Abstract
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Stem cell therapy is nothing new. It has become clinical routine and is already a curative therapeutic modality for certain indications like hematological malignancies. But this modality has been established in the academic environment guided by strong leaders and committed physicians like E. Donnell Thomas and others. If we applied today's regulatory and quality measurement standards to hematopoietic stem cell transplantation, probably not a single patient would have been treated and many lives would have been lost. Therefore, is it wrong to apply current industrial standards to the development of therapeutic stem cells, or are we losing faith, money, and patients' lives during this development? Is cell therapy becoming even more expensive than existing therapeutic modalities, like small molecules or antibodies, and unaffordable for most of us?
The potential applications of pluripotent stem cells have broadened significantly, as has the stem cell reservoir. Embryonic stem (ES) cells held much promise due to their pluripotency and immortality. But there are ethical concerns, not only on the consumption of human embryos (blastocytes) but also regarding the industrial handling of ES cells with regard to their purity and larger-scale production. It should not be forgotten that ES cell research instituted the entire field of regenerative medicine. But at present, it is still predominantly the playground of basic researchers and academic institutions (with exceptions, of course). Other solutions have been offered, one just more recently: induced pluripotent stem (iPS) cells. However, iPS cell technology is still new, and is rapidly changing and under intense scrutiny. We likely need to gather more information on what effects the reprogramming of adult cells really causes in the machinery of a reprogrammed cell and whether iPS cells actually qualify for clinical applications.
The sources of adult stem cells with regenerative potential have also broadened: stem cells can be isolated and established in vitro from almost any mesenchymal tissue – the younger the better (placenta, umbilical cord, endometrium, dental bulb, bone marrow, adipose tissue, etc.). This was the birth of disciplines like tissue engineering. The increasing understanding of the existence of mesenchymal stem cells (MSC) nurtured one of the first hypes of stem cell therapeutics! Almost anything seemed possible: new teeth, knees, heart valves, arterial vessels, and so on. The life-science industry started to blossom in the field of tissue engineering (including bioengineering and material sciences) only to wither, but it left behind some precious roots. There are many explanations as to why the frost came so early: the impatience of (venture capital) investors, the benchmarking (e.g., bioengineered cartilage and articular joints with titan implants as knee and hip replacement therapy), the yet-missing standardization of the manufacturing process, and the concerns of the regulatory authorities.
Yet the precious roots still remain for a more consolidated approach to stem cell therapeutics. Based on this experience, companies prevailed that focused on different strategies and were able to bridge the notorious translational gap. Realizing that there is no quick win, those companies applied their fundamental understanding of stem cell science to the translation of basic research into potential clinical application. Osiris Therapeutics was certainly an archetype in this field until their phase III studies did not reach the expected endpoints in all three indications: GvHD, Crohn's disease, and COPD. But there was a vast scientific literature that suggested stem cells should work in those indications. Choosing the right indication, along with the appropriate trial design, is certainly one of the major challenges to obtain a robust and sustainable proof of concept (PoC) that stem cell therapeutics will emerge and rank among the other established therapeutic modalities. But what drives the choice of an indication, except scientific evidence in a dish or in some mouse models? Considerations about a potential business case in larger cohorts of patients with indications like diabetes, congestive heart failure, or acute ischemic lesions are certainly valid, as well as the selection of indications with unmet medical needs, like ALS (Lou Gehrig's disease), AMD, or myotonic dystrophy, that might lead to orphan drug status and fast-track approval.
But how should an appropriate indication be selected by an academic institution, a VC-financed biotech start-up, or an established pharmaceutical company? Business-case-driven decisions are certainly a valid attempt to generate more cash flow, attract additional investors, or prepare a public issue. But experience in the past has shown that there are no quick wins by neglecting stem cell biology and the mode of action (MoA). It is certainly not a positive attribute of a company when the white-collar management team is larger than the R&D group, and the number of corporate executives and vice-presidents far exceeds the number of scientists.
We all experienced the hype in the 1990s when the first positive results in osteogenesis imperfecta and acute myocardial infarction (AMI) were reported. But this hype did not last much longer than the clinical improvement of the patients and the detection of grafted MSC in the host. As yet, there is no resilient evidence that MSC differentiate in vivo into the damaged tissue type. There are certainly reports on the intermittent improvement of patients with AMI measured by the patient's time in the intensive care unit, but there is apparently no lasting effect in those AMI patients. Instead of stem cell differentiation into contractile cardiomyoctes, the MSC rather seem to facilitate endogenous repair and support the formation of a smaller, more pressure- and volume-resistant scar in the infarcted myocardium. But this is a mechanism associated with the formation of typical granulation tissue, as seen in any wound healing and linked to functional vasculogenesis. The capability to form blood and lymphatic vessels efficiently is pivotal to the regeneration event in general.
What is the other issue that is crucial to the success of therapeutic stem cells? It is most likely the interaction of stem cells with the immune system. There is an assumed, or suggested, immunologically silent profile of hES, matched iPS cells, or immature MSC from the placenta or cord blood. In contrast, stem cells from adult tissue have a more realistically assessed immune profile. Although there is an increasing body of evidence of how stem cells interact with the immune system through the interactions of co-stimulatory signals on stem cells and immune effector cells, a modulation of metabolic pathways or the release of soluble factors, the entire mechanism is as yet not even cursorily understood.
But a combination of both promises (the induction of tissue regeneration and the immune modulating function of stem cells) seems to have a high likelihood of clinical and also commercial success. This would apply to progressive organ failure after the eventual destruction of tissue with reactive fibrosis in the course of chronic inflammation (due to viral infections) or autoimmunity. Therefore GvHD, Crohn's disease, and COPD are indications that fall into this category, as are various types of chronic liver and renal failure, and bacteria-induced septicemia. Although what all those medical conditions have in common is the exogenous or endogenous stimulation of the immune system with the consecutive loss of organ function, the degree and type of inflammation can vary significantly within the same diagnosis. Therefore, the stratification of patients within the same diagnostic entity is crucial to success. Successful clinical trials need to predetermine the degree of inflammation and reversibility of tissue damage prior to any stem cell therapy. The identification of biomarkers for the prediction of cell therapeutic efficacy along with a safety assessment for stem cell application (e.g., no existing tumor growth in the recipient's body) leads to an approach of personalized health care (PHC). Individualized (stem cell) medicine is not only a prerequisite for clinical success but also for commercial profit. The number of patients that need to be enrolled onto a clinical trial can be reduced, combined with a profitable reimbursement of the effective therapeutic modality. Therefore, diagnostic tools are as important for patient stratification and the quality management of therapeutic stem cells as the standardized manufacturing of stem cell products.
However, in any indication, clinical trials are still expensive despite the enrollment of smaller groups of patients; Geron had to raise US$50 million for clinical trials. At the same time, when smaller companies felt ready to bridge the translational gap and enter clinical validation of their therapeutic strategy, big pharma companies monitored and entered this field of pharmaceutical innovation and potential new revenues. Corporate partnerships were announced (e.g., Astra-Zeneca and Cellartis or Pfizer and Athersys), as well as private–public partnerships. Those partnerships have the potential to leverage open issues regarding the safety and efficacy of stem cells for therapy and remaining regulatory requirements.
Nevertheless, there is worldwide excitement over the therapeutic promise of stem cells, which is justified with caution. However, the hope is real that strategic partnerships will translate stem cell research into new therapeutic modalities. In the end, there is increasing evidence that hope will triumph over hype.