Bedside Cell Therapies: Point-of-Care Manufacturing Is Slowly Becoming a Reality

Cell therapies have been shown to be highly effective at treating many different types of cancer and other diseases. They are, however, highly costly and only available at limited locations, leaving many patients without the opportunity of realizing their benefits. Decentralized manufacturing models in which cell therapies, including genetically modified cell therapies, are produced in automated, closed manufacturing systems at the point of care — hospital, clinical trial site, and so on — are actively being pursued as a means to shorten therapy manufacturing times and lower treatments costs.

General Autologous Cell Therapy Manufacturing Challenges

Autologous — or patient-specific — chimeric antigen receptor (CAR)-T cell therapies have changed the way that many different cancers involving liquid tumors are treated, and in the process dramatically lengthened and improved countless patient lives.

However, these therapies are extremely costly to produce.^1–6 The logistics of preserving and moving patient cells from hospitals to central manufacturing centers and the need to return the correct modified cells (again properly preserved) to the right patients add time and complexity to the manufacturing process, which itself is challenging given the high variability of the starting cells, the quality of which depends on the status of each patient, and the general use of open systems and manual operations.^2,3

In addition, processes vary significantly from one drug developer to the next, making comparisons of performance difficult.² There is also a lack of deep understanding of the bioprocesses involved in adoptive cell therapy production.⁴ Regulatory requirements add more burdens and ultimately drive the use of centralized production sites.³

Automation Advantages

The variability in adoptive cell therapy manufacturing processes can largely be attributed to the fact that these processes are highly labor intensive and often performed in open systems. The higher number of manual operations also contributes to greater variability and a higher risk for contamination and general errors. Simplification and automation of these processes would help address many of these issues.²

Many believe that automation of cell therapy manufacturing will be essential for enabling widespread access to these treatments.⁷ Not only will it increase efficiency and cost effectiveness, it will also enable the realization of a standard level of quality across sites. Systems that operate using an open technical standard, contain standardized process analytical technologies (PAT), and leverage smart information technology will have the greatest impact, as they will enable collation of manufacturing and quality data and centralized product release.

Several closed, automated systems have been or are being developed for the production of cell therapies. The CliniMACS Prodigy^® from Miltenyi Biotec is an automated, GMP-compliant cell processing platform that enables manufacturing of cell therapy products on a single device and within a single process setup.⁸ The company also offers tubing sets, various accessories, reagents, and buffers. At least one group has published the successful industrialization of an academic Miltenyi CliniMACS Prodigy T cell transduction process for production of a clinical CAR-T cell product for use in clinical trials.⁹

Ori Biotech launched its Lightspeed Early Access Program (LEAP) in early 2022. The program allows select partners to gain pre-launch access to the Ori automated cell and gene therapy production platform in 2022 before full commercialization in 2023.¹⁰ The Ori system, according to the company, is a proprietary, full-stack manufacturing platform suitable for academic centers, contract manufacturers, and therapy developers.

Lonza, meanwhile, offers the Cocoon^® Platform, which was originally developed by Octane Biotech (Lonza now has a controlling stake in the company). In January 2022, Lonza announced that it is working with Agilent Technologies to define the ideal critical quality attributes (CQAs) for cell therapy manufacturing so that optimal integrated in-process controls and analytics, including both existing and new analytical technologies, can be incorporated to enable better control.¹¹ This strategy will enable the Cocoon Platform to become “smarter” and better ensure the consistent manufacture of high-quality products.

SQZ Biotech is developing a system based on work done at the Massachusetts Institute of Technology that integrates cell isolation, cell washing, Cell Squeeze^® intracellular gene-editing delivery technology, and product filling, among other operations.^12,13 In a press release in May 2022, the company reported that the average per-batch processing time for its SQZ^® POC system for research-use only runs was less than six hours. As importantly, comparable or improved product specifications were obtained for its red blood cell–derived SQZ^® Activating Antigen Carrier (AAC) therapeutic candidate for the treatment of HPV16⁺ solid tumors relative to current cleanroom-based processes used in clinical development in half the time with 90% fewer operator hours.¹³ Filing of IND submission for its red blood cell–derived SQZ^® TAC candidate in celiac disease, which will include use of the SQZ^® POC system, is planned for the first half of 2023.

A group of researchers from a number of European institutes and research centers is focused on making automated cell therapy manufacturing systems smarter through the use of PAT, advanced data analytics tools, and artificial intelligence (AI) solutions.¹⁴ Their goal is a system that transforms hospitals into smart manufacturing hospitals that can produce personalized CAR-T and other adoptive cell therapies at the point of care. The AI-driven CAR-T cell manufacturing concept was developed within the scope of the EY H2020 AIDPATH (AI-driven, Decentralized Production for Advanced Therapies in the Hospital) project and includes parallelization of the bioreactor and, ideally, transferability to other types of cell therapies.

A separate group of scientists in Europe have formed the SolidCAR-T project, which aims to develop CAR-T therapies suitable for treating solid tumors, with bile duct cancer as the initial target.¹⁵ Part of the project involves the creation of “mini-factories,” closed, modular production units that can produce high-quality CAR-T cells locally in a standardized, automated process with continuous monitoring. T lymphocytes from patients are transferred directly into a standardized “cassette” in which they are passed through different biochambers (joined together using sterile connectors) where different unit operations are completed. As with the AIDPATH design, the modular design allows for parallelization, scalability, and adaptability.

The Charité Comprehensive Cancer Center, meanwhile, is developing isolator-based automated production systems.⁷

Still Limitations of Centralized Cell Therapy Manufacturing

Automation does not overcome the challenges associated with centralized cell therapy manufacturing. While centralized production of CAR-T and other adoptive cell therapies minimizes the need for multiple regulatory filings, it also limits patient access.^5,6 There are only a few centralized sites with limited production slots. Waiting for an opening often means that very ill patients with rapidly changing clinical conditions require bridging therapies that can have serious side effects that could impact the outcome of the cell therapy treatment. In addition, only patients at hospitals located close enough to these production facilities to allow rapid transfer of their collected cells and modified cellular drug products can receive these lifesaving treatments. The transport requirement also further extends the time until the patient receives the therapy.

Overall, owing to the complexity and cost associated with centralized adoptive cell therapy manufacturing, these life-changing treatments are out of the reach of most patients. Decentralized manufacturing could potentially address both issues and increase patient access.

Decentralized Manufacturing Models

The growing availability of closed, automated production platforms and standardized, GMP-grade reagents for cell therapy manufacturing is helping translate the concept of decentralized manufacturing into a reality.¹⁶ In such a model, cell therapy manufacturing would take place at academic institutions and hospitals with GMP manufacturing capabilities.

Such a strategy would facilitate multicenter trials and increase access for patients around the world. It would also enable faster treatment of patients with aggressive diseases (no shipments to a centralized production site) and allow treatment decisions to be made by physicians, not dictated by production slot availability at biopharma companies.¹⁷ A high level of process control through real-time monitoring also enables smoother treatment scheduling. Some academic centers are also finding it possible to develop new therapies without the need for industry partners, which is particularly advantageous when the treatments in development target rare diseases.

In Canada, the immunotherapy network BioCanRx is establishing four point-of-care (POC) sites across the country at facilities with existing GMP production experience related to bone marrow transplantation.¹ The sites will leverage Miltenyi Biotec’s CliniMACS Prodigy system and standardized protocols. The first site in Victoria, British Columbia, is already up and running.¹⁸

Orgenesis is developing both cell therapies and mobile production units — Orgenesis Mobile Processing Units and Lab (“OMPUL”) technology — intended to enable POC manufacturing.¹⁹ The units, of which there are several types, will be distributed to the company’s POCare network of partners, collaborators, and joint ventures and can be used for validation, development, clinical testing, manufacturing, and/or processing of potential and approved cell and gene therapy products. In one example, Orgenesis is partnering with Johns Hopkins University, which will be opening a POC treatment facility in 2023.²⁰

Another company building a network of POC sites that will use a modular, digitized, near-to-patient GMP-in-a-box cell therapy–enabling platform is Ireland-based aCGT Vector.²¹ The company’s interconnected and digitalized ATMP (advanced therapy medicinal product) PODs will be located at international cellular therapy hospital centers of excellence. Its cloud-based proprietary digital platform will securely capture and aggregate manufacturing and patient outcome data (cell collection, selection, transformation and expansion, treatment administration, and post-administration health monitoring), which will be analyzed and used to improve subsequent therapies and procedures.

Some Partnerships Remain Crucial

While some academic institutions are leveraging automated cell therapy production platforms for internal cell therapy development without the aid of biopharma partners, few go it alone.²² Many collaborate with therapy developers, and most work closely with suppliers of the manufacturing platforms, reagents, analytical equipment, and other materials needed for successful GMP cell therapy process development and manufacturing. Collaborations will also be necessary to develop standardized production systems, software, protocols, regulations, and so on.⁷

The ProCell for Patient project is a collaboration between Robert-Bosch-Krankenhaus (RBK) hospital, Optima Pharma, and Universitätsklinikum Heidelberg (UKHD) that is developing an automated production system for CAR-T cell therapies.¹⁸ The partnership is enabling RBK to bring cell therapy manufacturing to the hospital, which would not be possible due to the regulatory requirements without an automated production system. Access to an in-house production system is expected to not only increase the speed at which CAR-T cell therapies can be produced but also give physicians running clinical trials at the hospital control over dosages and administration frequency.

Networks of hospitals collaborating with manufacturing platform developers can benefit from greater buying power with suppliers, as well as faster validation at lower cost.¹⁹ There is a general expectation that many of the new types of decentralized manufacturing networks in development today, which involve extensive collaboration between multiple members of the cell therapy value chain, will ultimately lead to the formation of new types of organizations that blur the lines that today separate hospitals from drug manufacturers and healthcare providers.⁷

Manufacturing Within Hospitals

Some centers within Europe that have implemented automated cell therapy manufacturing systems — most commonly the Miltenyi Biotec CliniMACS Prodigy or Lonza Cocoon systems — have received regulatory approval to conduct clinical trials using cell therapy products produced in-house.²

Investigators at Hospital Clinic de Barcelona reported the successful production of 28 CAR-T cell products in the context of a phase I clinical trial for CD19⁺ B cell malignancies using the CliniMACS Prodigy.²³ They found that the CAR-T cell products could be produced in as few as seven days and still be highly potent. In addition, the reduced ex vivo expansion time may have resulted in increased in vivo CAR-T cell persistence.

A joint U.S./Russian project conducted at Case Western Reserve / University Hospitals Medical Centers in Cleveland, OH, and the Dimitry Rogachev Pediatric Cancer Hospital in Moscow, Russia, found, that very similar CAR-T cells were manufac­tured using the CliniMCAS Prodigy at both POC sites, in much less time than current commercial products.²⁴

In addition, Sheba Medical Center in Israel reported successfully dosing four patients with a CD19 autologous CAR-T cell therapy using Lonza’s Cocoon automated manufacturing platform in August 2021.²⁵ Just before that, Lonza announced that CellPoint would use the Cocoon system for production of CAR-T clinical trial materials.²⁶

Shorter Manufacturing Protocols

Point-of-care or “bedside” cell therapy is not the only way in which researchers are seeking to reduce the time it takes to produce adoptive cell therapies. Researchers at the University of Pennsylvania have sought solutions for reducing the physical production time for CAR-T cell therapies.²⁴ These therapies generally first require production of a viral vector as the delivery agent for the genetic material used to modify the patient’s T cells. Then the T cells must be transduced with the viral vector (often a lentiviral (LV) vector). Extensive assays must be performed to fully characterize both the vector and genetically modified cells and ensure their quality and safety. From end to end, the process can take weeks.

The new CAR-T cell production process takes just one day.²⁴ The key is eliminating the need for T cell activation and dramatically shortening the long cell expansion phase.²⁷ This strategy not only reduces the time to generate the modified cells — it also affords greater preservation of their intrinsic stem cell–like properties, as the longer cells are expanded, the more differentiated they become.

If such a short production time is found to be acceptable by regulatory authorities, it would greatly facilitate decentralized cell therapy production. Sending patient samples to a central production facility would make no sense, as the distribution time to and from the facility would be far longer than the time needed to produce the therapies.^24,27

Manufacturing within Patients

Some companies are taking yet another approach to developing POC cell therapies. These firms are eliminating the need for production platforms of any kind. Instead, they have designed treatments that enable the body to generate CAR-T cells.²⁴

Umoja Biopharma has developed viral vector particles engineered with specific receptors on their membranes that bind to target T cells.²⁴ The genetic payload contains a CAR and a rapamycin-activated sig­naling protein that initiates IL-2–like signal­ing in the transduced T cells. Researchers at the Fred Hutchinson Cancer Research Center, meanwhile, have developed a new envelope protein that enables LV vector entry into cells. If such a vector is also encoded with a CAR to enable targeted delivery, in vivo transduction should be possible.

EXUMA Biotechnology has elected to transfer T cell modification to synthetic lymph nodes on a patient’s skin.²⁸ Blood is drawn and exposed to the viral vector. Within four hours, the T cells in the blood are modified. These modified CAR-T cells are captured and transferred subcutaneously to beneath the patient’s skin, where cell expansion up to 10,000-fold occurs, and the modified cells reach the tumor within two weeks. In addition to the dramatically reduced overall treatment time, patients do not need to receive lymphoid-depleting chemotherapy before administration of the cell therapy. In addition, the “logic-gated CAR-Ts” also require both the target antigen and the tumor microenvironment to become fully activated and therefore only work in tumor cells, reducing off-target effects.

Major Challenges to Decentralized Production Approaches

The companies, organizations, hospitals, and research centers pursuing the decentralized model for cell therapy manufacturing face several hurdles. One basic issue is the current lack of standardized processes and equipment.²² Even for apheresis, there are no standard single-use systems. Customized bags, tubing, and other components are required for each automated manufacturing system. Software systems also differ and do not readily communicate with one another, making it difficult to share and compare data.

The lack of experience in GMP therapy manufacturing is a large challenge for organizations that are new participants.¹ High standards for reproducibility, reliability, quality, and safety must be met. These manufacturing facilities must also be appropriately designed, including appropriate HVAC units, space for optimal workflows, and so on.²² Closed automated production systems eliminate the need for the highest-level cleanrooms, but the manufacturing environments must still meet certain regulatory standards related to personal protective equipment, airlocks, environmental monitoring, and more.

For networks of sites producing the same POC cell therapies, standard manufacturing protocols and process and product analytics must be used to ensure that the generated data are comparable.¹⁶ Similarly, quality systems must be closely aligned to ensure that quality, safety, potency, and regulatory expectations are all met. Meeting regulatory requirements can be particularly difficult, given that regulatory expectations are constantly evolving for this relatively new class of living drug products.

A Regulatory Shift Is Needed

Regulatory challenges facing POC cell therapies go beyond the rapidly changing expectations of health authorities. Many believe that producing living and genetically modified cellular drug products will require a complete paradigm shift from the established regulatory pathway.¹⁸ One reason given is that the current approval mechanism favors large pharmaceutical companies with centralized manufacturing facilities. A new approach is needed that simplifies the approval process for hospitals and research organizations, especially for those within networks sharing the same processes and producing the same products.

One proposal involves requiring only a single application for multiple manufacturers using the same equipment and protocol to produce the same product, with individual site licenses issued if approval of the product is granted. Another option would be to approve the viral vectors, other reagents, and processes used at a POC production and the POC center itself. Then patient-specific CAR-T cell therapies could be manufactured using those reagents, protocols, and equipment as needed under the overall approval.

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