The potential of cell therapy is beyond doubt, but its impact is limited by the lack of scalable manufacturing solutions. Existing processes remain disjointed, cost prohibitive, failure prone, and unable to meet market demand.

Last May, Cellares, a South San Francisco-based company founded in 2019, secured $82 million in a Series B round, bringing its total funding to date to $100 million. Currently in the development phase, Cellares’ automated platform will be suitable for producing CAR-T, hematopoietic stem cells (HSC), T-cell receptor (TCR), natural killer (NK), TIL (Tumor infiltrating lymphocytes), T-reg, and γδ T cells. The pipeline supports all processing steps in the production pipeline—enrichment, isolation, activation, gene transfer, expansion, and formulation—requiring no “touch time” between loading the source material to unloading the cell therapy product, ready for infusion.

The incorporation of flexible automation platforms such as the company’s Cell Shuttle—described as a scalable “factory in a box”—into biomedical research and bioprocessing workflows will require skilled process designers and operators who, unburdened from repetitive tasks in conducting small scale experiments, will need to understand the implications of slight fluctuations in parameters used to monitor complex automated bioprocesses.

Fabian Gerhlinghaus, PhD, is co-founder & CEO at Cellares.

GEN Edge interviewed Fabian Gerlinghaus, PhD, co-founder and CEO of Cellares, who discussed the Cell Shuttle, which offers a closed-system, single-use cartridge that automates the manufacture of cell therapy products, considerably reducing the vein-to-vein time of the process.

GEN Edge: While leading cell therapy companies struggle to treat 1,000 patients per year, an estimated 450,000 patients who need CAR-T cell therapies die without this life-saving therapy. By automating the process, these therapies will reach more patients more quickly. What are the technical challenges in automating the production of autologous and allogenic CAR-T cell therapy products?

Fabian Gerlinghaus: There are three methodological challenges in manufacturing autologous and allogeneic cell therapies. First and foremost, scalability, followed up by cost-efficiency and robustness—how do you make them in a way that is guaranteed to work. Those are the three big challenges I see.

Scalability is arguably the most important one here. Cell therapies are manufactured using a completely different paradigm. They are phenomenally efficacious in curing very aggressive types of blood cancers and are increasingly being applied to other cancers and solid tumors.

They are manufactured in a way that is completely different from any other class of drugs that we have seen in the past—small molecules, biologics, monoclonal antibodies. What all these other classes of drugs have in common is that you make a large batch and out comes drug products for hundreds of thousands of patients and everybody gets the same stuff. Autologous and allogeneic cell therapies are made to order from the cells of the patients or the donor’s respectively, as the starting material. For autologous cell therapy you get exactly one drug for one patient out of a very complex manufacturing process. In the case of allogeneic cell therapies, you maybe get 100 or 200 doses out of one donor cell collection. That is still very little.

Scalability of these personalized medicines is the biggest challenge. Right now cell therapy companies are really running into a bottleneck, given the absence of scalable cell therapy manufacturing technologies. If you want to produce tens of thousands of cell therapy doses per year per drug, and ultimately millions of doses per year as an industry, you need to automate the entire manufacturing process end to end, and you need to increase the throughput of the manufacturing platforms.

Those are two things we are working on at Cellares—building a platform that fully automates the cell manufacturing process and increasing the throughput of the manufacturing platform by an order of magnitude compared to anything else that is out there.

GEN Edge: How is Cellares’ automation workflow an advance over other culture automation platforms such as Sartorius’ CompacT SelecT or Cellmate systems or the AUTOSTEM platform?

Gerlinghaus:  The biggest advancement is true walk-away, end-to-end automation. What you are loading into the single-use cartridge at the beginning of a cell therapy manufacturing process is the starting material from the patients. The cartridge then automates all the cell therapy manufacturing steps: initial cell enrichment, cell selection, cell activation, gene transfer—using either viral vectors or electroporation—expansion in bioreactors, fill, finish, and formulation. What you are unloading at the very end is a cell therapy product that is ready for release testing and infusion into the patient. That is new.

That is closely correlated with an order of magnitude improvement in instrument throughput. Our cell therapy platform can’t just do this for one patient. It can do this for up to 10 patients simultaneously, which is really what you need if you are trying to help the industry scale from a few thousand patients per year per drug to tens of thousands of patients.

GEN Edge: What advances in the individual steps of the manufacturing process make it possible to run the entire process in a closed loop end-to-end system such as Cellares’ cartridge?

Gerlinghaus: We are making improvements to the individual cell therapy manufacturing unit operations. The biggest improvement is that we are offering the entire process in one closed single-use cartridge that is made for automation given that today the problem is anytime you move your half-finished cell product from one consumable or instrument made by one manufacturer, to the next consumable cartridge or instrument made by another vendor, anytime you have an open transfer step of cells or reagents, you are vulnerable to the risk of contamination which can lead to process failure. And process failure, in the case of cell therapies, oftentimes means the loss of a patient’s life.

If you want to make the process more robust and guarantee that the patients are actually getting access to the cell therapies that pharma companies are making for them, you need to reduce the risk for process failure and that means you need to eliminate opportunities for contamination and opportunities for operator error which is the second biggest source of process failure. We are eliminating the chances for operator error-caused process failure by fully automating the process. And we are eliminating the opportunities for contamination by fully closing the process.

The way we are closing the process is by integrating all the consumable cartridges that are usually separate consumable cartridges for separate instruments made by different vendors in one closed fluidic network inside our single-use cartridge that is made for automation. Our single-use cartridge is in effect an all-in-one cartridge that can execute all these cell therapy manufacturing processes in a closed and automated fashion. That is the biggest thing we bring to the table.

GEN Edge: As it is a closed system where many variables have to be checked continuously, there is need for a close integration with monitoring systems, particularly in the case of autologous 1:1 therapies where you may not have a clear idea of how the cells will behave once you inject them into your cartridge. What are these monitoring advances? Are you incorporating AI/machine learning tools to ensure quality control? What kind of parameters are you measuring to ensure QC standards?

Gerlinghaus: We’re offering a suite of in-process data points that we are gathering, which ultimately form rich in-process data products that can be mined by either the scientist or long-term by machine learning algorithms in an automated way. First, we are automating the ability to take a sterile, metered sample. That is something that is often done manually today and also constitutes a risk for contamination. That is automated [in our system]. That is already a big step forward—if you can define in a software, the frequency at which you would like to take a sample, the sample size, and from which of the cell therapy cartridges.

The second step is that you can choose in the software whether you want the sample delivered in the vial for operator pickup and analysis and third-party instrumentations. That opens all the flexibility in the world for you. You can now use whatever flow cytometer workhorse your particular lab is already used to using. We are also fulling integrating in-process QC instrumentation in the Cell Shuttle that offers cell size, density, viability, all metabolites, all the nutrients, acids, pH, temperature, dissolved oxygen—giving you the entire picture of what is going on in your cell culture at any given point in time.

GEN Edge: The Cellares platform can be used in manufacturing CAR-T production, HSCs, TCRs, NK cells, and TILs. Have these been applied in the context of solid tumors as well?

Gerlinghaus: We’re still in the early stages of development of the Cell Shuttle and anticipate market launch of the instrumentation in 2023. That said, we are very confident that this technology can in fact be applied for cell therapies for solid tumors and for congenital diseases. We are supporting 85% of cell therapy modalities out there. That includes a lot of T cell-based approaches, CAR-Ts, TCRs, gamma-delta T cells, TILs, and also hematopoietic stem cells, which are the workhorses for cell therapy approaches targeting congenital diseases.

Cellares’ Cell Shuttle automates the entire cell therapy manufacturing process.

GEN Edge: In cancer cell therapy, combinatorial therapeutic approaches are often used where for instance, cell products are combined with interleukins. How will the automation of cell therapy affect the combinatorial therapeutic protocols?

Gerlinghaus: I think it will be very empowering for pharma companies because we are providing a closed and automated solution in combination with a platform that provides a tremendous amount of process flexibility. Historically speaking, in cell therapy manufacturing you had to choose between a platform that gives you some degree of automation at the expense of flexibility or a plethora of point solutions, different benchtop instruments that give you all the flexibility in the world to run the process at the expense that it is very hard to scale.

At Cellares, we are bringing the best of both worlds together. We’re building a platform that allows you true walk-away end-to-end automation, so you have the automation aspect in combination with flexibility. The way we’re enabling that level of manufacturing process flexibility is through a very modular hardware architecture and a powerful software suite that exposes this modularity and flexibility in a software in a user-facing fashion. So, you can define your own cell therapy workflows in our software packages, which offers you a lot of flexibility to run different processes in the way you want them.

GEN Edge: What methodological advances has the Cellares platform included since the approval of Kymriah and Yescarta in 2017?

Gerlinghaus: The ultimate benefit of scalability to customers is that they will be able to meet patients’ demands for their cell therapy. Currently that is very difficult to do. Secondly, our technology will reduce the manufacturing cost for most cell therapies by up to 70%, given that we are eliminating most of the human labor, and making efficient use of clean room space. Finally, we are confident that we can reduce the risk of process failure by about a factor of 3. Flexibility is another advantage.

In addition, we have assembled the best possible board of advisors. Carl June, MD, is considered by many to be the godfather of cell therapy. His lab developed the cell therapy that was later commercialized as Kymriah. Timothy Moore is currently the president at PACT Pharma. He used to be the executive vp of tech ops at Gilead, responsible for commercializing Yescarta, the second CAR-T cell therapy approved by the FDA. He really knows the pain of commercial scale manufacturing of CAR-T cell therapies, firsthand.

That is also why PACT Pharma came on board and joined our early-access partnership program. The goal of the early-access partnership program is to ensure product-market fit. Rather than developing the technology in the secrecy of our own laboratory, we are taking a very collaborative approach and partnering with top-notch organizations in the cell therapy space. They are providing insight and expertise with regard to the processes that they would like to run on our platform. We are conducting user studies where we are testing our software platform with the end customers long before it reaches the market. In this way, through continuous dialogue with our customers over years, we are ensuring that we are getting it right the first time. Fred Hutchinson Cancer Research Center and PACT Pharma are the two early-access partners that we have disclosed so far.

GMP-in-a box, closed single-use cartridge.

GEN Edge: Is it likely that automation will increase the need for people with methodological skills who can design and develop automated workflows? What is your opinion on the balance between automation and skilled methodological knowledge?

Gerlinghaus: With regard to the design and development requirement, I agree wholeheartedly. We must differentiate between the design and development of cell therapy manufacturing processes on the one hand and the repetitive execution of an established process on the other.

Additionally, automated and flexible technologies with high throughput enable design of experiment (DOE) studies in which dozens and hundreds of permutations of process parameters can be explored simultaneously to optimize cell therapy manufacturing workflows quickly and efficiently. Process design and development is an area where human creativity and ingenuity is well leveraged to make better cell therapies and improve patient outcomes.

As it pertains to the repetitive execution of established cell therapy manufacturing processes, there is a shortage of qualified personnel in the industry today, which constitutes another hurdle to commercial scale manufacturing of cell therapies and prevents patients from gaining access to life-saving cell therapies. Furthermore, automated platforms are better suited to the repetitive nature of commercial scale cell therapy manufacturing as they make less mistakes and don’t have a need for creative self-expression. We need to fully automate manufacturing processes both for the sake of the patients as well as the employees in pharma, whose skills would be better leveraged supporting process design and development.

Anjali Sarkar, PhD, is a science editor with GEN.

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