With the unprecedented ability to destroy cancer while leaving healthy cells intact, CAR T-cell therapy is a groundbreaking treatment with the potential to usher the next generation of cancer-related healthcare. If this breakthrough is to change the face of cancer treatment for good, it cannot remain exclusive and prohibitively expensive as it is currently. Instead, it is up to us as professionals in healthcare and medical technology to devise and enact the means to effectively democratize CAR T-cell therapy, making it easily accessible to all patients in need. Only by these efforts will the potential of this groundbreaking treatment be fully realized. Let’s begin by taking a close look at the process by which the therapy is produced. 

Centralized Manufacturing and its Downfalls

Centralized manufacturing, distributed amongst only approximately 100+ laboratory centers, is currently the method by which CAR T-cell therapies are produced and the source of much of its inefficiencies. This approach contains several drawbacks contributing significantly to the inaccessibility of CAR T-cell therapy. To understand these drawbacks, we should first review the fabrication process. The high-level workflow involved in centralized manufacturing of autologous CAR T-cell therapy is as follows:

1. Patients’ T-cells are collected from their whole blood at a hospital or cancer treatment facility. 
2. Said T-cells are frozen and shipped to a centralized laboratory where they will be used to manufacture the CAR T-cell therapy. This includes undergoing various genetic manipulation methods and cell expansion, a process by which cells are multiplied into a much larger, usable volume. 
3. The new CAR T-cells are frozen for shipment back to their hospital or facility of origin. Here, they will be thawed and administered to the patient via intravenous injection, typically requiring only one session instead of multiple sessions imparting an immediate lifestyle benefit. 

Given the time-sensitive nature of cancer diagnoses and treatment, the shortcomings of this particular manufacturing approach may seem immediately apparent. It is a highly time-consuming bespoke production method, taking significant time to prepare and ship. Yet, this observation merely scratches the surface of centralized manufacturing’s true drawbacks when employed in the production of CAR T-cell therapy. 

Further shortcomings include:

• Limited production slots: While therapies are bespoke, slots are limited according to the manufacturing capabilities of the centralized lab, with only a small sample of patients eligible for treatment receiving access. Manufacturing bottlenecks are so severe that a mere 5,000 commercial doses are administered per 500,000 qualified patients, and, unfortunately, a considerable number of patients succumb to their illness before receiving treatment. Of all patients eligible for CAR T-cell therapy, STAT News estimates up to 20% die on the waitlist.
• Higher prices due to low production: Because the bespoke, centralized manufacturing process results in a low yearly production count, prices are driven even higher to provide a return on investment for involved manufacturers. Fees for this therapy currently range from $350k to over $3M. 
• Inability to scale: Highly intensive on labor and talent, the current manufacturing methods are far too expensive, complex, and time-consuming to scale effectively for broad accessibility. A team of highly trained, highly paid professionals must perform some 50 manual processing steps on various specialized instrumentation while consuming considerable quantities of disposable devices to produce one therapy that applies to only a single patient.This process is not scalable to produce hundreds of thousands of treatments per year. 
• Challenges with batch contamination: To mitigate the contamination of CAR T-cells during particular processing steps and open manipulations, all workers must be outfitted with full bodysuits, and labs must be equipped with proper cleanroom facilities. These requirements constitute significant costs to manufacturers but are critical to ensuring production success. Each time a cell therapy batch is handled, opportunities exist for accidental contamination, which may prevent the successful creation of CAR T-cells. Some manufacturers have reported process failure rates as high as 15%.
• Increased risk of manufacturing errors: Being complex and labor intensive, the production process is far more susceptible to human errors than a simplified, more streamlined approach would be. 
• Potential for reduced quality: In the case of centralized CAR T-cell manufacturing, both the manufacturing input (patient T-cells) and its output (therapy) must be frozen for transport and thawed for use. This can negatively impact the quality and quantity of input cells, potentially resulting in less effective treatment. 
• Challenges in patient access: Hospitals and treatment facilities where CAR T-cell therapy is currently offered are based in urban areas and major metropolises. Unfortunately, this means that patients in rural areas must temporarily relocate to receive treatment, often for as long as two weeks. This presents time and cost burdens to the patient and their family and caregivers.

Given these drawbacks, it is clear that manufacturing must be heavily reconsidered if CAR T-cell therapy is to be delivered to patients in need promptly and at a price the market can bear. To further compound matters, new forms of treatment are being developed and approved at an exponential rate, with around one thousand currently in the FDA pipeline therefore production advancements are in great need.

A Manufacturing Pivot: The Point-of-Care Approach with Closed System Automation

An approach needs to be developed that allows the current and future revolutionary treatment to reach all those in need. With this in mind, a pivot must be made towards a point-of-care approach that encapsulates the manufacturing and therapeutic aspects of CAR T-cell to streamline both for more accessible, affordable, and effective treatment. 

In a Point-of-Care, CAR T-cell therapy, treatment is produced and administered at the site where the patient is receiving care, with the entire vein-to-vein journey occurring in a single location. Because treatment facilities lack access to appropriate cleanrooms and proper cleanroom designations, the point-of-care approach must rely upon closed-system automation, utilizing automated instrumentation technology alongside a sterilized disposable set to manufacture a therapy dose ensuring integrity. This approach alleviates many of the pain points currently preventing therapy democratization and will optimize CAR T-cell manufacturing to deliver more positive outcomes than ever thought possible. 

At length, the benefits of closed-system automation in a point-of-care setting include:

• Enabling commercial-scale production: By significantly reducing manual labor, automation not only increases production output but ensures quality and consistency as well. Were treatment facilities to install multiple automated systems per location, manufacturing would quickly scale to serve a large volume of patients simultaneously while stringent quality controls could be maintained throughout. 
• Activating Economies of Scale: With more therapies produced yearly, manufacturing would transition from low-volume, high price towards high-volume, lower price. While lower prices will make the treatment more accessible to a wider variety of patients, manufacturers will also enjoy higher returns on investment with the significant increase in production volume. 
• Lower direct costs for each therapy: Reducing manual labor, eliminating off-site cleanroom requirements, increasing overall yield— all of these benefits of the automated point-of-care approach reduce the overall treatment cost. With increased yield and reduced waste, this manufacturing process would produce significant cost savings that may be passed on to patients, making the therapy more widely accessible.
• Shortened manufacturing timelines: Closed system automation not only eliminates the need for freezing, thawing, and shipment but consolidates all the manual processes previously required into a streamlined, automated workflow, resulting in a highly accelerated production timeline. This is particularly key in cancer treatment, where time is often of the essence for patients awaiting treatment. 
• Reduced needs for manpower and skilled labor: Automating the CAR T-cell fabrication process results in a simplified workflow that eliminates costly labor needs and ensures greater consistency and quality in the final product. 
• Reduced risk of contamination and processing errors: A system such as the one proposed would minimize chances of contamination and error during the manufacturing process by reducing human intervention and maintaining a closed, controlled environment, resulting in a higher yield of CAR T-cells. This would enable cost savings as well as improved patient outcomes. 
• Improved cell quality: Without freezing and thawing, the automated system uses fresh, never frozen, T-cells collected onsite. As freeze-thaw cycles can result in losses of cell viability and function, this results in higher quality therapies overall.
• Eliminated need for travel on the part of patients: With point-of-care closed system automation, patients will no longer have to travel to centralized therapy centers to receive treatment. Instead, outpatient methods may be deployed to improve quality of life while saving patients and caregivers time, money, and effort. 

While CAR T-cell therapy is today an expensive, exclusive treatment accessible to only a fraction of the patients in need, it need not always be that way. By transitioning from the current centralized manufacturing approach to a point-of-care approach addressing automated production and treatment, we stand to make this transformative therapy more affordable and accessible than ever, affecting full democratization. Deploying closed automated systems, CAR T-cell therapy would not only reach more patients than ever but would do so much faster, saving untold lives in the process. 

For a closer look at the mechanisms behind an automated closed system and the advancements in logistics, infrastructure, and production processes needed to make the regionalized point-of-care approach truly successful, stay tuned for our series’ conclusion. To learn more about CAR T-cell therapy and its benefits to patients, visit the MIDI Innovation Vault™.