Since the first personalized cell therapy to treat advanced leukemia was approved by the US FDA in 2017, multiple CAR T cell therapies have been commercialized to treat blood cancers. Earlier this year, an autologous cell therapy was approved for the first time to treat melanoma. As the field has progressed over the years, it has met with increasing success in addressing autoimmune disorders and rare diseases. Despite the successes, challenges remain and need to be addressed effectively.
Critical challenges in CAR T cell therapy manufacturing
There are several challenges in manufacturing autologous cell therapies, at the core of which are patient-specific logistics 1. Patient-to-patient variability in samples affects the consistency of the final products. Reproduction and scalability of the multiple manufacturing steps, along with meeting regulatory requirements, are additional barriers 2. To streamline and expedite the manufacturing process, the following key areas must be addressed.
Time to manufacture:
Autologous CAR T cell therapy is a vital treatment modality that involves collecting patient cells, modifying them outside the body, and reintroducing them to the patient. However, this process is labor-intensive and time-consuming, often taking several weeks from cell collection to infusion 1–3. Given the criticality of these therapies for patients in advanced stages of illness, it is imperative to reduce the manufacturing time and ensure timely access to treatment. By leveraging the latest technologies and automated, integrated systems, it becomes possible to streamline and expedite the conventional workflows, resulting in efficient and timely processes.
Scalability:
Scaling up production to meet clinical and commercial demands of cell therapies without compromising the quality and efficacy of doses is a real challenge 2. Autologous therapies are patient-specific and therefore require individual processing. Patient-to-patient variability in samples, and the viability of cells, often from critically ill patients present additional challenges with sample processing. Leveraging scalable instruments and introducing automation early in the process can address some of these challenges. Considering their criticality, cell therapy clinical trials often progress faster compared to traditional drugs, and cell therapy manufacturers need to be prepared. Given the complex regulatory barriers, any change in process once the therapy enters Phase III is almost impossible.
Cost of manufacturing:
The cell therapy manufacturing process is complex and expensive, involving specialized instruments, reagents, and consumables, and stringent quality control measures 1–3. The cost associated with these intricate workflows cannot be understated, easily exceeding an estimated 100,000 USD per patient. However, to make these life-saving therapies more accessible to patients, it is crucial for manufacturers to explore alternative approaches that can effectively reduce costs in the long run.
Patient safety and quality control:
When it comes to cell therapy, patient safety is always top priority. One of the primary concerns is the risk of contamination during the handling and processing of patient cells. Any deviation from strict aseptic techniques can compromise the safety and efficacy of the final therapy. Therefore, maintaining a controlled and sterile environment throughout the manufacturing process is crucial.
Additionally, quality control measures play a critical role in autologous cell therapy manufacturing. This involves comprehensive testing and analysis to confirm the identity, viability, and functionality of the modified cells 1–2.
Implementing closed-system manufacturing platforms and automated monitoring systems can further enhance patient safety and quality control by minimizing the potential for human error and ensuring consistency in manufacturing processes.
Cell Therapy Solutions instruments and innovations to support cell therapy manufacturing
The Cell Therapy Solutions (CTS) instruments and reagents developed by Thermo Fisher Scientific have addressed many of the challenges mentioned above by providing closed, automated and modular systems to help minimize risks and increase efficiencies with autologous CAR T cell manufacturing. These instruments can be used either standalone or as part of an integrated workflow that is closed, automated and digitized. This allows for a completely sterile environment for cell processing. Additionally, our standard single use bioprocess containers (BPCs) offer flexible, ready-to-use systems that are cost-effective and can be integrated seamlessly into closed cell therapy manufacturing workflows to enhance efficiency. For more information on our larger bioprocess containers (BPCs) for your cell therapy workflows, check out this infographic and this white paper.
Watch this animated video for a comprehensive overview of the CAR-T cell manufacturing process:
The process begins with the isolation and activation of patient T cells by leveraging a magnetic beads-based technology. Following activation and bead removal using a Gibco™ CTS™ DynaCellect™ Magnetic Separation System, cell washing is conducted using a Gibco™ CTS™ Rotea™ Counterflow Centrifugation system. The cells can then be engineered using mechanical electroporation with the Gibco™ CTS™ Xenon™ Electroporation System or the viral vector-based transduction using LV-MAX™ Transfection Kit.
Finally, the cells are expanded, washed again (using the CTS Rotea system for cell processing) and cryopreserved for lot release and subsequent quality control and analysis.
Figure 1. CAR T cell manufacturing workflow using end-to-end automation and closed, modular process.
This entire process typically takes 7-14 days from start to finish (Figure 1). While this is a streamlined process, the constantly evolving landscape of cell therapy manufacturing innovations is beginning to see faster and more efficient approaches.
For more information, read our blog post here: https://www.thermofisher.com/blog/behindthebench/overcoming-common-cell-therapy-manufacturing-challenges-with-a-closed-modular-and-automated-solution/
To learn more about cell therapy instrumentation at Thermo Fisher Scientific, please visit: www.Thermofisher.com/ctxmanufacturing
References:
- Tyagarajan S, et al. Optimizing CAR-T Cell Manufacturing Processes during Pivotal Clinical Trials. Mol Ther Methods Clin Dev. 2019;16:136-144. Published 2019 Nov 29.
- Abou-El-Enein M, et al. Scalable Manufacturing of CAR T cells for Cancer Immunotherapy. Blood Cancer Discov. 2021;2(5):408-422.
- Rodrigues M, et al. Optimizing commercial manufacturing of tisagenlecleucel for patients in the US: a 4-year experiential journey. Blood 2021;138 Suppl 1:1768. 26.
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