Allogeneic Versus Autologous Stem-Cell Therapy

Rapid progress is being made in stem-cell research and increasing numbers of therapies are expected to reach the market in the future. Stem cells are undifferentiated cells capable of undergoing self-renewal and differentiation into specific cell types (1). Their function is to replace tissue in response to normal cellular turnover or trauma (1). Harnessing the potential of stem cells can help combat many serious diseases with a high unmet medical need, including cardiac, neurological, and metabolic disorders (2–4). In the future, most cell-based therapies are likely to be:

• Autologous, with stem-cell expansion, where stem cells are harvested from a patient and culture expanded ex vivo to large quantities over many weeks and then returned to the patient

• Allogeneic, with stem-cell expansion, where culture expanded stem-cells originating from a single donor provide treatments to large numbers of patients.

The nature of a medical condition may dictate whether autologous or allogeneic therapy is most appropriate. For instance, allogeneic therapy may be the only option when emergency care is required because of the time needed to produce autologous therapy. However, there are many diseases where both autologous and allogeneic therapies are being considered.

Cell-based therapies are likely to be significantly more expensive to produce than small molecule and biological drugs due to the complexity of their manufacturing process. Given that profit is equal to retail price minus costs, whether a stem-cell therapy is commercially successful will be heavily influenced by its manufacturing cost. Understanding how manufacturing costs and processes are likely to differ between allogeneic and autologous therapies will allow an informed decision to be made by companies regarding which therapeutic type to pursue to produce a commercially attractive product. It is also essential to recognize that healthcare payers are evermore scrutinizing the cost effectiveness of treatments when making reimbursement decisions, so simply setting a high product retail price to attain a certain level of profit when faced with high manufacturing costs is not a realistic option. Having detailed data about manufacturing costs will also help companies optimize their manufacturing process to reduce production costs for autologous and allogeneic therapies.

To the author's knowledge, no data exists in the public domain about the cost differential to manufacture allogeneic and autologous therapy. The author sought to address this by determining the cost to manufacture one dose of allogeneic therapy with stem-cell expansion and one dose of autologous therapy with stem-cell expansion. The assumption was made that both allogeneic and autologous therapy had already been approved by regulatory authorities for an unspecified medical condition and shown to be equally safe and effective. The analysis focused purely on manufacturing costs and did not take into account any other costs such as R&D or product marketing. The analysis is timely as, up until recently, stem-cell research was focused almost exclusively on elucidating the science underpinning the discipline. However, companies have now begun to assess how to actually commercialize therapies (5, 6).

MANUFACTURING PROCESS

The widespread commercialization of stem-cell therapies is still many years away. Only limited information exists in the public domain for the best method to manufacture products on a commercial scale. The author interviewed industry leaders in stem-cell regulation, manufacturing, and commercialization to establish: the most likely commercially viable manufacturing process for allogeneic and autologous therapy; and the annual cost of each stage of the process?

The analysis was based on several key assumptions, which were that regardless of whether autologous or allogeneic therapy:

• Each treatment would consist of the same number of stem-cells (10⁸ mesenchymal stem-cells) and need to be culture expanded for the same length of time (three weeks)

• Each patient would require one dose of therapy

• 2500 doses would need to be manufactured annually to meet the national demand in the United Kingdom for an unspecified medical condition

• Automated cell culturing would be possible

• Growth factors and media used in stem-cell culture expansion would cost the same. (For further details on methodology and assumptions, see web version at BioPharmInternational.com.)

The expected manufacturing process for allogeneic and autologous therapy was determined to be similar (see Figure 1). Both groups would require the construction and running of a manufacturing plant with clean room facilities. Here doses would be produced via automated cell culturing using media components and growth factors. They would then undergo release testing, prior to being packaged and transported to a number of key hospitals around the UK that would provide stem-cell therapy services to patients. The key difference was that for allogeneic therapy, 10 donors would be screened and tested to find one with high quality stem cells, which would be used to form a cell-bank system that would provide treatments for 10 years. In contrast, for autologous therapy, each patient would undergo donor screening and testing; their stem cells would be harvested and shipped from one of the hospitals offering cell-based therapy services to the manufacturing facility for therapy production.

Figure 1: Annual cost of each parameter in a common commercial manufacturing process needed to produce 2500 doses of allogeneic and autologous therapy per year. (FIGURES ARE COURTESY OF THE AUTHOR)

COST DIFFERENTIAL

It was calculated that to manufacture one dose of allogeneic therapy would cost £930–1140 (US$1490–1830; €1030–1260) and to manufacture one dose of autologous therapy would cost £2260–3040 (US$3630–4890; €2500–3360) (see Figure 1). These figures include the cost of setting up a manufacturing facility. [For full breakdown of costs, see "Supplementary Material for Allogeneic Versus Autologous Stem-Cell Therapy: Manufacturing Costs and Commercialization Strategies".] The cost differential could almost exclusively be attributed to the finding that donor and release testing need to be performed in much smaller numbers during the large-scale, automated manufacturing of allogeneic therapy when compared to autologous therapy.

DONOR SCREENING AND TESTING

Donor screening and testing are needed to establish a donor's infectious status, genetic predisposition to pertinent diseases and susceptibility to cancer. Interviews undertaken suggest that donors are likely to be subject to the same degree of testing whether their stem-cells are used for autologous or allogeneic therapy. It is important to highlight that in-depth guidance on donor screening and testing has not been published by regulatory authorities.

Equivalent donor screening and testing for autologous and allogeneic therapies may seem counterintuitive given that in the former stem cells are returned to the patient from who they are harvested, and so less donor testing may be expected. However, three important reasons exist for equivalent donor testing:

• Cell characterization prior to expansion is needed to verify the identity of the cells.

• Cell abnormalities must be excluded.

• An individual may harbor a latent infection that must not be amplified and reintroduced.

For autologous therapy, each donor must be screened and tested at £990–1320 (US$1590–2110). For allogeneic therapy, 10 donors will need to be screened and tested to find a high-quality stem-cell sample to establish a cell bank system. It will cost £9900–13,200 (US$15,900–21,100) to screen and test 10 donors, and £250,000–500,000 (US$400,000–800,000) to create a cell bank system, which will provide 2500 doses annually for 10 years. Hence, donor screening and testing for allogeneic therapy is essentially £10–20 (US$16–32) per dose or patient (as each patient is assumed to be administered one dose).

RELEASE TESTING

Release testing of the final product is needed to ensure that it is fit for purpose. As with donor testing, release testing for allogeneic and autologous products is expected to be similar. This may seem counterintuitive because in autologous therapy stem-cells from a patient are returned to them after culture expansion. In both cases release testing must be performed to establish product safety, identity, purity, and potency. It could be argued that autologous therapies need more extensive release testing than allogeneic therapies because of the difficulty in obtaining a uniform outcome due to the inherent variability in different patients' stem cells.

Release testing is anticipated to cost £300–500 (US$480–800) per batch. In allogeneic therapy, each vial from the cell bank system will produce a batch consisting of 100 doses. Release testing for allogeneic therapy, hence equates to £3–5 (US$4.8–8) as only one dose is assumed to be given to a patient. In autologous therapy, each patient's therapy is a batch in itself, meaning that release testing will be £300–500 (US$480–800) per dose or patient.

DISCUSSION

The analysis determined that the cost to manufacture autologous therapy (£2260–3040 or US$3630–4890 per dose) will be more than double that to produce allogeneic therapy (£930–1140 or US$1490–1830 per dose) because current expert opinion is that with the former each patient will be required to undergo donor screening and testing and their final product will be subject to release testing. For allogeneic therapy, however, only a small number of donors will need to be screened and tested to find a high-quality stem-cell sample to produce a cell-bank system, which will provide treatments for around a decade, and release testing will be limited to each batch of the final product, which will provide approximately 100 doses of therapy.

Neither autologous nor allogeneic therapy will be able to compete with small molecule or biological drugs on retail price. To maximize their possibility of reimbursement from healthcare payers, stem-cell therapies will need to differentiate themselves by demonstrating good efficacy and safety in diseases that have significant mortality or morbidity (such as cardiac and neurological illnesses), where no satisfactory treatments exist or where the standard of care is particularly expensive over the duration of the illness (in terms of the cost of drugs, hospitalizations, primary care visits, nursing home care, physiotherapy). To justify their high price, stem-cell therapies will almost certainly need to modify disease progression or help restore normal physiological function rather than merely provide short-term symptomatic control.

Two fundamental factors will need to be met for cell-based therapies to be commercially successful, regardless of whether they are allogeneic or autologous. First, automated cell culturing will be required to achieve commercial-scale manufacturing, to deliver economies of scale, to produce a more consistent product each time, and to reduce the risk of microbial contamination (manual culturing carries a higher risk of pathogen contamination because of the need for an operator to be at close proximity to the samples). Second, it will be essential to control the cost of media components and growth factors used in automated cell culturing, as they will account for a significant portion of manufacturing costs.

The business models used to commercialize allogeneic and autologous therapy will differ substantially (see Table I). Allogeneic therapy is expected to follow an "off-the-shelf" business model, so could be used in both acute and chronic disease settings, which will maximize its commercial potential. The manufacturing of allogeneic therapy will be standardized because all doses will be produced from a cell-bank system, which will also mean that allogeneic therapy is relatively straightforward to scale up on demand.

Table I: Comparison of autologous and allogeneic stem-cell therapy.

For allogeneic therapy, immune rejection of administered donor stem-cells by the recipient remains a key concern. Mesenchymal stem-cells (MSCs) will almost certainly become a leading source of stem-cells in allogeneic therapy because they are considered immunoprivileged and so unlikely to invoke an immune response in the recipient (7). The hope is that using MSCs will abate the need for immunosuppressive drugs. Another fear is the possibility of transferring pathogens from the donor to recipients, but this risk will need to be completely excluded via meticulous safety testing when establishing a cell bank system.

In contrast, autologous therapy is anticipated to be commercialized using a "service-based" business model, a much more challenging business proposition for a number of reasons. The variation in stem-cells from different patients may mean that donor material from large numbers of patients does not yield therapy after culture expansion for the selected time period, particularly given that MSCs most probably culture expand less well with advancing age (8), which is precisely the age group at highest risk of being inflicted with medical conditions. In cases where donor material does not produce therapy after culture expansion for a specified duration, should culturing be continued? If yes, this would mean that therapies under production for different patients would be at different stages of the manufacturing process at a given point in time, causing logistical difficulties, increasing the risk of errors, and adding further to media and growth factor costs. Due to such issues, a considerable degree of flexibility would need to be built into any manufacturing process for autologous therapy and production would be more difficult to scale up on demand.

The length of time required to manufacture autologous therapy will prevent it from being used in acute patient care, which will reduce its commercial opportunity. There is also the fear that if an automated cell culturing machine runs cell lines from multiple patients simultaneously cross contamination could occur. This risk will need to be ruled out using GMP. Finally, patients will need to undergo two procedures for autologous therapy, one to extract stem-cells and the other to reintroduce them a few weeks later after culture expansion, which may raise medical and ethical considerations.

The assumptions for autologous therapy underlying the analysis probably represent the best-case scenario in terms of it being producible for all patients in the same time frame as allogeneic therapy using automated cell culturing. Therefore, manufacturing costs for autologous therapy may be much higher, if these assumptions are found to not hold true as our knowledge of stem-cell science and manufacturing increases.

The analysis undertaken has several key limitations: It assumes that it will actually be possible to manufacture both autologous and allogeneic therapy for a given medical illness and that both therapy types will have equivalent efficacy and safety. Both of these assumptions are unlikely to hold true with diseases in reality. It is also quite possible that for certain acute medical conditions, such as stroke or myocardial infarction, stem-cell therapy may need to be given within a finite window post-event, say 24–48 h, to achieve optimal results, which would rule out autologous therapy usage. Finally, it may be unwise to administer autologous therapy to patients with a personal or family history of cancerous, genetic or other pertinent disease.

It is important to highlight that this analysis assumed that each patient would need only one dose of therapy, but in practice multiple doses may be required to treat a medical condition. Additional doses of autologous therapy could be produced for a patient at no additional donor and release testing cost, if manufactured at the same time as the first dose and stored until required. Additional doses of allogeneic therapy could be produced from the established cell bank system, which in practice would be capable of generating much more than 2500 doses annually for ten years. The cost of release testing would, however, double in allogeneic therapy, if patients needed two doses as release testing is required for every batch consisting of 100 doses. Donor and release testing (along with cell banking for allogeneic therapy) essentially cost £1290–1820 (US$2070–2920) for the first dose of autologous therapy and £13–25 (US$21–40) for the first dose of allogeneic therapy, so the cost to manufacture additional doses of allogeneic therapy for a patient would remain approximately the same as the first dose, but the cost to produce additional doses of autologous therapy would drastically fall to ~40% of the first dose (from £2260–3040, US$3620–4870 to £960–1200, US$1540–1920) and become comparable to that for allogeneic therapy.

CONCLUSION

At present, allogeneic stem-cell therapy appears to be the more commercially attractive option for companies to pursue, both in terms of its manufacturing costs and logistics as well as in terms of its business potential because it will in essence be available as an "off-the-shelf" product, meaning it could be used in both acute and chronic disease settings. Yet, for certain medical conditions, autologous therapy is likely to prove the only feasible therapeutic option and still support an acceptable pharmacoeconomic calculation.

In the coming years, greater regulatory guidance is likely to be published on the production of cell-based therapies, which may more clearly define how allogeneic and autologous therapies should be manufactured, thereby allowing a clearer picture to emerge about therapy production costs and logistics. The field of cell therapy manufacturing is also advancing swiftly, meaning that improved large-scale, automated manufacturing technologies can be expected, which should positively affect the cost and logistical difficulties underlying cell-based therapy production.

ACKNOWLEDGMENT

This paper is based on the author's thesis submitted for a Master's in Bioscience Enterprise degree at the Univ. of Cambridge. The author thanks Dr. Catherine Prescott and Dr. Ruth McKernan for their supervision and support.

Dr. Nafees N. Malik, MB, ChB, MPhil (Camb), CSci, is an external lecturer at the Institute of Biotechnology at the University of Cambridge, nafees_malik@hotmail.com.

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