Ireland-based cell therapy company aCGT Vector is developing disruptive technology that is poised to transform the way CAR-T and other autologous cell therapies are manufactured. Locating PODular “GMP-in-a-POD” distributed manufacturing systems in cancer centers of excellence will eliminate complex and costly logistics challenges, dramatically reducing the cost of the novel personalized medicines and thereby increasing patient access.
Rapidly Growing Market
Although still in its infancy, the global market for chimeric antigen receptor (CAR)-T cell therapies has grown rapidly. One recent estimate pegs its 2021 value to be slightly more than $1.7 billion and to be expanding at a compound annual growth rate of nearly 65% to reach just over $33.1 billion by 2027.1 Lessons learned from early explorations of CAR-T therapy have led to engineering modifications for the next generation of cell therapy products using a wider range of cell types (e.g., T cell receptor (TCR), natural killer cells (NK), tumor-infiltrating lymphocytes (TIL), marrow-infiltrating lymphocytes (MIL)) for treatment of not just liquid but also solid tumors and an increasing array of other indications beyond oncology, including autoimmune, cardiac, and neurologic diseases.
This tremendous growth — despite significant ongoing manufacturing and logistics challenges — can be attributed to the nearly curative nature of these therapies for patients with very dim prognoses. The current autologous strategy requires the isolation of T cells from patient samples, genetic modification and expansion of those cells, and administration of the modified cells to the same patient. Under the existing paradigm, this approach requires that patient samples be shipped to a central manufacturing facility where one product is produced per batch. Making multiple products is therefore achieved by scaling out rather than scaling up, the latter of which is the traditional pharmaceutical industry approach to meeting commercial demand. With these distribution and manufacturing requirements, the cost of autologous therapies is by necessity quite high, and the sustainability of this strategy has come into question.
In fact, the cost of CAR-T cell therapies is limiting access, and much of the growth projections for the market depend on the identification and development of solutions to those manufacturing and logistics issues. One approach for many companies is the development of off-the-shelf (allogeneic) versions manufactured from cells harvested from healthy donors. Such an approach would allow production scale-up using conventional bioreactors and would enable significant cost reduction. However, serious hurdles here remain, particularly with respect to strong immune responses and rejection of the foreign cells.
A Local Solution
A third option is to upend the current paradigm for autologous therapies by moving from central to distributed manufacturing, locating production in hospitals and oncology centers of excellence close to patients. Doing so would eliminate the need to transport samples and final products, dramatically reducing cost and the time it takes to administer treatments to patients. Deployment of advanced, closed manufacturing systems with all production operations integrated into one unit with disposable components would simplify production, further reducing costs.
One company implementing this strategy is Ireland-based aCGT Vector, which has developed an “innovative, modular, digitized, near-to-patient GMP-in-a-box cell therapy–enabling platform,” according to Chief Executive Officer Gary McAuslan. “With this technology, we have established aCGT Vector as a specialist cell therapy clinical research and development and commercial manufacturing organization, uniquely positioned to translate transformative cell-based precision cancer therapies. Next-generation cell therapies will require next-generation technology platform manufacturing capabilities. aCGT Vector is a differentiated deployment enabling platform; one that will support the advancement of new cell therapies to and through the clinic and validate and demonstrate new technology platforms under GMP conditions on therapeutic targets for clinical and commercial deployment. By doing this proximal to the patient and the clinicians with decades of precision medicine expertise, therapies and technologies will advance faster than the current pace of deployment, ultimately increasing patient access” he adds.
"aCGT Vector will deliver cellular therapies through co-location of expertise more efficiently, with less burden being placed on patients, more safely within centers of excellence. Bringing more value for payers through data-driven optimized patient outcomes achieved by performing transformational and potentially curative cellular therapy procedures proximal to patients,” McAuslan concludes.
aCGT Vector’s interconnected and digitalized ATMP (advanced therapy medicinal product) PODs located in international cellular therapy hospital centers of excellence will capture data that will play a pivotal role in improving patient outcomes, promises McAuslan. The company is building a cloud-based proprietary digital platform that securely captures and aggregates manufacturing and patient outcome data from the patient when administered to the hospital — through cell collection, cell selection, cell transformation, and expansion to treatment administration and post-administration health monitoring— to capture important data that can be fed back into the system to improve subsequent therapies and procedures.
The PODs will be constructed off-site and delivered to hospitals or even pharmaceutical facilities without any operational disruptions. “The key is that they be proximal to patients. In larger cities where there are multiple cancer centers, it may make more sense to service all of them through a local central site, delivering a POD or PODs to a nearby CDMO specializing in cell therapy production. The logistics issues would still be eliminated and significant efficiencies will be gained,” McAuslan says.
Expanding into mRNA, Too
While aCGT Vector is primarily focused on CAR-T cell therapies and plans to pursue other next-generation CAR-T therapies once it has demonstrated that its PODular strategy is effective, the company is already looking at other areas where this type of approach could be advantageous. “We are adapting our PODular approach to bring to market an end-to-end mRNA and DNA vaccine manufacturing platform using Touchlight’s doggybone DNA (dbDNA) approach and Cytiva’s single-use FlexFactory closed manufacturing system,” comments McAuslan.
The company has identified a location in Tipperary, where the Tipperary County Council is developing a science and technology park. The intention is to expand an established technology incubator that already has 15 startups in residence. The council actually approached aCGT Vector, which according to McAuslan suggested that, to stay on the cutting edge, the focus should be on developing modular solutions for the production of mRNA- and DNA-based vaccines and therapeutics.
“The idea is to build a centralized facility focused on precision medicine that leverages modular manufacturing to ensure real flexibility so that, when the next pandemic arrives, manufacturing can be easily refocused to ensure an internal supply,” McAuslan explains. This new CDMO capacity would be targeted at emerging innovators, for which capacity shortages are a real issue, he adds.
Over the last 12 months, aCGT Vector has been investing in mRNA manufacturing platform technology and miniaturizing it to fit within a POD, including mRNA synthesis and formulation as lipid nanoparticles. The relationship with Touchlight makes it possible to address one of the key bottlenecks for mRNA today, which is access to plasmid DNA starting materials. On the other end, aCGT Vector has developed a closed, automated system for fill/finish, eliminating manual operations and the risks they pose. When all of these components are integrated together, McAuslan says they add up to a unique, cost-effective, and truly end-to-end PODular manufacturing solution for mRNA therapeutics and vaccines.
Founded through Collaboration
In Ireland’s St. James’s Hospital, Dublin, Professor Maeve Lowry, an oncologist who moved from Sloan Kettering in New York City stressed during a meeting in 2019 the need to bring pharma to the hospital when it comes to personalized autologous cell therapies. Hospitals have the expertise and understand the patient journey. They know what medications and treatments are needed to prepare patients for CAR-T cell therapy to optimize the chances for treatment success and how best to care for them during treatment.
The idea for aCGT Vector’s PODs originated with this focus on bringing pharma into a hospital, according to McAuslan. Other groups, such as the Fred Hutchinson Cancer Center and the Mayo Clinic, are also pursuing similar strategies. In addition to allowing advanced manufacturing of cell therapies to take place close to patients, the POD approach also allows for cell therapy companies to remain as standalone, discrete, and sustainable businesses within the nonprofit hospital environment.
To get things off the ground, aCGT Vector applied for a grant as part of the HEALED Consortium, which comprises RemedyBio as program lead, aCGT Vector DAC, Trinity College Dublin & St James’s Hospital, and the SFI Centre for Research Training (CRT) in Genomics Data Science at NUIG. This group, McAuslan observes, brings together deep capabilities in mass-scale functional biology, GMP clinical deployment, clinical and tumor microenvironment expertise in cancer, and molecular data analytics to create a world first in near-patient, personalized, functional cancer therapeutics.
The €6.8 million grant from the Disruptive Technologies Innovation Fund (DTIF), which is managed and funded through the Department of Enterprise and Innovation (DBEI) in Ireland, is part of a three-year, €10.5 million program to develop next-generation cancer cell therapies.
Three months after receiving the grant, aCGT Vector was invited by Professor Martina Hennessey, who leads the Trinity College Dublin Clinical Research Foundation at St. James’s Hospital, to look at their newly completed state-of-the-art ATMP facility, including a manufacturing cleanroom adjacent to the cancer patient –– as many as 4200 patients are treated annually. The CRF under Prof. Hennessy's watch oversees the administration of hemophilia and SMA gene therapies today, building an ecosystem of cell and gene therapy capability on the island that will position it as a gateway to the EU clinic and market. An agreement was put in place giving aCGT Vector an ideal starting facility and time to develop and license its GMP POD system. This first site was established in 2021. “What we essentially have is a world-class beta center surrounded by decades of clinical and cell therapy expertise, as this center is also a center for bone marrow transplants, already treating 200 patients annually on this Island. With this advantage, we can ascertain the optimal POD design for multiple hospitals that do not have GMP capability. We have labeled our solution as 'Precision 'Therapy-as-a-Service' (TaaS PODs), a paradigm shift not only in delivery of new therapies to the clinic, but potentially approved therapies to patients routinely. Not only are we bringing GMP manufacturing services proximal to hospitals, but we are enabling clinical trials across our TaaS POD network as it grows out in scale to digitally twinned PODs. This also positions us to demonstrate and validate new cell engineering technology platforms within our GMP environment, validating them on therapeutic targets, starting with CAR-T for blood cancer initially and TILs (tumor-infiltrating lymphocytes) for solid tumors" notes McAuslan.
The company plans to take that time to develop its PODs in order to avoid mistakes that could occur if they move too quickly. “We are acutely aware that we will be producing CAR-T therapies that will be administered to patients. It is critical that we select the right production technologies and the right digital system, have the right people, and properly set up the financial side of things so that we ensure that patients who expect to receive treatment will get the highest-quality therapies on time. Using the latest digitized technology platforms, such as its cloud-based digital platform, Cytiva's Flexfactory and Chronicle, and digital quality management systems such as Qualio will position it within hospitals to deliver therapies safely and continually improve them using data across its PODular network. aCGT Vector's CIO Gareth O'Sullivan is confident his decades of genomics data expertise will be put to good use in this global project." McAuslan states.
Point of Care within an International Network
The approach that aCGT Vector is taking involves integration of digital twin patient and PODular “GMP-in-a-POD” distributed manufacturing systems placed in cancer centers of excellence to support the delivery of precision medicines across a hospital-based ATMP GMP-licensed facility network. That makes the firm a “point-of-care” cellular therapy company, according to McAuslan.
"Once our network of PODs is in place, aCGT Vector will offer cell-therapy innovators accessible, agile, right-sized manufacturing and clinical trial capacity, allowing clinical trials to scale from N = 1 (10–20 patient trial) to multiples of N = 1 (>20 patient trials),” McAuslan says. The company will also be in a position to support therapy developers as their products move from early to late-stage clinical trials and onto commercialization.
“Our ultimate goal,” McAuslan asserts, “is to make cancer history by increasing accessibility to potentially curative personalized medicines and transforming the lives of cancer patients, by giving consultants localized treatment options and ultimately facilitating a paradigm shift toward the provision of distributed end-to-end point-of-care healthcare.”
To achieve that goal, the company is assembling a world-class team of cellular therapy experts within major cellular therapy centers of excellence. Strategic partnerships with cell therapy and technology developers is the aim of the company. One of aCGT Vector's first senior leaders, Dr. Aine Adams, joined from Takeda –– having tech transferred the first cell therapy being manufactured in Ireland and distributed fresh across the world. Dr. Adam's expertise with fresh cells is paramount to developing a point-of-care therapies-as-a-service offering in hospitals. This GMP ATMP facility network will be equipped with aCGT Vector’s state-of-the-art POD-based closed-system cellular processing standardization technology and digitization loopback platform, all of which will be located proximal to rare disease patients. In addition, aCGT Vector has entered into a strategic partnership with Cytiva/Danaher to bring the latest automated, fully closed, single-use cell therapy processing technology to each of its point-of-care hospital cell processing centers.
Addressing Regulatory and Reimbursement Considerations
In December 2021, Martin Ward, a patient of Professor Larry Bacon's ('Mr. CAR-T') team in St. James's Hospital Haematology Department, became the first patient to receive CAR-T treatment for cancer on this Island. Many more patients have since received this transformative treatment from Novartis with other versions to follow soon, increasing access to patients. This initiative by aCGT Vector with the CRF, Trinity College, and St. James's Hospital will ultimately bring more new modern medicines to more patients who are in desperate need of a therapeutic solution. Second- and even first-line defense and breakthroughs in solid tumors for these advanced therapies will further cement the need for pharma to be located proximal to patients," highlights McAuslan.
In the pharmaceutical industry, regulatory concerns must always be considered when developing and implementing any new therapeutic strategy. McAuslan believes that what aCGT Vector is doing falls under the heading of healthcare rather than pharmaceuticals. “We are not actually making a therapeutic. What we’re doing is more akin to a medical procedure,” he contends.
McAuslan hopes that, by implementing its PODs at multiple sites, aCGT Vector will be able to obtain an umbrella license. To make that possible, the company is putting a lot of effort into designing the optimum facility with the most modern technologies and procedures and into replicating that, including the digitalization aspect, which enables clear demonstration of true twinning of the entire system for regulatory agencies to review.
Digitalization also makes it possible, according to McAuslan, to have the systems at different hospitals and research centers in the network interconnected so they can share data and learnings. Data for not just 10 or 20 patients but a thousand and eventually even a million patients can be collated and analyzed. In addition to providing confidence to regulators, those data will also support decision-making by reimbursement authorities. “If we have the data to show that the cost of a CAR-T cell therapy treatment that is curative within a four-week period is much less than the cost of managing a cancer patient over five or six years until their death, that will place pressure not only on regulators to approve more of these treatments but also on payers to authorize reimbursement for them,” McAuslan remarks.
Additionally, aCGT Vector’s POD approach may help establish a new paradigm for clinical trials in multiple cancer centers of excellence, in which data can be collected from each and collated to inform regulators and reimbursement authorities, potentially leading to increased patient access to these personalized precision medicines.
Of course, the regulatory and reimbursement landscape is highly fragmented, with different countries and regions adopting different approaches. “As an emerging company with limited funding, we have to be very strategic in how we approach these aspects,” observes McAuslan. He is excited, though, about the opportunities that POD manufacturing approach affords with respect to bringing CAR-T cell therapies to Africa, India, and other areas of the world where the necessary infrastructure is lacking. “We can potentially increase patient access dramatically in a utilitarian manner. For that reason, we definitely have a global mindset and believe that we have a business that could have a significant, worldwide impact for many years to come.”
Driving Up Value
The key for aCGT Vector will be to validate its GMP-in-a-POD concept for CAR-T cell therapy manufacturing within or at least very near to cancer research centers and hospitals. That is happening through close collaboration with companies providing and innovating closed system single-use automated manufacturing systems, such as Cytiva, Ori Biotech, Miltenyi, Lonza, Multiply Labs, and others. These firms also need to demonstrate their technology by having it used in the production of an approved therapy. “We have as a result become both a therapeutic platform and a technology platform for new innovators — a hybrid model of a CDMO, CRO, and innovator all in one. It’s a different way of doing business, and a lot to take on,” McAuslan says.
It is also the reason why the leaders of the company are investing their own money and taking on the risk themselves. “In terms of the cost of logistics and the risk of failure, it is a no-brainer to bring manufacturing into the hospital — or on the roof, adjacent to it, or perhaps across the street, doing it correctly and under license,” he says.
McAuslan also stresses that onsite distributed manufacturing at hospitals is a completely different approach to manufacturing and will be inherently disruptive. “It will have ripples outward and could make cell therapy just fundamentally different and more available for patients,” he believes.
Ultimately, aCGT Vector believes it will drive up understanding of cellular therapy procedures and in turn increase pharmacoeconomic value to reimbursement payers. Doing so will bring promise to more rare disease patients through greater accessibility to these valuable transformative and potentially curative therapies.
“aCGT Vector will deliver cellular therapies through co-location of expertise more efficiently with less burden being placed on patients, more safely within centers of excellence, and by bringing more value for payers –– through data-driven optimized patient outcomes achieved by performing transformational and potentially curative cellular therapy procedures proximal to patients,” McAuslan concludes.
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