Dr Vivienne Marshall, senior director of the Center for Advanced Therapies at the South Texas Blood & Tissue Center, part of BioBridge Global, outlines some of the major barriers to wider adoption of cell and gene therapies: complexity, variability, and the lack of robust standards. Dr Marshall also highlights the critical role of blood centers as strategic partners, guiding CGT developers through the intricacies of apheresis, the lynchpin in isolating blood-derived materials.
The field of cell and gene therapy (CGT) holds revolutionary promise for providing novel treatments for a wide range of dangerous and life-threatening diseases. However, the inherent complexity and variability of cell therapies pose significant challenges to optimizing manufacturing and ensuring consistent safety and efficacy.
To address these issues and improve patient access to cell therapies, standardization and optimization are crucial at every step of the production process, starting from patient or donor cell collection. Industry alignment on starting materials and donor screening can help expand patient access to today’s cell therapies. Ultimately, this will also lay the groundwork for the next generation of therapies relying on new technologies and approaches.
Cell and gene therapies are unique in that they originate from human sources, which offers exceptional potential, but introduces multiple confounding factors. The speed of growth in this industry has contributed to a lack of robust evidence-based standards, particularly in the areas of cell collection and donor screening. The variability in cell therapies is driven in part by the multitude of approaches in development, including genetic manipulation strategies such as chimeric antigen receptor (CAR)-T, CAR-NK, and starting cell types such as T cells, NK cells, TIL, B cells and others. Each cell type is unique, and the corresponding approaches required to isolate them vary. The breadth of new enabling technologies adds further layers of variation, ranging from gene editing platforms like CRISPR to novel vectors and automated manufacturing platforms. Adding the inherent biological variability from one patient or donor to the next, and the potential for inconsistency is immense.
Due to the immaturity of the CGT industry, it remains unclear what the impact of these variables will be on the final therapeutic product. The industry has yet to coalesce around starting material collection standards, which has contributed to a wide range of differences in donor material requirements. As a result, CGT developers, especially those in the early stages, often struggle to define how to qualify their starting materials. This lack of definition and qualification can hinder their ability to understand how to recruit donors efficiently, potentially leading to overly stringent criteria that reduce the donor pool, waste time and increase costs.
To address these challenges, as CGT developers move to optimize starting material effectively, they need to seek strong partnerships with experienced blood centers. The right collection partner will have reliable resources like a strong donor database and skilled staff, and the experience necessary to optimize apheresis for a range of processes to meet a variety of developers’ needs. Blood centers have this expertise and have worked with hospitals in communities across America for decades to supply blood and tissue products to save lives and provide clinical treatment options. They are embedded in the community and are trusted by donors and healthcare organizations alike. They will also add value by providing guidance and assistance in regulatory considerations, recruitment and screening of donors, collection of starting materials, and performance of testing. Many have infrastructure for cell processing, and some have cell manufacturing capabilities.
Automated apheresis: a critical step
Automated apheresis is a key process in the efficient isolation of blood-derived starting materials for advanced cell therapies. However, it remains a time-consuming process with numerous variables that can impact the final leukopak product. Apheresis involves removing a specific amount of blood from a donor or patient and circulating it through a closed system, using centrifugation to separate the desired components for collection, and then returning the remaining blood to the patient or donor.
To optimize the apheresis process, developers need to work with apheresis experts at blood centers to ensure that their needs for clinical development can be met. This includes planning for regulatory requirements, donor screening criteria, defining the endpoint of the apheresis based on cell count, choice of anticoagulant, specifying the target cell types, cryopreservation, if needed, and defining validated shipping conditions.
Standardizing autologous apheresis
Developing standards to streamline autologous apheresis may be more straightforward compared to allogeneic processes. For example, there is less complexity when screening for infectious disease, since the blood components will be returned to the same patient after genetic manipulation and manufacturing. However, the delivery of the manufactured product back to the patient takes much longer, due to the length of the manufacturing process.
Today, there are often different endpoint requirements for apheresis. The goal is typically to collect a sufficient number of target cells, which can require patients to spend an extended period in apheresis or return more than once. This is more challenging for autologous patients depending on the disease stage, course of treatment, and consequent ability to endure apheresis procedures with limited venous access.
Standardization is also needed to define apheresis products post-collection, including total cell count, complete blood count, cell viability, and infectious disease testing results. Additionally, while cryopreservation is standard for commercial cell therapy products that serve many treatment sites, the cost and potential impact on cell quality sometimes deters early-stage developers. This means that cryopreservation may be implemented well into development of the product, with consequences for repeated validation of treatment end quality. The industry would benefit from more data to determine clear guidelines that characterize the impact of all of these variables in the process. More collaboration between source material providers and industry developers is needed so that data from clinical outcomes can be married to starting material variables.
There is discussion in the industry surrounding pros and cons of centralized vs. decentralized manufacturing. While technologies and methods for widespread adoption of decentralized manufacturing are still in development, standardizing the collection process will be critical to enable consistent quality across a growing number of production sites. An increasing number of blood centers are establishing manufacturing capabilities, which will provide access to more local facilities, reducing the need to transport fresh starting materials across country to manufacturing sites, and may reduce the need for cryopreservation of cellular starting materials to de-risk the transportation process.
Allogeneic apheresis: a different challenge
Allogeneic approaches will be required in order to efficiently expand access to more patients in need. Indeed, many companies start by developing an autologous therapy with designs to transition to allogeneic products in the future. The apheresis collection process is more straightforward because healthy donors can more easily withstand the apheresis procedure, but the qualification of donors to ensure the elimination of transmission of infectious diseases is more rigorous.
Since one donor will provide starting material for multiple therapies, or patients, more must be understood about the connection between donors’ many baseline factors, product efficacy, and clinical outcomes. Developers often want to identify “super donors,” after significant investment in extensive screening, who will regularly donate the best-quality blood products for their therapy.
However, the impact on donor management and the longevity of this approach once commercial volumes are needed is underestimated. Super donors may end up being ruled out if they travel to unapproved areas, become positive for a prevalent infectious disease, make simple lifestyle changes like getting a tattoo, or simply age out of the qualification criteria. A more sustainable approach is to fully understand the effects of all donor qualification criteria on clinical outcomes and minimize these criteria to maximize the potential donor pool. Since genetic manipulation of the cells can be more easily standardized than donor starting material, more investigation needs to be conducted directly relating clinical outcomes to donor characteristics, and this will lead to greater standardization of the complete process, resulting in better treatments.
As with autologous therapies, differences in regulations based on geography – for example US, EU, or Japanese regulatory requirements – need to be taken into consideration when qualifying donors.
No one company or subsector alone can develop cell therapy industry standards. Optimization requires collaboration between and across organizations, and blood centers – as experts in apheresis collections, donor management, cell-based product storage, cryopreservation, manufacturing, and hospital delivery and distribution services – will continue to be key partners for developers as the field endeavors to understand and adapt and to the factors that most influence therapeutic outcomes.
