Over the past decade, cellular therapy for the treatment of degenerative diseases, malignancies, autoimmune diseases, trauma and aging-related issues has become an area of intense investigation. A variety of cell and tissue sources, methods for ex vivo manipulation of cells including genetic modification are under development to treat a host of diseases, and for the repair and regeneration of tissues and organs. Despite the impetus for growth, investigators face a number of challenges. This is underscored by the slow emergence of commercially viable cell-based therapeutic products. Although the first successful stem cell transplantation was conducted in 1959, only a handful of cellular therapy products are currently available on the market (for example, Genzyme’s Carticel® for cartilage repair, Dendreon’s Provenge® to treat prostrate cancer and Advanced BioHealing’s Dermagraft® for foot ulcers).
One of the major challenges is the financial and resource commitment required to launch a successful product. DiMasi has estimated that it can take anywhere from $800 million to upwards of $2 billion [
1,
2] over a 10–15 years period to launch a viable product. As many cellular therapy initiatives are still largely investigator-initiated, this poses a daunting challenge for investigators to secure the necessary funding and resources to embark on the preclinical and clinical development of cellular therapy products. In fact, two independent workshops, one by the American Society of Hematology [
3] (http://www.hematology.org/Publications/Hematologist/2011/6450.aspx) and the other by the National Heart, Lung and Blood Institute of the US National Institutes of Health (NIH) [
4] have identified funding for translational and clinical research as a major challenge to the emergence of cellular therapies.
Translational research involves all the steps after discovery to clinical application in the development pathway of a cell-based product. Preclinical studies are the basis for moving forward to clinical investigation, and should provide proof of concept, information on the clinical route of administration, biodistribution, dose selection and escalation scheme, and toxicity. Additionally, scale-up studies are required to manufacture clinically relevant doses of cells under Good Manufacturing Practices (GMP) condition, and “dry-runs” are needed to validate the manufacturing process and identify critical steps that require quality control. Thus, a majority of these studies do not qualify for traditional funding through existing grant mechanisms which tend to focus on hypothesis-driven research; yet these studies are required by all regulatory authorities as the basis for the risk assessment of the cellular product.
To address this gap, institutional changes will need to be made by various granting agencies to issue new requests for applications (RFAs) aimed at specifically funding translational research to accelerate clinical investigation of cell-based therapies. In addition to issuing new RFAs, traditional grant mechanisms need to be altered to include different review criteria, a multidisciplinary panel of reviewers and shorter review cycles. Partly in response to these concerns and based on extramural recommendations, a new funding stream has been made available by the NIH in the form of Research Project Grants (RO1s) on Early Phase Clinical Trials for Blood Cell Therapies (http://grants1.nih.gov/grants/guide/pa-files/PAR-11-204.html). Other initiatives including the California Institute of Regenerative Medicine are also beginning to address this issue by providing substantial funding ($3 billion over 10 years) for translational stem cell research.
In addition to funding translational research, implementation of translational research remains a major challenge. For example, selection of appropriate animal models to demonstrate efficacy of cells, toxicity, and biodistribution to the satisfaction of regulatory authorities is often a difficult dilemma; this is particularly important as the cells have multiple modes of action, and can exert complex, tissue-specific effects that need to be investigated and understood as a whole smaller immunodeficient rodent models are useful for assessing functionality, retention and safety issues related to the administered human cells, but have limited utility in providing anatomical and physiologically relevant data. Larger animal models may be more relevant, especially when assessing specific delivery devices, route of administration, cell dose, volume, etc. However, the animals often need to be immunosuppressed in order to evaluate human cells which can in turn have confounding effects on toxicity or mechanism readouts; alternatively, homologous cells may be used but these may require additional bridging studies to relate them back to the eventual clinical product. Additional studies with large animal models are expensive, and often limited to specific centers housing the appropriate infrastructure, resources and expertise, making them financially and scientifically less accessible.
Barring a few documents [
5,
6] from the International Conference on Harmonization of Technical Requirements for Registering Pharmaceuticals for Human Use (ICH), there are no real guidelines for conducting preclinical studies to support regulatory filings; most regulatory authorities prefer to review studies on a case-by-case basis. This is a sensible approach given that the field is in a relatively nascent state, but often results in confusion and additional challenges to investigators and sponsors as they weigh the risks, costs and benefits of doing expensive, preclinical studies that may ultimately be less predictive of the clinical scenario than anticipated.
Consensus panels and workshops that can provide recommendations on preclinical study requirements, including appropriate animal models, would be well received by the field. Some efforts have already been made in this direction with recent guidelines issued by the FDA for allogeneic pancreatic islet cell products [
7], cellular therapy for cardiac disease [
8], and products intended to repair or replace knee cartilage [
9]. The European Medical Agency (EMA) has also put out a reflection paper citing additional preclinical study requirements including tumorigenic potential, biodistribution and niche,
in vivo differentiation, immune rejection and persistence for stem cell-based products [
10], in recognition of their multiple modes of action. Building on these efforts, a concentrated, internationally harmonized effort to develop consensus guidelines for preclinical translational studies for different types of cell-based products is now urgently needed to address this global bottleneck in the field of cellular therapy.
Another major challenge is the lack of definitions for the composition of cellular products, which makes it very difficult to compare studies in which similar cell types are often isolated, propagated, identified and characterized using varying definitions. Standardized definitions and assays are therefore needed to address this problem. An example of a partial success story is the development of a standard definition for mesenchymal stromal cells (MSCs). Until about 5 years ago, different groups defined MSCs differently and termed them mesenchymal stem cells, mesenchymal stromal cells, bone marrow stem cells, bone marrow stromal cells, and more recently as stem or stromal cells from various other tissues, including adipose tissue, umbilical cord tissue, umbilical cord blood, amniotic tissue and other sources. The cells had all been isolated, propagated and characterized using different techniques. The International Society for Cellular Therapy (ISCT) prepared two white papers [
11,
12] to provide a minimum standard definition of MSCs as a relatively homogeneous population of cells that express CD105, CD73 and CD90 (>95% positive as measured by flow cytometry) and lack hematopoietic markers such as CD45, CD34, CD14, CD11b, CD79a, CD19 and human leukocyte antigen (HLA) Class II (<2% positive). Further ISCT definitions specified that MSCs must adhere to tissue culture plastic, and be shown to differentiate into osteoblasts, adipocytes and chondroblasts under standard differentiating conditions.
Importantly, the ISCT has strongly recommended that these cells be referred to as “mesenchymal stromal cells” as opposed to “mesenchymal stem cells,” due to the lack of clear evidence of the extent of true “stemness” of these cells.
Standardization of the definition of the composition, morphology and functionality of MSCs by ISCT has provided investigators as well as regulatory agencies an opportunity to be able to compare in a valid manner, clinical and non-clinical information regarding these cells. This is particularly important in providing a more comprehensive safety profile of the product. It can also lead to a more efficient and rapid regulatory approval process.
Often, different groups of investigators and sponsors are compelled to repeat preclinical safety and toxicity testing already undertaken by other groups that are not available in the public domain due to intellectual property concerns. Sometimes the data are not suitable for publication purposes as they support the safety of the administered cells but do not provide novel insight into mechanisms of action. A public repository of such preclinical studies, at least those undertaken by academic sponsors, would greatly aid the field by eliminating the need to repeat costly, Good Laboratory Practice (GLP)-compliant studies required for regulatory filing. The repository would be the equivalent of a publicly-accessible Cellular Master File (CMF), similar to the Device Master File held by regulatory agencies, and would enable investigators to build on existing data.
We have outlined some of the challenges facing cell therapy research. Nonetheless, there is cause for optimism. The NIH has addressed in part, some of the deficiencies in funding, although the issue of funding non-hypothesis-driven, preclinical validation studies remains a concern. Another positive sign is the emerging interest of the pharmaceutical and biotechnology industries in the field of cellular therapy. While this will address some of the funding issues, other areas still require attention, including the need for a consensus on appropriate preclinical animal models and the requirement for standardization of cell preparations. Many of these challenges will be overcome when effective cell therapy is documented for a major indication. To get there requires considerable effort on the part of funding agencies, regulatory bodies, scholarly societies and investigators in cell therapy all working in concert.
Declaration of interest
The authors have no conflict of interest to report. AK holds the Gloria and Seymour Epstein Chair in Cell Therapy and Transplantation at University Health Network and the University of Toronto.
Higher Education Press and Springer-Verlag Berlin Heidelberg
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