Enhancing Speed in CAR-T Cell Manufacturing with Cell Therapy Solutions

In autologous cell therapy manufacturing, speed is essential

Autologous Chimeric Antigen Receptor (CAR) T cells represent a transformative therapeutic strategy in the management of cancer. The CAR-T cell manufacturing process consists of first harvesting apheresis material from a patient, isolating and activating the T cells and subsequently genetically modifying them to introduce the targeting moiety.¹ Cells are then expanded until a sufficient cell number is achieved for dosing and the cells are washed to remove upstream media components and activating reagents, and then formulated with a cryopreservative.¹ Overall, the entire process end to end is approximately 14-21 days.

Several steps in CAR-T cell manufacturing can cause shear and stress, which are detrimental to the cells. Additionally, prolonged timelines and extended periods spent in ex vivo expansion can reduce cell viability and adversely affect cell health. Overall, these factors, compounded by the fact that the cells are harvested from diseased donors, substantially increase the risks of process failure.² Indeed, clinical studies have cited manufacturing failure rates as high as 13%.^2,3 Furthermore, the CAR-T cell manufacturing process time is a crucial consideration for patients. Delays generated in manufacturing and are costly when time is absolutely of the essence. In some instances, patient samples are shipped halfway across the globe to manufacturing centers, and the therapeutic product is then shipped back to patient centers for infusion.⁴ Disease progression is also a significant barrier, as highlighted in one study where 13% of patients who submitted apheresis starting material never received their treatment.³

Collectively, these key learnings from the clinical development of various therapeutics suggest that the speed of CAR-T manufacturing is second only to patient safety. Furthermore, speed from starting raw apheresis material to finished CAR-T therapy represents a key metric in the success of CAR-T manufacturing and, ultimately, CAR-T cell manufacturing costs. In the context of logistics, cell therapy manufacturers can save valuable time by the decentralization of manufacturing and utilizing multiple sites simultaneously to significantly reduce transit time of patient material for manufacturing as well as shipping the therapeutic back for infusion. However, decentralization of manufacturing may expose vulnerabilities and inconsistencies in the manufacturing process if a significant reliance on open, manual unit operations and poorly defined raw materials exists. Thus, a second, and much more critical aspect for cell therapy manufacturers is the concept of process robustness that can be achieved through the utilization of high-quality raw materials as well as closed automated processing equipment to help alleviate process variability and T cell vulnerability from either batch to batch or geographical site to site.

Read our Cell Therapy Handbook to learn more

 

 

Closed, automated and modular solutions enable rapid CAR-T cell manufacturing

The complexity of CAR-T cell manufacturing poses a barrier to the wider accessibility and uptake of transformative CAR-T cell-based therapies. A highly robust, closed, and automated CAR-T manufacturing process that utilizes high-quality raw materials will exhibit a higher success rate in a shorter amount of time, which overall will drive CAR-T cell manufacturing costs down. Thermo Fisher provides CAR-T therapy developers with modular and flexible instrument solutions that specifically address CAR-T cell manufacturing process robustness, speed, and scalability in addition to high-quality media and consumables required for CAR-T cell manufacturing.

Watch this video for a concise overview of the CAR-T cell manufacturing process.

The ability to complete T cell isolation and activation in a single, automated step can enable a simpler workflow, resulting in time savings and process control improvements. In addition, the development of non-viral and scalable CAR-T workflows can support increased genome editing efficiency, enhanced precision, and higher expansion of CAR-T cells. Thermo Fisher now provides off-the-shelf technology to enable one-step isolation and activation while integrating several CAR-T process steps in a closed, automated workflow.

Another recently published study demonstrated an automated and shortened lentiviral-based workflow of autologous CAR-T manufacturing using the Gibco CTS™ Detachable Dynabeads™ CD3/CD28, release buffer, and the Gibco™ CTS™ DynaCellect™ Magnetic Separation System.⁵ Under the control of the Gibco CTS Cellmation Software, T cells were isolated with the CTS Detachable Dynabeads. Post isolation, the cells were transduced with a lentiviral vector carrying a CD19-CAR and transduced cells were subsequently washed, debeaded, and concentrated with the Gibco™ CTS™ Rotea Counterflow Centrifugation System. CAR-T cells were cryopreserved using the Thermo Scientific CryoMed. Collectively, this study demonstrates the feasibility of utilizing a 24-hour CAR-T cell therapy manufacturing process. More importantly, though, this study showcases the degree of automation that is possible to further facilitate a CAR-T cell manufacturing process when select, critical equipment is utilized to provide a complete solution.

The CTS™ Rotea Counterflow Centrifugation System supports high viability and low-shear environment for cell processing.

• The Gibco CTS Rotea system is a fit-for purpose cell processor proven in PBMC isolation and CAR-T cell therapy applications. Utilizing a counterflow centrifugation method that produces low-shear environments, the CTS Rotea system enables versatile, gentle cell processing from research and development to clinical manufacturing
• The CTS Rotea system enables speed from discovery to clinical manufacturing via flexibility in customer-specified and fully customizable optimization of protocols.

The Gibco™ CTS™ DynaCellect™ Magnetic Separation System supports isolation and activation with high purity and viability.

• The CTS DynaCellect system functions through a continuous flow automated bead removal system that offers significant advantages over other isolation and bead removal solutions up to 1L volume (10 billion cells) in 70-100 minutes.
• The system can offer rapid and efficient processing of cells with an overall recovery rate of 91% when using Gibco CTS Dynabeads CD3/CD28 at a processing speed of 50 mL/min.

The Gibco™ CTS™ Cellmation Software for DeltaV System provides critical instrument automation and enables digital integration of instruments.

Watch this Fast Facts Video: Automating the Cell Therapy Workflow with Gibco CTS Cellmation Software

• Instrument automation is crucial for integrating unit operations and minimizing process variability with multiple batches of patient samples.
• The Gibco CTS Cellmation Software provides the capability to connect modular cell therapy instrumentation an Emerson DeltaV system to simplify and streamline workflows.
• This software is powered by Emerson’s DeltaV Distributed Control System (DCS), developed following GAMP5 methods, and is fully compatible with cGMP processes.

Taken together, speed is second only to patient safety in autologous CAR-T cell manufacturing. When you partner with Thermo Fisher, you can ensure that critical equipment is modular, digital, and compatible with other CTS cell therapy instruments, allowing for the most robust and automated CAR-T cell manufacturing, ultimately ensuring clinical success.

 

To learn more about cell and gene therapy instrumentation, visit our website: www.thermofisher.com/ctxmanufacturing

To learn more about Cellmation Software, visit us at Gibco CTS Cellmation Software for DeltaV System

Request a Demo: Closed, Automated and Integrated Cell Therapy Instruments

 

References

1. Tyagarajan, S., Spencer, T. & Smith, J. Optimizing CAR-T Cell Manufacturing Processes during Pivotal Clinical Trials. Molecular Therapy Methods and Clinical Development vol. 16 136–144 Preprint at https://doi.org/10.1016/j.omtm.2019.11.018 (2020).
2. Zynda, E. & Singh, A. Overcoming the Challenges of Cell Therapy Manufacturing.
3. Schuster, S. J. et al. Chimeric Antigen Receptor T Cells in Refractory B-Cell Lymphomas. New England Journal of Medicine 377, 2545–2554 (2017).
4. Ellison, A. & Kansteiner, F. Automation, decentralization and the future of CAR-Ts: Advancements in cell & gene therapy manufacturing (Part III). Fierce Pharma (2024).
5. Ahmadi, M. An automated 24-hour CAR-T manufacturing process. Cell Gene Ther Insights 10, 441–452 (2024).