Cutting the cost of CAR-Ts – Innovative strategies to make cell therapies more affordable

T cells are the most extensively studied cell type in the development of cell therapies, constituting 58% of active UK ATMP clinical trials (1). CAR-T (Chimeric Antigen Receptor T cell) therapy uses synthetically engineered receptors targeting a specific ligand in T cells to target and destroy tumour cells. Following three decades of development (2), CAR-T therapy has shown significant benefits in patients with B cell malignancies (3), and is being explored for broader indications such as autoimmune disease.

Currently, commercially available CAR-Ts are predominantly autologous therapies, being made for individual patients by extracting their T cells and modifying them in the lab. CAR genes code genetically engineered proteins that fuse an antigen recognition domain from a monoclonal antibody with the intracellular T cell signalling and costimulatory domains of the T cell (4). These proteins are then expressed on the surface of the T cells.

Major Steps in CAR-T Manufacturing Process (5,6)

CAR-T therapies typically take around 1-2 weeks to create, although exact processes can differ depending on the provider. Generally, the procedure involves:

• Leukapheresis

The patient’s T-cells are extracted using a separation process called leukapheresis, which collects cellular components from the blood. They are then sent to the manufacturing facility which may require them to be cryopreserved for transport.

• T-cell Selection & Activation

T cells are further purified from the leukapheresis and then activated using CD3/CD28 co-stimulatory antibodies or activation reagents and cytokines.

• Gene Transfer (Transduction or Transfection)

Viral vector is added to the T cells, or for non-viral approaches, electroporation or other novel techniques can be used to insert genes into the cell

• T-cell Expansion, Formulation & Cryopreservation

T cells are expanded to the required number of cells for a dose. Harvested cells are then cryopreserved for transport.

• Transport and Patient Administration

CAR-T cells are transported from a central manufacturing site to the hospital/medical centre and administered to the patient.

Despite the well-established protocols of production and high efficacy of these therapies, CAR-Ts only reach a limited number of patients. This is largely due to the cost, with the price of CAR-T therapies often reaching £400,000 per patient (8). One way to tackle these costs is by optimizing the current manufacturing process.

A variety of strategies are being investigated to reduce the expenses of CAR-T therapies. Some companies (1) are developing new technologies to automate parts of the manufacturing process, reducing labour costs and human error. A wider conversation within the cell and gene therapy (CGT) industry is looking at decentralised manufacturing, producing therapies at the point of care (9,10) or even in the patient themselves, removing the need for ex vivo manufacturing and reducing logistical costs.

The benefits and drawbacks of various CAR-T manufacturing strategies (7)

There is no single solution to make CAR-T therapies more affordable. However, the ongoing development of strategies to reduce manufacturing costs is a promising step to making these innovative and life-changing therapies available to everyone who needs them. worth waiting.

At MFX, we’re developing our Cyto Engine technologies to seamlessly scale up or down. This allows a greater understanding of the biology of CAR-Ts that enables faster process translation, and the ability to scale up cell numbers whilst maintaining the same microenvironment during manufacturing.

References:

1. CATAPULT, Cell and Gene Therapy. Cell and gene therapy catapult. UK ATMP Clinical Trials Report. 2022.
2. Charrot S & Hallam S. CAR-T cells: future perspectives. HemaSphere. 2019. 3:2.
3. Xin T, Cheng L, Zhou C, Zhao Y, Hu Z & Wu X. In-vivo induced CAR-T cell for the potential breakthrough to overcome the barriers of current CAR-T cell therapy. Frontiers in Oncology. 2022. 12:809754.
4. Levine BL, Miskin J, Wonnacott K & Keir C. Global manufacturing of CAR T cell therapy. Molecular Therapy: Methods & Clinical Development. 2017. 4: 92-101.
5. Wang X & Riviere I. Clinical manufacturing of CAR T cells: foundation of a promising therapy. Molecular Therapy – Oncolytics. 2016. 3: 16015.
6. Vormittag P, Gunn R, Ghorashian S, Veraitch FS. A guide to manufacturing CAR T cell therapies. Curr Opin Biotechnol. 2018;53:164-181.
7. Ayala Ceja M, Khericha M, Harris CM, Puig-Saus C, Chen YY. CAR-T cell manufacturing: Major process parameters and next-generation strategies. J Exp Med. 2024;221(2)
8. Tumaini B, Lee DW, Lin T, Castiello L, Stroncek DF, Mackall C, et al. Simplified process for the production of anti-CD19-CAR engineered T cells. Cytotherapy. NIH Public Access; 2013; 15(11):1406.
9. Lopes AG, Noel R, Sinclair A. Cost analysis of vein-to-vein CAR T-cell therapy: automated manufacturing and supply chain. Cell Gene Ther Insights. BioInsights Publishing, Ltd.; 2020; 6(3):487–510.
10. Orentas RJ, Dropulić B, Lima M de. Place of care manufacturing of chimeric antigen receptor cells: Opportunities and challenges. Semin Hematol. W.B. Saunders; 2023; 60(1):20–4.

Embracing Inclusivity: The CGT Circle X Pride – A Recap of The CGT Circle’s First-Ever Workshop

Last month The CGT Circle held it’s first ever workshop event at Stevenage Bioscience Catalyst (SBC), supported by MFX and SBC and facilitated by The Honeycomb Works. A session focussed on building and sustaining truly inclusive cultures. This event was not just informative but incredibly engaging and sparked much enthusiastic and thought provoking discussions.

Leaders from various startups, James Kusena PhD (VP of Operations & Product Owner at MFX); Sheila Johnson (HR Consultant); and Pedro Correa de Sampaio (CEO of Neobe Therapeutics), shared their insights on putting inclusion into action, even while navigating the high-pressure world of securing funding and driving impactful change. It was motivating to hear their real-world experiences and challenges, and how they strive to create inclusive environments in their organizations. 

The guests weren’t just passive listeners, they got to collaborate on practical exercises. It was a hands-on opportunity to put some of the ideas discussed into action. The activities were designed to help the audience gain a tangible understanding of what they can do to start building an inclusive culture in their own spaces, whether at work or in communities.

Some of the key takeaways that can help to make a real impact:

1. Creating an intentionally inclusive culture requires specific actions and policies. The workshop emphasized the importance of communicating expected behaviors, holding individuals accountable for bad behavior, and establishing well-defined policies and processes. A public commitment to inclusivity will reinforces the organization’s dedication and accountability to fostering a respectful and inclusive environment.

2. Inclusive recruitment, a crucial area for impactful change, involves ensuring a fair hiring process that attracts diverse candidates. Implementing to a structured recruitment process minimizes biases and maintains consistency. Actively engaging with initiatives to increase diversity in STEM widens the talent pool, while regularly collecting data and feedback identifies areas for improvement and measures progress.

3. Supporting managers in promoting an inclusive culture is essential. Inclusion should be integral to their role, with clear behaviors provided as a guide. Regular conversations and support help them navigate challenges, and including inclusivity in performance reviews ensures accountability and rewards their efforts.

4. Regularly measuring the impact of inclusivity efforts is crucial. Observing behaviors and gathering feedback on how people feel about the workplace can boost success. Collecting aggregate and demographic data early on helps establish a baseline, track progress, and identify areas needing more focus

We were delighted to support this event and look forward to hearing more from The CGT Circle and The Honeycomb Works on these important topics!

How to Innovate? The MFX way

Césaré Cejas, PhD gave a recent talk at the Bioengineering Symposium, a jointly organised event held by the Oxford University Bioengineering Society and Warwick BioSoc on the topic of “conceptualising innovations to confront current challenges in cell and gene therapy.

Here’s some of his key learnings from co-founding and building MFX to where it is today!

Understand the industry

To precisely define your problem. What are the current challenges in the CGT industry? Scalability is definitely on top of list to properly translate process development to high-throughput manufacturing without the need for process re-optimisation. MFX leverages the geometric form factor to ensure fluid streamlines are identical in small and larger scales. How the fluid (media) interacts with the cells can significantly affect shear, which in turn affects cell expansion.

Know your customer

To give voice & value. Identify your potential user and understand the pain points in their process and ask them about their “ wishlist.” In an ideal world, what do they seek in terms of hardware that improves their process? In MFX , we leverage understanding things at a small scale to make process improvements at a large scale: scale-down to screen, then scale-up and scale-out.

Know your landscape 

To know your position and market offering. Understand what others are doing in the space to develop strategy, which products/customers to keep satisfied, manage closely, monitor, or keep informed. When it comes to bringing something new to any market, resistance is expected but education and information help enable adoption of new innovation.

Design, validate, iterate

Rinse and repeat. Assess information from customers and competitive landscape, and iterate technology accordingly, making sure there is market need. Innovation needs to have a purpose. One can have the most ingenious idea but if customers don’t find a use for it, it then does not provide value for them and it’s not “innovative.”

Build relationships

Network to stress-test the innovation. The CGT industry is built on relationships. A lot of the processes are relatively new and experimental, and because of ongoing challenges relating to optimisation and scalability – there is appetite for new innovation that improves accessibility and improves the journey from discovery/screening to commercialisation.

The Best Cell and Gene Therapy Conferences in 2024

What are the best Cell and Gene Therapy conferences to attend in 2024?  We asked our VP of Commercial Lindsey Clarke what her top picks are for the coming year.

It really depends on what your reasons are for wanting to attend an event. Do you have some exciting data that you want to share with the community? Are you looking to find out about the latest trends in technologies or what exciting things are happening in the industry? Is it to get an understanding of the bigger picture macro environment that could help with your work? Is it to get an idea of the latest trends in relation to the specific cell or vector types you are working with? Or is it that you’re looking to connect with others working in the industry and build your own personal network?  Each and every one of these is a valid reason for attending an event. But depending on your reason – there are different events which would suit you best.

ISCT, ASCGT, and ESCGT – keeping up with the latest scientific advances

At the same time as enjoying winter sun in between meetings, January is also the time to polish up abstracts for the big scientific society meetings that are coming up in May in North America – ISCT and ASGCT.  The society meetings tend to be widely attended by the technical crowd and those running the early clinical trials, so there’s many of the scientists involved in basic research in academia and industry, as well as data from the clinic.  Lots of posters and talks on science and clinical progress make these events a great opportunity to find out what’s happening in the field. They’ll also be well attended by technology suppliers so you can find out about the latest pieces of kit that could help your research. And if you can’t justify the transatlantic flight, Europeans can look forward to their regional ISCT event and ESGCT in the latter part of the year.

Advanced therapies – a UK-based CGT event

Another global event that happens early in the year is Advanced Therapies in London. The ExCel is a vast events centre in east London, conveniently connected via the Elizabeth line direct to Heathrow.  With London being such a hub of cell therapy, there’s always a strong local crowd as well as many international guests.

Meeting on the Med and Mesa – bringing key stakeholders together on both sides of the pond

If connecting with colleagues globally is important for you then it might be worth looking into the work of the Alliance for Regenerative Medicine which is the leading international advocacy organization for the industry and brings together many key stakeholders.  It also holds two large events annually – one each side of the pond – Meeting on the Med and Meeting on the Mesa!

CAT-TCR – drilling into the details within cell therapies

If you’re looking for scientific detail, then events focussing on cell types such as CAR-TCR by Hanson Wade provide a more narrow scope, meaning you’ll get to meet others working in very similar fields.  Other niche events include important topics around manufacturing, analytics, regulations, supply chain, and automation.  By attending a niche event you’ll be guaranteed an audience equally interested in the event’s topic.

Alternatively if you want to learn from the broader bioprocessing community, then often the large bioprocess industry events have a cell and gene therapy manufacturing stream to them.

To round up  – there are so many events which offer different things depending on what you’re looking for. You may want to mix up your conference schedule to include some big showcase general events that cater to the whole industry for broad updates and learnings, some local events to meet with the industry in your part of the world, and some really niche events to focus on the deep science of your area of interest.

Where can you find MFX in the next few months?

• January 10-11 2024 – ESACT-UK, Stevenage
• January 16-19 2024 – Advanced Therapies Week, Miami
• February 27-29 2024 – CAR-TCR, London
• March 19-20 2024 – Advanced Therapies, London
• May 29-20 – ISCT, Vancouver

Data and Digitization – The key to better biology and more effective therapies

Data is the cornerstone of any scientific endeavor. But throughout history it’s been managed pretty poorly. Most data ever gathered on cells remain in hand-written lab notebooks, gathering dust on shelves after the experiment’s ended. Small snippets of data make it to the public eye through accepted publications, which shape future experiments and lines of investigation. But all that other data collected from hours of planning experiments and measuring endpoints that isn’t up to publication standards – like negative data – is essentially lost. Imagine how much more could be learned if all the data collected over the past century on cells was lifted, centralized, and analyzed.

Whilst this may not be feasible for the past, using digital systems could make this a reality in the future. Things like electronic lab notebooks are already used in the lab, helping to digitize note taking at the source making it easy to record, transfer, and store data. But the evolution of digital tools and equipment will:

• Automate monitoring of cells and the cell culture environment during and after experiments
• Process data to make it exploitable (e.g., images of cells into cell circularity, cell size, cell count, cell eccentricity)
• Organize data so it can be easily visualized
• Analyze data through machine learning algorithms to help uncover insights that isn’t currently possible

Before we can unlock the incredible power of digital systems, research labs and manufacturing sites need the right infrastructure and equipment. Communications standards are starting to come together to allow this, for example with OPC-UA, but there is an unmet need for hardware that can generate the actual data during cell culture.

At MFX, we build platforms that can manage up to 30 bioreactors in one device, with each bioreactor generating hundreds of thousands of data points thanks to integrated online sensors and mutualized analytical equipment. All the data is processed, organised, and presented to the user in a digestible format, and we partner with the best machine learning providers to generate insights.

The benefits of this are countless and include:

• Reducing process development time
• Reducing the number of experiments necessary to uncover insights
• Making it easier to transfer knowledge from one person/organization to another
• Discovering new treatments faster

What’s more, these benefits building exponentially as your database expands. Now, that’s an exciting future for biology.

Making cell therapies comPATible with large scale manufacturing

Process analytical technologies (PATs) cover a wide range of tools, playing an important role in initiatives such as quality by design (QbD), real-time release, and continuous manufacturing [1]. They are already widely utilized in pharma and biopharma manufacturing, and for the large-scale deployment of cell therapies, they are critical to ensure:

• Safety – Maintains a consistent process and product quality through in-line and on-line monitoring and analysis
• Speed – Allows insights into the process helping accelerate R&D and process development, especially when couple with data analytical tools
• Cost-effectiveness – Insights into culture throughout the process can help optimize reagent usage, reduce process duration, and lower batch failure rates

During process development, many parameters need to be measured across hundreds of experiments to identify the critical process parameters (CPPs) and critical quality attributes (CQAs) required for the desired cell product. Without PATs, this turns into an intractable (both costs and logistics-wise) amount of sampling and manipulation, and an enormous amount of Capex for analytical equipment.

Common parameters measured during process development include:

In-process

• pH
• Dissolved O2
• Temperature
• Dissolved CO2
• Metabolite concentration
• Amino-acid concentration

End of process

• Cell count
• Cell viability
• Phenotyping
• Karyotyping
• Potency assays

At manufacturing scale, CPPs and CQAs need to be measured constantly to demonstrate batch safety through quality control. With hundreds of thousands of patients per year who could benefit from cell therapies, maintaining the current practices of manually sampling and analysing swathes of data will become commercially and logistically unviable.

So how can you implement PATs into the cell therapy manufacturing process?

Automation

Online automation allows for multiple measurements to be taken in parallel, avoiding the need for sampling. For example, using specialist microscopes coupled with trained algorithms next to a bioreactor can supply increasingly accurate cell count and viability measurements, with fluid loops from the bioreactor maintaining a closed culture system. MicrofluidX has gone one step further, directly implementing microscopes on their bioreactor thanks to their bioreactor form factor.

If there isn’t capacity for online measurements, automation can be harnessed in other ways to save time and reduce manual handling, like automating sample prep for flow cytometry.

Mutualization

All these PATs can add up when running multiple bioreactors in terms of costs, space, validation requirements, logistics and maintenance. This is why mutualization is key, and it can be done in a few ways. Robotics can manage the movement of bioreactors to and from pieces of analytical equipment in closed systems, while autosamplers can manage the movement of samples from different bioreactors to one piece of analytical equipment. This drastically decreases Capex, increases productivity of your equipment, and removes variability from manual handling.

At MFX we combine all these approaches to deliver a cost-effective, analytically driven bioreactor platform. Our Cyto Engine™ can be deployed in both process development and large-scale manufacturing. 

[1] Clegg, I. 2020. Specification of Drug Substances and Products, Second Edition. Elsevier, pp 149-173