Sean Chang, Product Manager, Cell and Gene Therapy at Thermo Fisher Scientific
It has been four years since the first Chimeric Antigen Receptor T-cell (CAR T) therapy drug, Kymriah1, was approved by the US Food and Drug Administration (FDA) for the treatment of B-cell acute lymphoblastic leukaemia (ALL). Since then, four more CAR T-cell therapies for hematologic cancers have been approved by the FDA2, and the cell therapy pipeline continues to grow as more pharmaceutical companies and emerging biotechs join the effort to unlock the full potential that this transformative medical technology could hold.
A critical role of the immune system is to identify and destroy cells it recognises as abnormal; however, it isn’t always capable of recognising or destroying cancer cells for several reasons. Cancer cells can lose or mask the molecules that would identify them as a threat. Additionally, cancer cells are capable of inactivating immune cells, and can work to create a microenvironment that is hostile towards immune cells. T cell therapies leverage the immune system’s own T cells to fight cancer. To generate a T cell therapy, immune cells are harvested from a patient and engineered to express chimeric antigen receptors, a protein structure that enables the T cells to fight cancer once reintroduced back to the patient.
While the approach is still relatively new, the success of existing cell therapies, both approved and in clinical trial stages, is promising. In studies, nine out of ten people3 with acute lymphoblastic leukaemia whose cancer didn’t respond to other treatments or recurred, were able to achieve full remission with CAR T-cell therapy. These therapies are usually a last resort for patients who have not had success with traditional treatments, like chemotherapy and radiation. Therefore, the ability to provide such an effective treatment to this patient population as well as potentially replace current treatment modalities possesses the capacity to transform oncology care. In addition to treating hematologic cancers, cell therapies have the potential to treat other cancers, autoimmune disease, infectious disease, damaged cartilage, spinal cord injuries, weakened immune systems and neurological disorders.
Building on these promising successes, the cell therapy industry is rapidly leaving its infancy stage. The number of developers in the regenerative medicine space is now up to 1,085, according to the 2020 Annual Report4 from the Alliance for Regenerative Medicine (ARM), with cell-based immuno-oncology accounting for half of all Phase I trials, and the FDA predicting5 approval of ten to 20 cell and gene therapy products a year.
This rapid expansion has fuelled the industry need to overcome challenges associated with the complex manufacturing process and the shifting regulatory environment with the ultimate goal of making cell therapies more cost-effective and accessible to patients.
Fortunately, the growing cell therapy market has established defined needs, and provided a great opportunity for innovation. Developers are introducing new workflows as well as fit-for-purpose instruments and materials that allow for increased consistency and scalability, addressing many current barriers to widespread adoption.
Addressing Manufacturing Inefficiencies
Autologous CAR T-cell therapies are created using a patient’s own cells, resulting in a one-to-one drug product that can only be produced once a patient has been diagnosed and selected as a candidate for the therapy. The very nature of the treatment prohibits the use of scalable manufacturing workflows and can be very expensive due to their personalisation. Once approved for treatment, patients often have to wait weeks to receive the treatment, to accommodate the autologous cell therapy manufacturing process.
As soon as the patient’s input material is taken and they being their waiting period, a complex, multi-stage process begins behind the scenes. The stages involved in the cell therapy manufacturing workflow – isolation, activation, gene modification, expansion, harvest, formulation, fill/finish and cryopreservation – require multiple touch points along the journey. Not only do each of these stages need to go as planned, but every time the developer manipulates the cells, there is a risk of human error or contamination. As a result, the CAR T-cell therapy production process is intricate and time-consuming, leading to a high price tag for the final drug product.
“Off the Shelf” Cell Therapy
Production of an individual autologous therapy typically takes around three weeks, and introduces the risk that during the elapsed time from apheresis to final drug product administration, a patient’s disease state may progress to the point where CAR T therapy is no longer a viable treatment option. For this particular patient population, having a cell therapy at the ready could be their only means of reaching remission.
For cell therapies to reach the viable economy of scale that would allow them to be used as a frontline treatment for cancer, clinical researchers are investing significant effort into developing “off the shelf” options. These approaches would allow for a batch of drug product to be manufactured in advance and cryopreserved; available on demand for treatment of multiple patients. While autologous cell therapies will remain important and won’t be replaced by these newer allogeneic workflows, these “off the shelf” cell therapy workflows could enable more scalable, cost-effective manufacturing processes.
The allogeneic strategy utilises healthy donor cells instead of a patient’s own. In addition to enabling a much larger scale of production, engineered healthy T cells are often in better condition to fight disease. This is because cells harvested for autologous manufacturing are often “low quality”, reflective of the patient’s disease state itself or compromised as a result of harsh treatments like chemotherapy. As a result, these cells – even once engineered to target and fight the cancer – aren’t always able to do so as effectively as donor derived, healthy, high-quality cells.
Allogeneic cell therapies do not come without risks; introducing foreign cells to a patient can illicit an immune response, rendering the therapy ineffective, or inducing graft versus host disease (GvHD). Thus, in order to leverage donor cells, allogeneic therapies require an additional step to first modify the cells to mask their “foreign-ness.” Gene editing technologies like Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and Transcription Activator-Like Effector Nucleases (TALEN) are commonly used to knockout the genes that trigger adverse events. To accommodate the complexity of the dual step edit, electroporation has emerged as the preferred gene transfer platform, allowing for both gene editing of the T cells and introduction of the CAR, which will eliminate the need for viral transduction.
Fit for Purpose Technology
To bring the initial cell therapies to market, developers were forced to adapt existing pharmaceutical solutions to fit their needs. However, the demonstrated viability of this treatment modality has emphasised the need to focus on development of fit-for-purpose instrumentation and materials with a prioritisation on scalability and regulatory compliance. New product innovations over the past few years are driving improvement to the current autologous workflows, and optimisations to the manufacturing process for both allogeneic and autologous workflows, which remains the key to reducing treatment costs and drastically increasing accessibility.
A retrospective understanding of the manufacturing process pain points and scalability of the cell therapy workflow has driven advancements in viral vector production platforms. A switch from adherent production systems to suspension culture systems allows for scalability. In current cell therapy manufacturing workflows, lentiviral (LV) production accounts for almost 40% of the costs associated with autologous therapy production but is also one of the few truly scalable part of the autologous workflow. Investing in high titre, robust LV production could significantly enhance the autologous workflow, driving down costs and contributing to a more consistent and reproducible drug product. The first of its kind, a complete lentiviral production system was recently developed with products manufactured specifically for use in cell and gene therapy applications using a scalable suspension cell platform. This Gibco CTS LV-MAX Production System is the first complete optimised system that provides scalable, high-yield lentiviral vector production capabilities.
As a result of the fit for purpose innovation approach to support scalability and streamlining of cell therapy, researchers are re-thinking material inputs such as reagents and media used in workflows. Traditional cell culture media formulations oftentimes include raw materials that support robust cell proliferation at the expense of cell health, which may not be ideal for cell therapy applications. While proliferation might be the desired functional result for many pharmaceutical applications, it is not ideal for cell therapy applications, where rapid proliferation rates could compromise cell health and ultimately their functionality. In order to support the greater demands of healthy donor allogeneic workflows, developers are looking to new fit-for-purpose media options, such as the Gibco CTS OpTmiser Pro Serum Free Media, which maintains cellular youth in healthy donor cells while still dramatically enhancing healthy donor T-cell proliferation.
Automating Cell Therapy Manufacturing in a Closed System
Perhaps the principal focus area of advancement and innovation within the cell therapy manufacturing space is towards single-use technology (SUT) and closed systems. New products supporting closed system manufacturing represent significant movement towards the ability to automate the cell therapy workflow and will be a critical capability necessary to enable developers to provide more cost-effective, accessible and safe CAR T-cell therapies.
Closed system manufacturing approaches provide manufacturing capabilities in a sterile platform without exposure to the surrounding environment. Steps that can be encompassed within a closed manufacturing set up directly translates to fewer touch points requiring human intervention. This dramatically reduces contamination and virtually eliminates human error while promoting reproducible and consistent drug products. Innovations in closed systems solutions have been made to improve the efficiency and safety of cell processing operations spanning the entire workflow from cell isolation and activation, gene editing, cell expansion, wash and concentration. An example of recent breakthrough technologies designed specifically for closed manufacturing of cell therapies is the Gibco CTS Rotea Counterflow Centrifugation System. Gibco CTS Rotea Counterflow Centrifugation SystemThis instrument can be used from research through clinical development and commercial manufacturing and can seamlessly be adapted to existing customer workflows. In conjunction with new instrumentation to support closed manufacturing systems, SUTs enable streamlining and regulatory compliance of the workflows by ensuring sterility, as all components are pre-sterilised and disposable. Combining these two capabilities mitigates risk, ensures product safety and eases regulatory burden.
The Path to Commercialisation
Commercialisation starts at the regulatory level, but that landscape is constantly evolving, and it can be challenging for developers to keep up. Developers can set themselves up for success by using equipment and products that scale from research use to cGMP-grade for commercial manufacturing, allowing them to cut process development times and avoid delays by eliminating the need to learn, optimise and validate new systems. Using raw materials and instrumentation designed with the intention for use in clinical applications can prove valuable in avoiding regulatory setbacks.
The development and advancements in scalable, closed and automated solutions for autologous and allogeneic manufacturing workflows through fit-for-purpose materials and instrumentation have helped establish a more efficient path to commercialisation. Innovation in this space continues to move forward, and technological advancements within this space will support enablement of a greater number of cell therapies to enter into the commercial space, potentially driving evolution of cell therapy to be a viable frontline treatment, and ultimately reaching and helping more patients.
About the author
Dr. Sean Chang is a Product Manager in the Cell and Gene Therapy business unit at Thermo Fisher Scientific and is working on the integration and automation of cell therapy manufacturing workflow. He also gained extensive technical experiences in cell therapy from previous roles, including R&D and PD scientist.
References
- https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/kymriah-tisagenlecleucel
- https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products
- https://www.webmd.com/cancer/lymphoma/features/car-t-gene-therapy-risks-benefits
- http://alliancerm.org/wp-content/uploads/2021/03/ARM_AR2020_FINAL-PDF.pdf
- https://www.fda.gov/news-events/press-announcements/statement-fda-commissioner-scott-gottlieb-md-and-peter-marks-md-phd-director-center-biologics
