By Tim Valko and Matt Yedwabnick, Atara Biotherapeutics
When the first chimeric antigen receptor (CAR) T-cell therapies were approved by the FDA in 2017, those in the immunotherapy field collectively felt this breakthrough would fundamentally change outcomes for those with life-threatening cancer. FDA-approved autologous, or patient-derived, CAR T therapies have shown remarkable efficacy in blood cancers, extending countless lives. However, despite their promise, autologous therapies remain limited to relatively few liquid cancer indications and, compounded by struggles with manufacturing and product development, have not yet realized their full potential as broadly applicable cancer treatments.
In contrast, allogeneic, or donor-derived, cell therapies offer the potential to overcome these limitations and are being studied in both solid and liquid cancers in a wider range of patients than can be currently served by autologous cell therapies. Even so, manufacturing cell therapies is complex and time-consuming and requires strict regulatory compliance. Several key challenges remain that must be overcome to advance cell therapies, including supply, scalability, and storage issues.
1. Supply Constraints
All cell therapy products, whether autologous or allogeneic, are dependent upon the cells and tissues from which they are manufactured. For autologous therapies, harvesting enough T cells from a patient can be difficult. In fact, many cancer patients have fewer lymphocytes than normal in their blood and the number of viable therapeutic cells is often severely limited either by the disease itself or by cytotoxic treatments such as chemotherapy and radiation. As such, variability in patient age, immune system, and disease state can affect expansion and reproducibility between batches of cell therapies, which must be consistent to obtain reliable results in patients. In contrast, allogeneic cell therapy products have the potential for less variance and improved cell quality because donors have not been exposed to chemotherapy or other cytotoxic treatments. Although variability in donor material is inevitable, it may be mitigated with sheer numbers of healthy donors to ensure a large enough pool of raw material to minimize the impacts of variability.
We at Atara Biotherapeutics are developing allogeneic EBV-specific T-cell immunotherapies to fight Epstein-Barr virus (EBV). EBV is one of the most common human viruses, with 90 percent of adults worldwide harboring dormant infections. Once infected, the body creates T cells to target and destroy EBV-infected cells. These T cells have unique characteristics that make them prime candidates for the development of an allogeneic T-cell immunotherapy platform. Healthy EBV T cells can be donated by individuals, manufactured, and then stored as inventory, with the goal to make them available within days of patient need. In addition, by using EBV T cells as the basis for our platform, we eliminate the need for T-cell receptor (TCR) or human leukocyte antigen (HLA) gene editing.
EBV is associated with many cancers and autoimmune diseases, and we are currently investigating our allogeneic EBV T-cell immunotherapy candidates in a wide range of EBV-associated diseases where the patient’s own immune system is not able to adequately fight the virus. In these cases, EBV T cells are designed to directly attack the EBV-infected cells that are causing disease. Allogeneic EBV T cells from donors may reinforce a patient’s natural immune function and target disease at its source.
EBV T cells can also be modified to add receptors on the surface of the cells that target cancer cells to fight blood cancer and solid tumors. These CAR T therapies are designed to attack specific cancer targets.
Most importantly, to help ensure we can provide these therapies when necessary to patients in need, Atara has assembled a large network of healthy donors to minimize unpredictability and help maximize the potential of these products. Through this network, we’re able to plan production well in advance of need, building an inventory of cells to hold at the ready.
Raw materials (including cell-culture media, good manufacturing practices (GMP)-grade cytokines, and leukapheresis products) are limited and often expensive. Because of their potential to impact safety, purity, and potency of the final cell therapy product, raw materials must meet stringent quality standards and should be selected appropriately to mitigate introduced risks to manufacturing facilities and final cell therapy products, extremely important as companies prepare for commercialization and compliance evaluation. Considering the limited raw material source options, manufacturers should diversify supply chains using multiple material suppliers to be more robust. At Atara, we worked hard to establish each element of our commercial supply chain. We have evaluated each element from operational, quality, and compliance perspectives to help ensure that expectations for a successful commercial product launch are met.
2. Scalability Issues
Currently, both autologous and allogeneic therapies are manufactured at a relatively small scale since these processes are manual and laborious. Consequently, cell therapies are potentially prone to human error, resulting in increased risk of contamination, batch loss, batch-to-batch variability, and high manufacturing costs. This is due in part to difficulty of cell recovery and expansion and the lack of proper equipment and analytical assays to track differentiation of cells during process development.
Like the difficulty of obtaining enough viable T cells, expansion of these cells may also be an issue. When developing autologous therapies, a patient’s immune system is already impaired by the illness they are facing, which may add to variability in the T-cell population harvested for further development. This may yield differences in the expansion and persistence of certain T cell phenotypes that may affect short- and long-term efficacy. In particular, malignant cells may contaminate cell products, potentially harming a patient rather than helping to treat their condition. Additionally, throughout the manufacturing process, environmental parameters should be monitored to ensure consistency, product quality, and sterility. For these personalized therapies, “scaled-out manufacturing” – setting up multiple, simultaneously running, parallel production lines in the same manufacturing facility, may be used to increase output. Still, only one production lot may be created to treat one patient.
The ability to scale up and scale out will be essential to decrease variability while also increasing patient access to these therapies. For specific adherent cell types, such as induced pluripotent stem cells (iPSCs) that can differentiate spontaneously, cell growth must be balanced with scaling to get the desired degree of differentiation at the desired time. In contrast, allogeneic cell therapies may be scaled up to meet demand but must also be expanded without compromising function. T cell exhaustion and culture-associated cell aging, or senescence, restrict the number of population doublings, overall culture times, and quantities. Importantly, overcultured cells may also lose efficacy in patients. At Atara, we’re able to grow EBV T cells in suspension, allowing us to passage and scale up product yields.
Unfortunately, current cell manufacturing equipment is not truly designed for cell therapy products, but rather more for cells to be factories of proteins or other products. Design and automation of production technology moving forward can provide more control of the bioprocess. Automation can also eliminate in-process variation through the use of robotic arms that can repeatedly and consistently perform a pipetting or a mixing action, or even a whole cell culture sub-process, with consistent speed, force, and accuracy rather than being dependent upon human precision, which may lead to reduced variability and increased process reliability.
At Atara, we’ve developed stirred-tank bioreactor processes that may allow use of a single donor batch to treat thousands of patients. Thus far, we’ve been able to scale the process in several cases from static, gas-permeable vessels to bioreactor production in order to potentially provide hundreds to thousands of doses from a single donor. By investing in scalable technologies, we aim to produce enough drug to address unmet medical needs in many different patients.
Because of its promise, we’ve seen exponential growth in cell therapy, but this expansion has led to a real talent deficiency within the bioanalytical field. Scalability on a global level is not just about technology but also being able to hire enough qualified staff. To address this issue, we’ve continued to develop and train our technical teams and expanded our personnel pool to the wider biotech sector rather than being limited to a small talent pool with expertise in cell therapies. We have also incorporated technological advancements such as stirred-tank bioreactors to maximize efficiency.
We’ve found fostering cross-functional teams essential to create flexibility as you move through the product life cycle. For instance, involving the supply chain team early in the product development cycle will help to prevent later-stage issues from surfacing in the transition to a GMP setting.
Lastly, the lack of analytical assays to track differentiation and measure the effects of manufacturing on cells makes process development and control of the cell product significant hurdles. As such, the cell and gene therapy market has focused heavily on analytical development in recent years, but there are still many challenges to be addressed. We’ve found it is essential to analyze the mechanism of action and performance of your product through in-depth characterization of the therapy.
3. Storage and Logistics Challenges
Once created, cell therapies must be stored in large quantities and safely kept alive. Most require ultra-cold storage and transport, -150˚C or colder, carefully controlled to limit exposure to room temperature using cryofreezers, cartons, vials, and shippers. Temperature is monitored throughout transport, confirmed, and validated before thawing and administering to the patient. Driven by the needs of mass COVID-19 vaccination, cold-chain capabilities across facilities in the U.S. and ex-U.S. have become more widespread and there is more comfort in handling these types of products than ever before.
Still, for autologous therapies, decentralized manufacturing that takes place close to the point of care is preferred, mostly due to the need for a highly monitored, temperature-controlled supply chain that benefits from close proximity between manufacturing and patient. Manufacturing an autologous cell product regionally or at the clinical site may alleviate some of the time pressure but is a major challenge economically. However, economies of scale in the decentralized model are lost compared to the centralized model often associated with the development of allogeneic therapies, in which ordering, quality control, and quality assurance are done in one place. By leveraging regional distribution, efficient distribution to locations across the country may be achieved, helping avoid timing or delivery delays.
As we and other manufacturers move closer to large-scale commercialization, there must be a concerted effort to continuously overcome these challenges through approaches that include the incorporation of new technology, developing better analytics for more accurate characterization, ensuring suppliers are ready for compliance evaluation, and addressing the limited pool of qualified talent from which to hire. At Atara, we remain committed to advancing the manufacture of allogeneic cell therapies and developing new treatments to potentially address EBV-associated diseases, such as Epstein-Barr virus associated post-transplant lymphoproliferative disease (EBV+ PTLD) and autoimmune diseases, as well as other cancers unrelated to EBV that we are investigating, like mesothelioma, with our next-generation CAR T portfolio. By leveraging the unique biology of EBV T cells, we hope to harness the power of the immune system to potentially treat a wide range of diseases, expand patient access, and one day change the way many different diseases are treated.
About The Authors:
Tim Valko serves as senior vice president, global manufacturing and supply chain at Atara Biotherapeutics. In his role, Tim applies his experience in biopharmaceutical manufacturing, operations strategic planning, and clinical and commercial supply chain to deliver Atara’s immunotherapies to patients. Tim has been involved in the launch and commercial supply for more than 20 marketed biopharmaceutical products. Tim is currently board chair of Rx-360 Supply Chain consortium. Tim received his B.S. in biology at Adrian College in Michigan.
Matt Yedwabnick serves as the vice president of global supply chain at Atara Biotherapeutics. He has 15 years of industry experience in biotech operations and supply chain, including operations risk management, strategic planning, and clinical/commercial supply chain. Prior to joining Atara, Matt held various leadership roles across Amgen’s global supply chain. His experience includes leading cross-functional initiatives across drug product manufacturing strategy and risk quantification. Matt received his bachelor’s degree in chemical engineering at Michigan State University and earned his M.B.A. from UCLA Anderson School of Management.