Exploring Dedicated Donor Paradigms As a Solution to Advanced Therapy Sourcing and Commercialisation Challenges
By dominic clarke, global head of cell therapy at hemacare
By dominic clarke, global head of cell therapy at hemacare.
Starting material sourcing has long been considered a bottleneck for the burgeoning cell therapy industry. Cell and gene therapies are a major leap forward in medicine – a promise of treatment tailored to the individual that can cure disease rather than simply managing symptoms. Stem and immune cell therapies are in development for diseases ranging from cancer to diabetes to macular degeneration and Parkinson’s. Many of these treatments are showing enormous potential in clinical trials. But are cell-based medicines ready for industrialisation?
The last few years have seen explosive growth in cell and gene therapies entering clinical trials. The Alliance for Regenerative Medicine (ARM) reported 1,066 advanced therapy trials to be underway by early 2020, a 67% increase over the last four years. The number of cell therapies approved by the FDA and EMA totalled 18 as of February 2020, and that number is expected to double over the next two years.
Scale up or scale out of a therapeutic to commercialisation first and foremost requires establishing a safe and reliable source of raw materials. Unlike traditional medicines, however, the raw materials for cell therapy cannot easily be scaled up for mass production; biological raw materials rely on access to human donors. The result is that the cell therapy manufacturing sector is facing two distinct challenges – the sheer volume of donors necessary to support a fast-growing industry and the mandate for a reliable, consistent product. Donor pool management, and the concept of dedicated donors, has the potential to mitigate both issues.
Cell therapy development and resource management
Development pathways may differ according to the product, but cost-effective resource management is essential to every pathway. Dedicated donors – recallable donors reserved to a specific project – can help solve sourcing issues while mitigating risks associated with donor-to-donor variability.
Cell therapy products are based on tissue – often apheresis material – collected either from the intended patient (autologous therapies) or a third-party donor (allogeneic therapies). Even autologous therapies require a varied donor pool for process development because processing steps need to be robust enough to treat as wide a range of patients as possible.
When an autologous cell therapy is being developed, sourcing can be problematic. Patient donors are impacted by their disease and may be unable to donate sufficient healthy cells. Even when the target cell yield is sufficient, there is notorious variability in starting material from patient donors. In this case, having access to a large, diverse donor pool and a reliable, recallable donor pool is necessary for finding a compatible donor.
A healthy donor with highly similar physiological characteristics to the patient can ‘stand-in’ for the patient during process development and quality control testing. Using dedicated donors rather than searching through an extensive database can provide consistent access to someone with a highly sought-after genetic profile that closely matches an individual patient. Dedicated donors can also be used to safeguard patient access to multiple doses of a consistent product.
Allogeneic therapies can be sourced from multiple donors. Still, the need for a product that is highly consistent in terms of quality and efficacy makes donor-to-donor variability a challenge. The ratio of target cell subtypes to contaminating cell types per apheresis unit, for example, directly impacts downstream efficacy. Even in a healthy donor, cell yield and viability can be impacted by lack of sleep, stress or other factors. Excessive starting material variability can result in failure to meet quality expectations, leading to failed or slowed manufacturing runs, which add to overall development costs.
Nevertheless, it is a mistake to begin the allogeneic therapy development process with highly restrictive donor criteria because that immediately impacts donor availability. The diversity of the real-world patient population necessitates flexibility in establishing donor criteria for clinical trials, in order to ensure that the collected data is valid for the greatest possible number of intended patients. From a regulatory standpoint, once donor criteria are established, those criteria will be applied throughout the clinical trial period to ensure proper controls are in place. It makes sense to have broader enrolment criteria early on since the clinical outcomes will inform decisions about which patient populations stand to benefit most from the product.
Rather than restricting donor criteria to reduce variability, we can instead allow for more variety in the donor pool and compensate for that natural variability by adjusting those factors that are more easily controlled. Processes such as starting material collection, target cell isolation and expansion and cold chain management should be optimised and standardised to produce a consistent, high-quality product. Having a reliable and recallable donor pool and dedicated donors who are reserved for specific cell therapy projects can minimise variability without restricting donor access.
Donor pool management is critical for resource management. Donor recruitment and qualification are costly undertakings, particularly for large donor pools. Donors are screened for various physiological characteristics, including HLA type, blood type, the presence of transmissible disease and other specific criteria clients may require for their project. Every donor also undergoes a general medical exam immediately prior to donation, to assure that they are healthy enough for the procedure.
Stem cell therapies are a good example of this cost-benefit challenge. Stem cell therapy development can involve either autologous or allogeneic starting materials. Access to a large donor pool is essential to sourcing the right donor at the right time but the high cost of characterising stem cell lines established from apheresis material impacts how many donors a client company can resource for their project. Being able to recall a specific donor multiple times helps both biological supply companies and pharmaceutical developers streamline costs and alleviate sourcing and consistency concerns.
Access to dedicated donors curtails recruitment and donor characterisation costs. Reliable, recallable donors donate regularly. They may have highly sought after physiological or genetic characteristics, such as consistently high yield or a rare HLA tissue type. They are familiar with the best diet and nutrition practices for donation, are responsive to outreach calls and have lower starting material variability from collection to collection. Maintaining a pool of dedicated donors can significantly bolster starting material access and offer consistency when needed.
The donor pool challenge
Research institutes, whether academic or independent, require healthy donor material for various projects. Those projects tend to be limited in size and scope due to the availability of government funding and faculty or student interest. Demand for healthy donor material tends to remain steady or increase slowly over time, depending on which specific projects are being pursued. Donor material is often procured through networking with local hospitals and clinics, and collection does not necessarily need to be GMP-compliant.
For biopharmaceutical companies, the situation is considerably different. Choosing a donor pool for starting material sourcing is a critical component of cell therapy product development and a limiting factor on the size and number of projects resourced for the company’s development pipeline.
Healthy donor material is needed throughout the lifecycle of any cellular therapy. The quality of that material directly impacts the quality of the final product every time it is sourced.
With any critical raw material, establishing a robust supplier relationship is important. Pharmaceutical developers and supply companies need to collaborate and partner early in process development to make sure both parties are aligned with immediate and extended goals to increase the chances of long-term success.
The amount of and consistent access to healthy donor material necessary for process development, quality control and patient administration steadily increases as therapies proceed from phase I to phase II or III of the clinical trials, as a natural outcome of increased patient enrolment. When products are approved for clinical use, the need for starting material sourcing increase dramatically. Consistency and quality are critical to all phases of development and to the long-term continuity of the product or products.
Unlike basic research institutes, biotechnology companies must be more knowledgeable of and compliant with current regulatory guidelines. When people think of the difference between research use-only (RUO) raw materials and GMP-compliant materials, they often see it as a difference in quality but, ideally, RUO and GMP materials should both offer the highest possible quality. Cell and gene therapy starting material designations are determined by the extent of quality review and documentation required by regulatory laws.
Because any successful drug candidate must ultimately be GMP-compliant, companies should source RUO materials produced using the same optimised handling methods and protocols as GMP-compliant material. It is also judicious to gain access to GMP-compliant starting materials early in development, to streamline the transition from lab to the clinic.
Donor pools are key determinants of starting material quality. Most pharmaceutical companies realise that it is best to partner with a supplier who has access to a large donor pool since that will enable them to find the right donor. Large donor pools require expertise in data collection and management but finding the right donor is only part of the solution. No one donor is always available when needed, or available over the long term. Using dedicated donors solves this problem by preventing sourcing bottlenecks and assuring reliable access to consistent, high-quality starting material.
Mapping out donor pathways
Cell and gene therapies pursue diverse pathways to patient treatment and therefore require unique strategies for successful commercialisation. No matter which pathway is pursued, starting material, and thus donors, are needed throughout the process.
Chimeric antigen receptor (CAR) T cell therapies are considered the ‘poster child’ of cell and gene therapy because of their astonishing success in treating aggressive cancers. CAR-T cell therapy is currently an autologous treatment that modifies a patient’s own immune cells to fight their cancer. To commercialise CAR-T therapies, manufacturers surmise that they may have to scale out, rather than scale-up, i.e. decentralise manufacturing, to get starting material processing as close to the patient as possible.
One way to accomplish this would be to carry out pre-processing steps at the collection centre. Cell therapy developers already coordinate with hospitals and clinics for starting material collection. Having a collection centre with its own GMP-compliant cleanroom would streamline early processing steps such as target cell isolation and quality validation.
Starting material for process validation assays and patient donor starting material would be collected at the same location, using the same trained staff, instrumentation and methodology. This would help shorten the delay between the collection of autologous starting material and eventual administration of the therapy to the patient. Cryopreservation of pre-processed starting material at the collection site simplifies cold chain logistics and mitigates any loss in cell viability and functionality during transport to the manufacturing site. This solution also simplifies sample tracking and verification since fewer steps are involved between collection and patient administration.
Allogeneic CAR-T cell treatments
An alternative strategy for CAR-T cell therapy development is to adapt the original design process to create allogeneic CAR-T therapies. The primary challenge of these re-imagined ‘off-the-shelf’ CAR-T cells is to avoid graft-vs-host disease (GvHD). Donated cells from an unrelated donor can cause a harmful, and sometimes life-threatening immune reaction in the patient. Genetically editing donated cells to be less immunoreactive would help lower the risk of an adverse immune response. This, in turn, unlocks the possibility of sourcing material from a broader pool of donors. This strategy is already being tested in clinical trials, though it could be years before it is commercialised.
Meanwhile, leveraging a dedicated donor pool can provide more timely relief for patients. Due to the impacts of their disease, the amount of healthy starting material available from an autologous donor often falls short of what is needed. Healthy HLA-matched donor material is often used to mimic donor immune response for autologous cell therapy process development. In some cases, it is necessary to find an HLA-matched donor for the treatment itself.
HLA-matched recallable donors can be recruited to source multiple therapeutic doses with essentially identical starting material – the same starting material used for process validation and development. Cell therapy developers could potentially plan ahead, cryopreserving multiple collections from the same dedicated donor or donors to be utilised at different points in process development and manufacturing process validation. This avoids sourcing delays and lowers starting material variability from the outset, saving both time and resources.
High-resolution stem cell donor screening
Cancer is just one of the many diseases that cell therapy can potentially address. Stem cell transplants from highly characterised unrelated donors are showing promise in the treatment of Sickle Cell Disease (SCD). A recent retrospective study outlined a new strategy for high-resolution HLA screening of unrelated donors. Using a novel HLA characterisation technique, the authors showed that the patients who received transplants from the most closely matched donors had lower rates of GvHD and higher overall survival rates. As we advance, one can hope that this technique can identify the best possible matching donors for stem cell transplant patients.
Allogeneic cell therapies, by their nature, can provide treatment to a larger number of patients. However, medical research has taught us that the immune reaction elicited by foreign tissue is a formidable hurdle to overcome. Nevertheless, various cell types, notably mesenchymal stem cells (MSCs), have a modulatory function that can suppress an overwhelming immune response. Consequently, MSCs and other immunomodulatory cells are being used as the foundation for a variety of cell therapies – including heart disease, Alzheimer’s and, most recently, a potential treatment for COVID-19 related pneumonia.
Expanded access to recallable donors
Starting material variability is a challenge for essentially all cell and gene therapies. This variability can result in sourcing bottlenecks while developers look for donors with desirable traits and/or closely matching physical characteristics. As therapies scale up from small clinical trials to general use, the potential lag (and the accompanying cost) in sourcing appropriate material only grows larger.
A large network of reliable, recallable donors can help solve this issue by providing a higher chance that the right donor will be available in a timely manner. Access to dedicated donors takes this solution one step further. Recallable donors reserved for a specific project are already highly characterised. They can be notified ahead of time of when they will be asked to donate, and their WBC yields and cell subset profiles tend to have lower variability from collection to collection than cells collected from unrelated donors. Lower starting material variability has a positive impact on planning from early development through to commercialisation because it consistently lowers overall risk.
Effective management for long-term continuity and scalability
By their nature, cell therapies are costly; they are complex to manufacture, have significant scale-up challenges and rely on a product that is uniquely vulnerable and responsive to its surrounding environment. Reducing potential bottlenecks in the translation of these therapies from early development to commercialisation is necessary to assure their success.
In summary, donor pool management is a key factor in managing raw material sourcing. Even within large donor networks, it can be hard to find just the right donor. Certain genetic traits are exceedingly rare. Cell type profiles and white blood cell yields are surprisingly variable even amongst healthy donors – both physiological characteristics and behavioural traits impact cell health and overall collection quality.
Reliable, recallable donors simplify starting material sourcing, but while regular donation may appeal to some altruistic donors, it is hardly intrinsically gratifying. Access to reliable and recallable donors is only made possible by developing and nurturing genuine, long-term donor relationships. Establishing donor trust and obtaining a long-term commitment is accomplished by ensuring that donor comfort and safety always come first. Committed recruitment and proactive outreach to new and established donors are what keep a donor pool strong.
Dedicated donors are a relatively new paradigm in donor pool management. Effective donor pool management means identifying and retaining reliable donors with highly desirable genetic traits or demographic characteristics. A well-run donor program will effectively guide biopharmaceutical clients on how best to mitigate risk in their starting material supply chain. This, in turn, will have a significant positive impact on starting material sourcing throughout the development life cycle of the client’s product or products. As a greater number of cell therapies head to commercialisation, a dedicated donor program offers a promising solution to the inevitable sourcing challenges.
Other useful resources:
Medicines in Development | 2020 update: https://phrma.org/-/media/Project/PhRMA/PhRMA-Org/PhRMA-Org/PDF/A-C/MID-cell-and-gene-therapy-2020.pdf
 The Alliance for Regenerative Medicine Releases 2019 Annual Report and Sector Year in Review. ARM. Mar 2020
 Gluckman E., et al. The role of HLA matching in unrelated donor hematopoietic stem cell transplantation for sickle cell disease in Europe. Bone Marrow Transplantation. Mar 2020
 Leng Z., et al. Transplantation of ACE2- Mesenchymal Stem Cells Improves the Outcome of Patients with COVID-19 Pneumonia. Aging and Disease. 11 (2): 216-228. 2020