are public with the remaining being private. Public policy regarding UCB is in its infancy throughout most of the world. The potential of stem cell banks can be tapped by initiating an awareness campaign and a customized marketing plan.
Stem cells are the basic building blocks of life. They are found in the body’s organs, tissues, blood and immune system, and have the ability to regenerate into additional stem cells or differentiate into specialized cells, such as nerve or blood cells. The adult stem cell’s job is to regenerate and repair tissue. Every time our body heals itself from a cut or injury that is the healing power of adult stem cells working inside us. It is the self-healing power of the adult stem cell which offers scientists the possibility of a creating new therapies and cures for a wide variety of diseases.1-3
In the field of stem cell biology, basic research and rapid movement toward translational research and eventually to clinical practice is on parallel run. For successful use of stem cells in clinical practice, there are several areas that need to be looked at, such as efficacy, safety, toxicity, delivery routes and techniques, to ensure that the cell type used is safe and efficacious to conduct human clinical trials. But the most important is to select the
tissue source and the type of stem cells or differentiated cells that possess the greatest potential for curing a specific disease. If all these criteria are met with success, it would be easier to obtain regulatory approvals that are required for effective translation of use of stem cells from “bench-to-bedside”.
Thus the development of clinical-grade cell-based therapeutics is a challenging process due to their specific and complex nature, high innovation level combined with rapid developmental boost and recent implementation of severe regulations. According to these newly introduced regulatory standards, the manufacturing of cell-based products must be fully GMP/GLP compliant with a rigorous GMP quality control, fulfilling all pharmaceutical requirements for medicinal products. This begins already at the choice of starting raw material and goes all the way to release of the final product by the qualified person. The costly GMP/GLP facilities, the manufacturing license and the firm quality assurance systems are now defined as prerequisite for development and manufacturing of cell-based products.
STEM CELL BANK
Stem cell bank, a repository for all types of stem cells, i.e. cord blood, adult and embryonic resolves the issue of obtaining standardized cells/research materials for comparison and reproducibility of results in basic research as well as in its therapeutic applications. Parameters for quality control procedure in the stem cell bank are checking of chromosomal abnormalities, testing of infectious diseases such as human immunodeficiency virus (HIV) I & L, human T-lymphotropic virus (HTLV), hepatitis C virus (HCV), hepatitis B surface antigen (HBS Ag), cytomegalovirus (CMV) ability of stem cells to undergo freeze-thawing processes, immune compatibility of the stem cells with patients potentially requiring the cells, presence of viruses within the stem cells that may cause disease, ability of
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the stem cells to give rise to the required adult cell types when required and ability of the stem cell numbers to be increased to useful amounts. While the banking of hematopoietic stem cells (HSCs) from different sources (bone marrow, cord blood) is already a well-established and standard procedure, there is less experience with other cell types, e.g. mesenchymal stem cells (MSCs) and their intermediate products.4
CORD BLOOD CELLS AND CORD
BLOOD BANK
One of the scientifically and clinical most promising raw material is certainly umbilical cord (UC) or UCB. It has been shown to be a viable alternative to bone marrow and peripheral blood and has clear advantages over the other sources of stem cells. It requires less restriction for matching, as the naive immune system appears to cause less severe graft-versus-host disease (GVHD). Since the first successful transplant in a child with Fanconi anemia in 1988, UCB has emerged as a feasible alternative source of hematopoietic progenitor/stem cells for allogeneic transplantation.5 It is used to treat a variety of oncologic, genetic,
hematologic and immunodeficiency disorders when a human leukocyte antigen (HLA)-matched adult donor is not available.6,7
To date, more than 10,000 patients worldwide have received a UCB transplant. Additionally, several investigational human trials involving cell types derived from UCB have been initiated.6-8
As the clinical utility turn out to be apparent, collection and banking of UCB became more widespread all over the world.9
The first unrelated UCB bank was started at the New York Blood Center in 1992 and has the highest inventory of 48,808 UCB. The expansion of UCB banking has led to the establishment of UCB quality standards by professional groups such American Association of Blood Banks (AABB) and the Foundation for Accreditation of Cellular Therapy (FACT/NetCord).10,11 These
best-practice expectations pertain to collect, process, test (e.g. HLA typing, infectious disease testing) and cryopreserve UCB for potential future use as therapeutics.12,13 Another most important
task is to HLA type UCB and allow for listing on a registry for rapid search and acquisition.14 At present there are at least 142
public (three in India) and 25 private (seven in India) UCB banks worldwide.12
Public banks are typically “not-for-profit” with their primary purpose being creation of an inventory of UCB units for unrelated use. UCB is donated to the bank, and the units are made available to suitably matched recipients regionally, nationally or internationally. Making samples from the public cord blood bank available to the masses would mean performing a six-part HLA typing on all the samples apart from the genetic screen for inborn errors.15 This type of program in general is funded in part
or entirely by public funds. The alternative approach involves “for-profit” companies which encourage parents to bank their child’s UCB for their own (autologous) or a family member’s (related, allogeneic) use should a need arise. For a fee, the UCB is processed and stored as a form of “biological insurance”.16
STEM CELL BANKING IN INDIA
With India’s booming birth rate of 26 million births per year17 and
genetic diversity, the country would be poised to be the largest collector of UCB in the world. However, to set up a stem cell bank it requires proper networking among hospitals for supply of cord
blood. The major problem faced in India is collection of UCB due to high cost and comparatively less functional public banks. In addition, considering a large population with deliveries in public hospital due to low cost, UCB storage in India needs increased public-private partnership model where UCB can be stored by affordable and non-affordable people as well.
Reliance Life Sciences (RLS) established the first public bank ReliCord in 2002 and later extended the cord blood stem cell banking services to families. This cord blood repository has been accorded a license by Food and Drug Administration (FDA), Government of India and also has been inspected and accredited by AABB. It was the first cord blood repository to be set up in India and South Asia. The other public cord blood banks with nominal presence are Jeevan Stem Cell Blood Bank and StemCyte which are not-for-profit stem cell bank. ReliCord, Jeevan Cord and StemCyte collectively have 5,000 units of UCB.
Similarly, seven private banks have been established to date in India. These are LifeCell with maximum inventory of 19,000 followed by Cryobanks having 17,000 plus samples and about 4,500 between Cryosave, Cord Life, Baby Cell, Stem One and International Stem Cell Service (ISSL) (personal communication from Dr Phagun Shah, Medical Advisor, Cryobank, India). Four of these are certified by ISO whereas LifeCell is also accredited by AABB. Most of these are affiliated with or are subsidiaries of international companies. Wherein Cryobanks International India plans to increase to 250 plus towns, LifeCell already has 40 collection centers across Asia. Narayana Health City, Bengaluru also recently came up with a public stem cell bank and Sri Ramachandra Deemed Medical University and Medical Center (SRMC), Chennai, in association with LifeCell has formed the therapy center TRICell.16
The investments from the cord blood banks in India are mainly focused on the facility building, technology development fees and its day-to-day operations. Some of these companies have partners with experience in pharma industry. These companies have established a sale force wherein trained medical representatives visit the prospective client’s home and explain the concept, collection and processing, and provide confidence on the storage facilities and even get in touch with the obstetrician, gynecologist on regular basis and get pregnant patient population from them. This will increase the customer base significantly as this opportunity is not restricted to expectant parents alone. Stem cell banking companies are making use of ready customer-base by tying up with hospitals, medical institutes, research institutions and biotechnology companies and stem cell therapy centers to aid in stem cell research as well as to enable this therapy within India. Another phase in stem cell banking is about to begin with companies launching new banking services (like collection of stem cells from menstrual blood, cord tissue and adipose tissue).
UMBILICAL CORD BLOOD
TRANSPLANTATION IN INDIA
Most UCB banks in India have been opened in the last few years, and UCB transplantation is in its infancy, very few reports are available for application to acquire and constitutional hematological disorders and none for metabolic disorders. Till date approximately 32 patients have been transplanted using related or unrelated UCB. Of these 2 patients of relapsed leukemia were transplanted using mismatched sibling cord (UCB processed at LifeCell and Cryobank) and one died of
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disease relapse and other of sepsis. One child was transplanted using fresh fully matched cord and the child is well 12 years on and did not go through any cord bank. In 15 patients mainly for relapsed leukemia and aplastic anemia, unrelated cord blood was used with transplant related mortality (TRM) of 55% at Apollo Hospitals, Chennai. While one patient of leukemia transplanted at Gujarat Cancer and Research Institute (GCRI), Ahmedabad, expired due to disease related mortality after transplantation. The high mortality rate appears to be due to selection of high risk cases under this group (personal communication with Dr Revathi Raj, Chennai, and Dr Sandip Shah, Ahmedabad). To date, around thirteen cases of thalassemia have been treated using UCB transplantation. Of these, six cases were transplanted using fully matched sibling UCB at Apollo Hospitals, Chennai. UCB units were obtained from LifeCell and cord bank. Thalassemia free survival was 83% and all patients had additional bone marrow from siblings as there was inadequate cell dose in cord blood (personal communication with Dr Revathi Raj, Chennai). Similarly, seven unrelated UCB units were utilized to treat thalassemia cases at Gujarat Cancer Research Institute (GCRI), Ahmedabad. The unrelated UCB units were procured from ReliCord and StemCyte UCB banks. TRM was 0% at both the centers. At GCRI, Ahmedabad, two thalassemia patients had disease free survival after 2 years and 1 year of transplantation, and one remained hospitalized post transplantation. Failure of engraftment was observed in four cases which is likely to be due to low number of total nucleated cell (2‒3 × 107) used in transplantation (personal communication from Dr Sandip Shah, Ahmedabad). Considering large number of thalassemia patients born in the country, these transplantations are comparatively very less mainly because of cost prohibition, lack of sufficient UCB depository and because public UCB banks are in early stage of development. In the coming years with an increased transplantation using UCB as a source of HSCs, more experience will undoubtedly be gained.16,18
REGULATORY ENVIRONMENT IN INDIA
AND OTHER COUNTRIES
At present, the role that any government should play in UCB banking remains unclear. However, in developed and developing countries with a universally accessible healthcare system, public policymakers will soon be confronted with the difficult task of deliberating the merits and economics of establishing a national network of public UCB banks, including the value of private banking of UCB for autologous/family use. A policy framework may be necessary to guide this decision-making and to address the socioethical and legal issues surrounding UCB banking and uses.
The guidelines from the Indian Council of Medical Research (ICMR) and Department of Biotechnology (DBT) are available to assist with stem cell research and UCB issues.19 Additionally, the
aforementioned standards (AABB, FACT/NetCord) could facilitate the effort to establish public UCB banks throughout India. Roughly 0.25% of the global shares of UCB transplants are done in India, and only three ICMR licensed UCB banks are operational in the country.18,20 The field of UCB stem cell therapy is still gaining
experience in India, and there are many regulatory and policy issues pertaining to the allogeneic transplantation for inherited disorders and transmissible infectious diseases that are yet to be
addressed in addition to the draft guidelines by ICMR and DBT. There are unique ethical issues related to private UCB banking, and policymakers cannot chart the future of UCB banking in the country without taking into account the existence of private banks and their potential role in meeting future clinical needs, as well as their contribution to research in this domain.16
India has great potential for UCB banking due to a high birth rate and genetic diversity. Nearly 70% of patients of Indian origin who require bone marrow transplantation do not find a match within their own family. Hence, unrelated UCB is a widely accepted source of progenitors for HSC transplantation. However, to date the total number of UCB transplants performed in India has been very low mainly due to high cost and limited number of UCB units available against the estimated requirement of 30,000 units. Moreover, in India, private UCB banking dominates and limits general public access to promising therapies. But with the existence of three public UCB banks, these figures are likely to improve in the coming years. This will offer a diverse source of high quality grafts for patients of Indian origin worldwide. Private banks will also continue to grow in India, as many families opt to store UCB in private banks with possible advantages in degenerative disorders in the future. To meet the future transplantation needs of the country, full participation and substantial investment by the government are necessary. Establishing a foundation, including infrastructure (facilities, technical and quality assurance expertise, etc.) will support a UCB program which will be representative for all regions of the country.16
While standards appropriately cover, UCB banking guidelines regarding other issues including those with ethical implications (e.g. patient access, clinical applications) are lacking in particular for autologous UCB transplantation. Further, worldwide, clinical trials for a variety of diseases are ongoing despite inadequate pre-clinical studies and regulatory/safety oversight. However, the clinical research environment in India is currently undergoing a tremendous flux, with regulators coming under severe criticism from the press, public and the elected government.21 There are
new ICMR-DBT draft guidelines on stem cell research, and the Central Drugs Standard Control Organization (CDSCO) draft on compensation toward injury due to participation in clinical research that are responses to several questions that we face today.22,23 If these guidelines are to have lasting credibility then
they should be implemented. These stringent guidelines for stem cell research and therapy are yet to be legislated. The Union Health Ministry is planning a law to regulate this sector. The guidelines have to become law in a strict sense to attract global attention.
WHAT IS THE GLOBAL AND INDIAN
SCENARIO OF STEM CELL THERAPY?
In the still emerging scenario of banking guidelines, a few FDA approved stem cell products are making into the clinics in various parts of the world. Osiris Therapeutics recently announced the approval of its product Prochymal by Canadian regulators to treat children suffering from acute GVHD, a potentially deadly complication of allogeneic bone marrow transplantation. Osiris also got similar approval in New Zealand for Prochymal. Another product by Osiris is Osteocel an allograft containing MSCs and osteoprogenitors and sold to NuVasive, Inc. in 2008. In Korea, Pharmicell has successfully developed “Hearticellgram-AMI”
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autologous product and received approval from the Korea Federal Drug Agency (KFDA) in July 1, 2011. Hearticellgram-AMI uses autologous stem cells and is a personalized stem cell therapy product which overcomes immune rejection. Another Korean company, Medipost got approval for their product “Cartistem” in January 2012 from the Korean FDA for the treatment of OA. In India, patient’s treatment through stem cell therapy has already paved its way. LV Prasad Eye Institute (LVPEI) has treated the largest number of patients (780) in the world for corneal blindness using cultured limbal stem cell therapy since the institute started the procedure in 2001. The therapy is used to restore vision in cases of corneal damage due to burns or chemical injury. Some hospitals and stem cell companies are offering stem cell therapy for spinal cord injury, Parkinson’s disease, stroke and cardiovascular indications. Stempeutics Research, a group company of Manipal Education and Medical Group, is the only company in the country which has developed Stempeucel, an investigational medicinal product which is undergoing the last stage of phase 2 clinical trial for the indication of critical limb ischemia (CLI), osteoarthritis (OA) and liver cirrhosis (LC) and is
expected to enter phase 3 trial by early 2013. The company plans to launch Stempeucel in the Indian market by mid-2015.
CONCLUSION
With everyday advancements in stem cell technology from the research and clinical perspective, stem cells do promise a healthy future for the coming generations in India. Currently, UCB and cord-tissue banking are more popular. For optimal utilization of these facilities, it is important to create concept awareness. At present, lack of awareness among the common people about the huge potential to be gained from the storage of cord blood stem cells and highly technical nature of the process is the key reason for a small customer base in the country. It is still considered an ultimate preventive healthcare luxury due to high-cost barriers. Increased awareness levels among the masses about the concept and a strong legalized and less commercialized environment can work positively toward making stem cell banking an integral part of Indian healthcare.
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