Allogeneic cell and gene therapies rely on procuring cellular starting material, typically from healthy adult donors or cord blood units (CBUs). This creates unique supply chain and scalability challenges that do not exist for traditional pharmaceuticals. However, a model for overcoming these challenges exists.
Hematopoietic stem cell transplantation (HSCT) is an allogeneic cell therapy that has been used for decades to treat patients with blood cancers and disorders. Successes in overcoming challenges in HSCT can be directly applicable to emerging allogeneic cell therapies that require starting material from adult donors or CBUs.
A Solid Infrastructure Framework for Emerging Allogeneic Cell Therapies
In the early 1980s through the early 1990s, clinicians were slow to adopt the use of related and unrelated allogeneic HSCT. Since then, there has been a steady increase in allogeneic HSCT with more than 8,000 transplants a year administered in the United States from 2015 through 2020, according to data reported to the CIBMTR (Center for International Blood and Marrow Transplant Research).
With the scale has come challenges in donor availability, collection capacity, and logistics, as well as the need to improve therapy efficacy. This has led to a cell procurement and data collection infrastructure that benefits emerging allogeneic cell therapy developers.
A Large, Diverse Donor Pool is Essential
The allogeneic cell therapy infrastructure starts with donor registries. These U.S. and global registries are critical because approximately 70% of patients who need allogeneic HSCT do not have a fully matched donor in their family.
As the use of HSCT has scaled, ensuring donor availability becomes more of a challenge. Organizations like the National Marrow Donor Program (NMDP) / Be The Match, which operates the Be The Match Registry in the United States, have continually invested in understanding and eliminating non-medical barriers that may prevent a donor from moving forward with donation.
Having access to a large, diverse registry with willing donors who match the therapy requirements is essential for allogeneic cell therapy developers to scale. This is clearly demonstrated in two case studies from Be The Match BioTherapies. Be The Match BioTherapies supports cell and gene therapy developers as part of the NMDP / Be The Match.
The first case study involves a client developing an allogeneic natural killer (NK) cell therapy that had both human leukocyte antigen (HLA) and KIR matching requirements. The donor pool started with a segment of approximately 7 million potential donors. From this 7 million, Be The Match BioTherapies filtered potential donors based on known demographics, including age, sex, race, HLA, and KIR, prior to determining which donors to contact.
On average, to achieve one collection, 131 potential donors were contacted; 34 completed screenings to assess for therapy-specific attributes not available in the upfront filtering, which resulted in two that passed screening to move on to an informational session; and one donor qualified and completed collection.
If the cell therapy developer needs to collect one donor a month for a year, those numbers increase to 1,529 potential donors contacted and 411 screened to achieve 21 that pass screening and move on to have an informational session, consent to and schedule collection, and two that qualify for and complete collection.
Even cell therapies without HLA matching requirements require large donor pools. In the case of an allogeneic CAR-T developer without HLA requirements, one collection required contact with 118 donors and the completion of 22 screenings to get to one qualified donor and collection. For one collection a month for a year, those numbers increase to 1,413 donors contacted and 261 screened for 12 qualified donors and collections.
As allogeneic cell therapies progress through clinical stages and the patient population grows, the volume of donors needed per month will also continue to grow.
Be The Match BioTherapies has made concerted efforts to educate potential donors about opportunities to donate for cell and gene therapy development to improve the likelihood of a donor moving forward with supporting these therapies.
Cell Collection and Delivery Experience are Key
An infrastructure for allogeneic cell therapy must include collection centers and logistics. In HSCT, approximately 90% of donors have their cells collected via apheresis. In fiscal year 2022, the NMDP / Be The Match facilitated apheresis collections for nearly 5,500 adult donors. Facilitating these collections requires a geographically diverse contracted network of apheresis centers across the United States to ensure that there is capacity to collect high-quality product.
A geographically diverse collection network can also reduce a barrier to donation: travel. The NMDP / Be The Match has strategically added apheresis centers to its network to align with where the majority of donors on the registry live. This helps minimize the level of effort it takes for a donor to be part of the collection.
This is a key factor for scalability for allogeneic cell and gene therapies, too. The same approach has been leveraged in building a network to support collection for emerging allogeneic cell therapies. Again, their geographic distribution aligns with where most potential donors are located.
After collection, donor cells for both HSCT and allogeneic cell therapy must be transported. HSCT transports are time critical and temperature sensitive; more than 50% have an international donor or patient. In addition, these transports are susceptible to supply chain disruptions — from scheduling collections through product delivery.
These challenges led to the development of a strong logistics infrastructure and key relationships. For example, the NMDP / Be The Match established relationships with the emergency management community that allows for continuous movement of fresh product when a weather event — such as a flood, hurricane, or blizzard — occurs. If a delay occurs, the organization has backup plans in place to help ensure an on-time delivery to the transplant center.
Examples from HSCT demonstrate cell therapy supply chain disruptions are inevitable even with well-designed plans. Allogeneic cell and gene therapy companies must have a strong collection network and logistics infrastructure in place — or work with an experienced partner that does — to overcome disruptions.
Data Collection and Tools are Important for Improved Patient Outcomes
Therapy efficacy is the most critical piece in therapy development. The HSCT field demonstrates how a data collection infrastructure and related tools can lead to continuous optimization and therapy efficacy improvements over time.
CIBMTR is a collaboration between the NMDP / Be The Match and the Medical College of Wisconsin that supports research in cellular therapies to improve patient outcomes. It facilitates critical observational and interventional research through scientific and statistical expertise, a large network of centers, and a unique database of long-term clinical data for more than 630,000 people who have received allogeneic or autologous HSCT and other cellular therapies.
CIBMTR has collected patient and donor data for decades, and its database includes information such as demographics, HLA typing, infectious disease markers, and collection data, along with outcomes. The NMDP / Be The Match and CIBMTR have leveraged the data to publish and evolve donor selection guidelines to maximize survival. These guidelines were published in Blood. For example, the organizations found that using permissive matching versus non-permissive matching at one locus decreased transplant-related mortality.1
Allogeneic cell and gene therapy developers can leverage data like this to support cell source optimization and population modeling for cell bank design. The data can also be used for observational studies and clinical trial design to help improve cell therapy outcomes over time.
Addressing Allogeneic Cell and Gene Therapy Pain Points Supports Scalable Advancement
Many pain points exist today for allogeneic cell and gene therapy developers. However, the infrastructure and tools built for HSCT can help address these pain points to support the growth and commercialization of allogeneic cellular therapies. Be The Match BioTherapies harnesses the experience, relationships, and infrastructure built over the past 35+ years to help cell and gene therapy companies bring emerging therapies to patients sooner.
We offer Adult Allogeneic Cell Sourcing and Cord Blood Unit Sourcing services for allogeneic cell therapies in clinical trials or commercially available. This allows sponsors and developers to access high-quality starting material for their therapy.
Our adult donors and CBUs are on the Be The Match Registry — the most diverse registry of potential unrelated donors and cord blood units in the world — which the NMDP / Be The Match has managed for more than 35 years. In that time, our organization has facilitated more than 120,000 cell therapies.
That allowed us to develop sophisticated search-and-match and logistics capabilities to identify donors that match the characteristics an investigator needs and deliver the cells where they are needed. We are monitoring the cell collection and processing needs of the industry and working to enhance the capabilities within our network to make sure we can fulfill the needs of the industry as it evolves. Additionally, our Cord Blood Bank Alliance offers cell therapy developers a single point of access to the domestic cord blood unit inventory.
Our CIBMTR Bioinformatics Consulting Service provides models, analyses, and interpretations to help sponsors define their targets and build their off-the-shelf cell banks. For example, donor pool modeling helps allogeneic cell and gene therapy companies understand the odds of finding donors that match their cell therapy criteria as well as how allogeneic donor choices for source material could impact therapy efficacy. Population modeling helps allogeneic cell therapy companies determine the best cell bank design to maximize target population coverage.
Our CIBMTR CRO Services team specializes in cell therapy clinical trial design and oversight. Our in-house HSCT and cell therapy physicians offer clinical insights to help sponsors and investigators optimize protocol design and lay the groundwork for a successful clinical trial.
These services are a direct result of the experience gained in managing the challenges of the first allogeneic cell therapy, HSCT. Allogeneic cell and gene therapy companies can leverage the successes in allogeneic HSCT to address pain points and support the growth and commercialization of allogeneic products.
Reference
- Dehn J., S. Spellman, C.K. Hurley, et al. “Selection of unrelated donors and cord blood units for hematopoietic cell transplantation: guidelines from the NMDP/CIBMTR.” Blood. 134:924–934 (2019).
