By Navjot Kaur, PhD
Emerging cell and gene therapies offer transformative outcomes for some of the world’s most challenging diseases. As these powerful and significant developments mature, it is increasingly important for scientists to safely and efficiently manage a critical part of the clinical trial process: biospecimen management.
Cell therapies—including those based on chimeric antigen receptor (CAR) T cells, natural killer (NK) cells, and gene-modified hematopoietic autografts—offer the potential to make a significant impact on patients’ lives by using transformed live cells, derived from either patient or healthy donor, to eliminate cancer or fix genetic deficiencies. If this potential is to be realized, the novel biospecimen management challenges posed by cell therapies must be addressed. These challenges include the need to keep cells viable despite multiple cold-chain transportation steps and ex vivo modification.
To meet these challenges, cell therapy manufacturing often begins in laboratories adjacent to patient sample collection sites, but as more therapeutics are approved and more clinical trials are launched, it is necessary to expedite the development process from discovery and clinical trials to commercial manufacturing and delivery.1 An additional challenge, one that is relatively uncommon outside of cell and gene therapy, is the building of long-term biorepositories of cryopreserved cells. These cells, which include cells that have been modified to serve as therapeutics, must remain viable if they are to enable the collection of mechanistic data and the tracking of clinical outcomes.2
Unique challenges in cell therapy biospecimen management
Biospecimen challenges in cell therapy trials are different from those in more standard biopharmaceutical clinical trials. At the forefront of these is the safe and proper management of biospecimens taken from each patient. These biospecimens require special care because they are the core of the therapeutic that will ultimately reach the patient. That is, they will be modified and then returned to the patient. If biospecimens are not collected, transported, and manipulated properly through the manufacturing process, the therapeutic could underperform or fail due to the biospecimen’s quality and not the therapeutic’s design, leading to poor clinical trial performance and adverse patient outcomes.
As cell therapies are often initially targeted toward orphan or refractory disease, many are fast-tracked and given accelerated approval. Additionally, they commonly have smaller target patient populations than other biopharmaceuticals and thus smaller trials. The general therapeutic manufacturing process begins with patients’ cells being collected at clinical sites and transported under the most stringent safety conditions in coordination with regulatory requirements.2 Cells are then manipulated with methods including gene modification (examples of this approach include CAR T-cell therapies and T-cell receptor–based therapies), antigen priming (an example of this approach is Provenge, a dendritic cell therapy), and metabolic reprograming (an example of this approach is sirolimus, a chemotherapeutic). Depending on the therapy, the cells must be held in their collected state or induced and proliferated through careful control of media and cytokines/growth factors. Finally, the cells must be prepared for reinfusion at the clinical site.
Because of the nature of the challenges listed, manufacturing may begin at the academic medical center where the patient’s collection occurred; however, this is not scalable and fails to allow the therapeutic to be provided to the majority of the patient population. Cells must therefore be sent to distant manufacturing sites, such as those run by contract manufacturing organizations and pharmaceutical companies, requiring cryopreservation both from clinic to production and then back to clinic. Because it is critical to ensure no temperature-related degradation occurs, well-established cold-chain logistics must manage and document each specimen’s condition.
Cell therapy can be allogeneic, when cells are collected from a healthy donor and given to treat a patient, or it can be autologous, when cells from the patient are modified and returned for administration to the same patient. Biospecimen cells need to be transported under cryopreservation conditions, and then they must be carefully thawed to maintain the viability and functionality of the cells that are to be delivered to the patients at the clinical trial sites. Portions of the specimens must also be set aside during the clinical trial—before and after the biomanufacturing process—for various testing requirements. From qPCR to ELISA to flow cytometry, a range of tests must analyze the therapeutic steps being taken, and these tests necessitate both short- and long-term storage.3,4
Many research centers must generate subsamples for distribution to third-party laboratories and clinical partners, requiring aliquoting of the biological samples. If this process is not managed properly, the cells deteriorate during freeze-thaw cycles. Since the source biospecimens from each patient are much smaller in actual quantity, extraordinary care is needed at every step of the workflow to ensure that researchers do not lose valuable biological material.
In addition, any cell or gene therapy trial strategy for biospecimen management must include support for stable short- and long-term storage separate from the manufacturing process. Delayed biological events are possible with both cell and gene therapy products, necessitating long-term data collection. Any therapeutic changes that patients experience due to genomic modification need to be tracked for up to 15 years, making long-term cryogenic storage of the modified cells necessary.5
Best practices for biospecimen management in cell therapy
As cell therapy trials expand, researchers, along with every partner in the workflow, must understand the best practices for managing living/active samples during clinical trials.
- Work closely with regulatory agencies to fully understand and plan trials according to established protocols. For multi-region clinical trials, it is especially important to understand
requirements for every region in which the clinical trial is being conducted. In the context of many gene therapies and certain hematopoietic autografts, developers should also be familiar with expedited approval pathways, such as RMAT designation in the United States and PRIME designation in the nations of the European Union.
- Ensure that all clinical practitioners and personnel, from biorepository logistics to storage organizations, are fully aware of all safety and regulatory requirements. Since cell and gene therapies are still emerging, and patient risk is elevated, biorepository operations have a special responsibility to manage any biospecimen management safety concerns along the full workflow.
- Plan for specimen preservation along the entire workflow, from initial collection and therapy manufacturing to patient delivery and long-term storage. Unlike traditional treatment regimens, the specimen is also the therapeutic pathway, making safe preservation, management, and storage critical to the progress of clinical trials and, ultimately, to demonstrations of therapeutic efficacy.
- Develop rigorous cold-chain transport logistics. Cryopreservation at multiple stages requires detailed, multifactor tracking of each sample. This allows the sample to be clearly and permanently linked to a specific patient at every point of exchange and every process step, including long-term storage.
- Plan for long-term biorepository and sample management. In addition to biospecimen management during the active trial, biospecimens must be stored safely and securely long term. This step includes having a thorough appreciation of the regulatory factors related to managing the type of data generated by these trials.
Cell therapy programs are still relatively new, a factor that has led some major life sciences research institutions to retain all aspects of clinical trials within a single research organization or network of researchers.6,7 In addition, clinical trials for these treatments enroll far fewer patients in a given geographical area, creating the need for multiple biorepository locations that are able to serve distanced patient populations. This compels some researchers to set up their own biorepositories and biospecimen management systems to maintain sample integrity and traceability.
Researchers’ desire to maintain close control of biorepository functions in these circumstances is understandable. Yet there are distinct advantages to working with expert biorepository operations. These partners can help to efficiently and compliantly manage every aspect of biospecimen capture, transport, and storage. When researchers need to focus less on managing biospecimens, they can focus more on advancing cell and gene therapy science.
Finding the right biorepository partners
Working with biorepository experts can help prevent errors, protect patient safety, and enhance the efficiency of cell and gene therapy trials. Factors to consider in potential partners include:
procedures: Every touchpoint of the workflow should use advanced biospecimen digital documentation and tracking tools that tightly associate each specimen with its source patient.
Customizable cold-storage logistics and transport procedures: This includes real-time shipment tracking using automated tracing software and GPS-based tools. All partners should also work closely with clinical researchers to minimize transport times along the entire workflow.
Large-scale, custom-built cryogenic storage facilities: These specialized facilities, which may be strategically located across the globe, offer flexibility with storage temperatures ranging from those needed for cryogenic (−196°C) and ultra-low (−80°C) storage, to those needed for refrigerated and controlled room temperature storage. With systems that are continuously monitored and often reliant on multiple backup systems, cryogenic storage facilities can prevent accidental specimen loss due to local power failures or other unplanned events.
Robust biospecimen data management systems: Instant digital access to comprehensive biospecimen data allows researchers to efficiently manage biospecimen inventory, submit work requests, and generate standard or custom reports. State-of-the-art data management capabilities also allow researchers to conduct advanced data mining and analysis of trial and biospecimen data. As regulations in cell and gene therapy clinical trial data management evolve, partners must be prepared to ensure that their systems keep pace.
Collaborative mindset: When biorepository experts and researchers work closely together, they can better address the risks associated with imperfect or poorly planned biospecimen logistics by refining standardized procedures and tools to reduce the risk of errors or inefficiencies.
By considering biospecimen management early in the cell therapy clinical trial planning process, researchers can ultimately help lower costs, reduce rework, and simplify many clinical trial management tasks. As a result, researchers can spend more time doing what they do best: the scientific work that advances life-changing cell therapies to patients faster.
Navjot Kaur, PhD, is business segment manager, mRNA and gene therapy workflows, at Avantor.
- Alliance for Regenerative Medicine and the National Institute for Innovation in Manufacturing Biopharmaceuticals. Project A-Gene: A case study-based approach to integrating QbD principles in gene therapy CMC programs. Published June 24, 2021. Accessed December 1, 2022.
- Meneghel J, Kilbride P, Morris GJ. Cryopreservation as a Key Element in the Successful Delivery of Cell-Based Therapies—A Review. Front. Med. (Lausanne) 2020; 7: 592242. DOI: 10.3389/fmed.2020.592242.
- U.S. Food and Drug Administration. Long Term Follow-Up After Administration of Human Gene Therapy Products. Guidance for Industry. Published January 30, 2020. Accessed December 1, 2022.
- King D, Schwartz C, Pincus S, Forsberg N. Viral Vector Characterization: A Look at Analytical Tools. Cell Culture Dish. Published October 10, 2018. Accessed December 1, 2022.
- Gene therapy needs a long-term approach. Nat. Med. 2021; 27: 563. DOI: 10.1038/s41591-021-01333-6.
- Lindgren C, Leinbach A, Annis J, et al. Processing laboratory considerations for multi-center cellular therapy clinical trials: A report from the Consortium for Pediatric Cellular Immunotherapy. Cytotherapy 2021; 23(2): 157–164. DOI: 10.1016/j.jcyt.2020.09.013.
- Harrison RP, Rafiq QA, Medcalf N. Centralised versus decentralised manufacturing and the delivery of healthcare products: A United Kingdom exemplar. Cytotherapy 2018; 20(6): 873–890. DOI: 10.1016/j.jcyt.2018.05.003.