Why cell therapy manufacture is a team sport

Louis van de Wiel, Vice President, Site Head EU Manufacturing, Kite, a Gilead Company, reveals the complexity that sits behind the process of individualised cell therapy – and why team culture makes it work

This thought leadership series has been paid and developed by Kite, a Gilead Company.

In 2018, we were preparing to build a European facility to produce individualised cell therapies for the treatment of cancer.

Roll on two years and the team has achieved what at the time appeared a major challenge, putting 1,000 tonnes of steel, 1,800 solar panels and 176km of network cable into the creation of a centre of excellence for cell therapy near Amsterdam in the Netherlands.

In my experience, completing the design and build of a facility such as this, through to qualification, licence and becoming fully operational, would normally take four to five years. Our ambition was always to do this within two years, a goal we achieved despite the unprecedented challenge of a global coronavirus pandemic.

Indeed, while undoubtedly putting new hurdles in our path, the arrival of COVID-19 into our lives has transformed our business and operations by presenting an opportunity to be adaptable, flexible and responsive – and to continually evaluate and mitigate risk.

“There is huge complexity involved in cell therapy manufacture, with hundreds of personnel responsible for ensuring the quality and supply of an individual patient’s cells”

It’s been a complex process that’s required highly technical and skilled personnel. Not only did we build a specialised facility from the ground up, but we built an organisation, from 10-15 people two years ago to more than 400 now. We put energy and emphasis into creating the right team and a culture where everyone understands the values and drivers, allowing us to operate in a collaborative and cohesive way.

Now the new €130 million, 19,000m2 manufacturing facility near Amsterdam is able to support delivery of up to 4,000 cell therapies each year for eligible cancer patients across Europe.

But backtrack to August 2018 and the very first European patients were also receiving treatment, part of an expertly crafted operation that ran in parallel to the build. Our supply chain group worked with the existing US team to manage the shipment of patients’ cells to the US for modification and their return for treatment.

Having a fully operational site in Europe versus the US has several advantages; reducing transportation time, strengthening the chain of custody and, potentially, cutting lead time to the patient by approximately one week. This allows us to potentially provide the therapy quicker for eligible cancer patients who have stopped responding to or have progressed despite other treatments. At this stage of their disease, for patients who have no other options, a week can make a difference.

The journey of the cell

The very nature of cell therapy manufacture means employees work in tightly controlled environments to ensure adherence to good manufacturing practice standards and, ultimately, to ensure the quality and integrity of the product.

Ultimately, it’s a team sport between Kite and Gilead and the 100-plus qualifying hospitals across Europe, all of which have been individually trained and assessed to ensure they are fully compliant with the necessary procedures and meet exacting standards.

So, what does the journey of the cell look like?

To achieve consistent, timely delivery of a high-quality product requires a robust and efficient approach to engineering patient’s own T cells, which in itself encompasses apheresis, cell modification and final formulation – coupled with rigorous quality control testing throughout – reflecting the highly complex nature of the manufacturing process.

Understandably, teamwork is vital and requires an integrated network and seamless communication between Kite and the treating hospital. The journey starts with the hospital making a treatment reservation through KiteKonnect and shipping of the apheresis kit to enable the process of extracting the patient’s own white blood cells, kickstarting both the chain of identity and chain of custody.

Here, our quality and supply chain experts are integral to every stage of the cell therapy manufacturing continuum to ensure the product is returned to the patient in a timely manner.

As soon as apheresis has completed, the cells are shipped in temperature-controlled conditions to our facility near Amsterdam where they are assessed for quality and condition. One patient equals one individual treatment, so it is critical to preserve the chain of custody and chain of identity to ensure the product comes back to the same patient.

Why chain of custody and identity is critical

The chain of custody and chain of identity must, therefore, go hand-in-hand. In this way, not only do we know which cells belong to which patient, but we have precise location and up-to-the-minute feedback on storage conditions to ensure quality and safety is paramount at all times.

Once the cells have completed this first stage, the manufacturing process can begin, with T cell selection, activation, and genetic modification using viral vector technology to ensure the ability to recognise the patient’s cancer cells. Cell expansion follows to multiply the modified cells into their millions.

Further critical quality testing then takes place to ensure the cells are of a required standard and to create a finished purified product, which will be stored and returned to the originator hospital in temperature-controlled conditions (see diagram below).

Several quality attributes will be tested at this stage and the cells must meet these rigorous criteria and specifications. There is huge complexity involved in cell therapy manufacturing, with hundreds of personnel responsible for ensuring the quality and supply of an individual patient’s cells.

As part of this process, the supply chain team simultaneously coordinate with the hospital to prepare the individual so when the cells are infused back to the patient they are primed to potentially fight the cancer.

Individualising the approach

In stark contrast to basic biopharmaceutical products with a robust starting material, the cells of a patient with cancer who has already undergone multiple treatments will not have the same quality. Consequently, there can be unforeseen hurdles during the process and I am proud that the team has managed each situation to safeguard the patient’s cells and ensure they receive treatment in an efficient and timely way.

This is particularly important when you consider the turnaround for each individualised product from starting material to the patient is typically four weeks – versus months or even years for a standard biopharmaceutical product.

Additionally, each patient equals one product batch – we do not keep inventory – and the potential impact on the patient if something happens to that batch is why we are so passionate. From quality manufacturing, facility engineering, supply chain, we’re driven to make sure the batch is returned to the patient safely and effectively.

What of the future? For me, it’s all about leadership, clarity, direction, and commitment of the entire team. It’s about the opportunity to be involved in an innovative field of cancer therapy where the body is stimulated to fight cancer cells. It’s about optimising the manufacturing process to become more effective and efficient. But, most of all, it’s about the patients, their care partners and families


This was supported by Kite, a Gilead Company
UK-CTH-2020-11-0075 | Date of preparation: December 2020

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Welcome to the CAR-TCR Summit Europe 2021

Accelerate the Bench to Bedside Development of Novel CAR Immunotherapies for Safe, Effective & Affordable Advanced Therapies

With CAR-TCR therapies on the cusp of achieving global approval, there are still many bottlenecks that are preventing this from becoming the ‘sell-out’ therapy that the field had hoped for.

The CAR-TCR Summit Europe (16th-18th February 2021) will unravel the technical challenges across R&D, translation, scale and delivery to provide your team with the platform to learn, collaborate and gain actionable insights to advance your therapy for clinical and commercial success.

This year’s focused agenda will delve into the technical bottlenecks encountered in every stage of the CAR-TCR drug development cycle, providing more comprehensive analysis from 55+ expert speakers across 3 streams of content including:

Research & Development Track:

  • Explore the emerging CAR-X landscape with Glycostem & Carisma Therapeutics
  • Breach the solid tumour microenvironment with Refuge Biotech Atara Biotherapeutics
  • Optimise target identification with Celyad Anocca AB
  • Investigate next-generation gene engineering techniques with Precision Biosciences

Translation Track:

  • Develop ‘off-the-shelf’ platforms with Leucid Bio
  • Provide a mechanistic rationale for combination therapies with Agenus & Ziopharm Oncology
  • Discuss ‘gold standards’ and innovations in assay development  GlaxoSmithKline & bluebird bio
  • Understand and minimise toxicity with Kite: A Gilead Company & The NHS

Manufacturing & Commercialisation Track:

  • Advance automation for cheaper, faster manufacturing with Gracell Biotechnologies & Glycostem
  • Gain regulatory guidance to initiate clinical trials in Europe from MHRA & Norwegian Medicines Authority
  • Maximise real-world evidence for value demonstration, and innovative reimbursement models with Janssen
  • Expedite batch release and maintain high-quality products with Novartis & Immatics

For agenda details and full speaker line up, find out more here

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Triumvira Immunologics raises $55M in Series A funding round for new form of cancer cell therapy

The company hopes to use the money to bring its T-cell antigen coupler cell therapy technology – currently in preclinical development – into human clinical trials. German drugmaker Bayer’s venture capital arm led the round.

Novartis plans to seek approval for CAR-T in slow-growing lymphoma after Phase II success

The company said the study of Kymriah in follicular lymphoma met its primary endpoint, though it did not disclose the trial data. It plans to submit approval applications to the FDA and EMA next year.

Preparing for an influx of cell and gene therapy approvals

Cell and gene therapies offer some of the most groundbreaking advancements in patient care the pharma industry has ever seen. However, to fully realise the potential of these innovative therapies, integration across the supply chain is critical – particularly with reimbursement and logistics.

As of the end of 2019, there were 17 cell and gene therapy products approved by the FDA. Now, there is more momentum than ever to bring these innovative medicines to market, and the FDA anticipates that it will approve 10 to 20 cell and gene therapy products a year within the next five years.

These therapies can offer new opportunities to patients with conditions where there are few treatment options and no cures. But the potential these products offer could remain largely unrealised if manufacturers and their partners are not prepared. Cell and gene therapy innovators and other stakeholders across the supply chain need to set themselves up for the greatest chance of success by addressing three key challenges: access barriers; logistics; and the need for stakeholder education.

Addressing access barriers through innovative payment models

While cell and gene therapies offer novel treatment to patients who have limited options, the cost associated with each product – anywhere between $375,000 and $2 million – can create significant access barriers. This challenge is compounded compared to traditional treatments that typically require multiple doses, as many cell and gene therapies are one-time treatments.

This situation increases the risk for payers covering the cell and gene therapy, given that the long-term magnitude and durability of the product is not known at the time of first regulatory approval and patients switch insurance carriers throughout their lifetimes.

“Stakeholders across the industry have recognised the increasing need to consider alternatives to the standard payment system if cell and gene therapies are to become widely available”

Stakeholders across the industry, such as manufacturers and payers, have recognised the increasing need to consider alternatives to the standard payment system if cell and gene therapies are to become widely available. As a result, a variety of payment models have been discussed:

  • Value-based model: The payer pays only a portion of the full price upfront. If the therapy achieves prespecified outcomes, the payer remits the remainder in full. This model spreads the financial risk, therefore, between the payer and manufacturer, and has been the most commonly employed method to date.
  • Pay-over-time model: The payer agrees to a fixed price for the therapy but pays in regular installments, like with an annuity, spreading the cost over time.
  • Subscription-based model: This model offers the payer a flat rate for coverage of various cell and gene therapy products, which provides predictability and helps them offset the potentially high upfront costs of these therapies and realise longer-term cost-savings.

We have already begun to see payers and manufacturers of cell and gene therapies attempt to adopt alternative payment models for their products, and more should continue to do so as additional therapies come through the approval pipeline. With a range of interdependencies that affect the success of cell and gene therapies, manufacturers need to develop their reimbursement strategy early in the commercialisation process. It’s critical for manufacturers to consider various payment models for cell and gene therapies ahead of approvals so that they can maximise patient access for their products.

Ensuring therapies reach their patients

Manufacturers have noted that the delivery of critical shipments is one of the biggest challenges facing the advanced therapy industry, as if you cannot connect cell and gene therapies with patients their efficacy is irrelevant. The inclusion of patients into the cell and gene therapy supply chain, the potentially life-altering impact of the therapies and their high cost leaves no room for failure.

These therapies require timely delivery and maintaining precise temperature control is integral for the patient and the product. It calls for near-perfect execution ranging from mapping the best transportation route and planning for multiple contingencies (such as closed international borders), to how the packaging itself is evaluated, validated and used to maintain product integrity in all conditions.

Successful execution of these processes requires both manufacturers and other supply chain partners to maintain a robust logistics platform. Currently, many manufacturers are developing different logistics plans for each of the stages of a clinical trial, only to find out these processes don’t scale when it is time to commercialise. Developing a plan early that can scale will position a product for success as more therapies are reviewed and approved. Manufacturers need to work with their 3PL and distribution partners to ensure control and oversight throughout the product journey to the patient – failure to do so will put patient outcomes and commercial success at risk.

Promoting stakeholder education

Many stakeholders – spanning payers, providers and patients – do not understand the full clinical, logistical, operational, financial or reimbursement components associated with cell and gene therapies. Manufacturers can leverage the preliminary data they’ve gathered throughout their initial commercialisation journey to support education and awareness efforts with these key stakeholders.

As payers conduct product reviews earlier and earlier in the development lifecycle, their demand for pre-approval information continues to grow. However, recent research shows that a gap still exists between the evidence sought by healthcare decision makers and what is being shared by manufacturers. COVID-19 has also caused delays in providing information in a timely and relevant manner, causing even more challenges for stakeholders.

The use of Pre-approval Information Exchange (PIE) is one way to combat these challenges. PIE allows manufacturers to communicate ahead of approval to partners with accurate, and unbiased information on products or indications, and share information early that may result in a “place saved at the table” for their product. This information equips stakeholders with the education needed to understand a product’s value story and positioning. Partners embedded in the industry – particularly those with a patient-centric focus – can also offer manufacturers the information they need to showcase the value of these products to patients.

The cell and gene therapy space is continuing to evolve. Through analysing payment models, working with partners to navigate logistical challenges and leveraging data, patients will have more opportunities than ever to access the next generation of medicines. Overall, the collaboration between stakeholders across the supply chain will facilitate a world in which we see 10 to 20 cell and gene therapies not only approved each year but out in the market directly impacting patients.

About the authors

Alex Guite is vice president services and alliances at World Courier. As strategy and services lead, Alex is responsible for developing and executing key strategic initiatives.Before joining World Courier in 2013 as head of pricing, Alex spent nearly 3 years with Oliver Wyman as a consultant in the Health and Life Sciences practice.

Ana Stojanovska is vice president, reimbursement & policy insights at Xcenda. She has extensive practical knowledge in working with key stakeholders to motivate local coverage of new products by both public and private payers and providing strategic compendia analyses and ongoing coding support. Prior to Xcenda, Ana worked for a bipartisan, non-profit health policy organization in Washington DC, where she helped lead research, health policy analysis, media outreach, and fundraising.

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BMS, bluebird refile FDA approval application for CAR-T therapy in myeloma

The companies’ resubmission of their application Wednesday seeking approval for idecabtagene vicleucel was in line with the timeline they provided in May, when the FDA sent a refuse-to-file letter in response to their initial submission.

BMS ‘bet’ with Celgene shareholders in balance after CAR-T refile

Bristol-Myers Squibb and bluebird bio have refiled their CAR-T therapy for multiple myeloma, leaving the outcome of a three drug “bet” with former Celgene shareholders dependent on a fast review from the FDA.

BMS gave Celgene’s shareholders a “Contingent Value Right” (CVR) to sweeten the $74 billion merger last November.

Each shareholder got one CVR that pays out $9 if three of Celgene’s pipeline drugs are approved by the FDA by certain deadlines.

The multiple myeloma CAR-T known by the name of idecabtagene vicleucel – shortened to the slightly more catchy ide-cel – must be approved by March 31 next year.

This filing for relapsed and refractory disease provides further details in a Chemistry, Manufacturing and Controls (CMC) module to address outstanding questions from the FDA, which rejected a previous submission in May.

So far only one of the drugs has been approved on time – MS drug Zeposia – and the FDA is due to make a decision on the third CVR drug, another CAR-T therapy for certain lymphomas, on 16 November ahead of a 31 December deadline.

The timetable for ide-cel is also tight: as a Breakthrough Therapy it is entitled to a faster six-month review from the FDA.

After an initial rejection in May, BMS is now relying on the FDA maintaining the drug’s Breakthrough Therapy status for it to get approved on time.

A six-month review would set up an FDA decision date in January, but a standard 10-month review would likely push a decision beyond the 31 March deadline.

There was no word from BMS on whether the FDA has granted the Priority Review – the regulator may decide that the clinical data does not support this, or it may reject the drug outright.

The impact of COVID-19 may also be a worry for holders of the CVR, which can be traded publicly under the ticker BMY-RT.

Disruption caused by COVID-19 has led the FDA to cancel several advisory board meetings, where experts provide non-binding advice to the regulator about the pros and cons of potential new drugs and therapies.

The FDA warned in May that COVID-19 could delay decisions as it prioritises resources to review potential vaccines, drugs and therapies to combat the coronavirus pandemic.

Analyst Mike Bailey told CNBC news in June that reviews of cancer drugs were unlikely to be affected – but given the many uncertainties during the pandemic this could change very quickly.

Originally codenamed bb2121, ide-cel was developed by Celgene and bluebird before the merger with BMS.

It works differently from other CAR-Ts on the market by targeting B-cell maturation antigen (BCMA), which is often found on the surface of malignant B-cells that cause multiple myeloma.

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Gilead’s Kite gains some height after second CAR-T approval in US

Gilead’s $11.9 billion purchase of Kite Pharma in 2017 didn’t follow the script, with two big write-downs in the value of the asset since then, but a fresh approval for a CAR-T therapy could claw back some value.

Late last week, the FDA approved Kite’s Tecartus (brexucabtagene autoleucel; formerly KTE-X19) as a treatment for mantle cell lymphoma (MCL) patients who have failed earlier lines of therapy, giving the company a second approved cell therapy – and the first without direct competition in the market.

Tecartus will launch with a $373,000 list price, around the same as Gilead/Kite’s first CAR-T – non-Hodgkin’s lymphoma therapy Yescarta (axicabtagene ciloleucel) – which was approved back in 2017.

Yescarta launched with blockbuster sales predictions but has failed to make much headway in the market, bringing in just over $450 million last year with flat quarter-on-quarter growth.

It competes in some indications with Novartis’ rival Kymriah (tisagenlecleucel) product, which has also underwhelmed since launch with sales of less than $300 million in 2019.

Both drugs have been held back by small target populations and a lengthy treatment process that carries no small amount of toxicity risk.

Yescarta’s lacklustre performance caused Gilead to take an $800 million charge in the fourth quarter, which came after an $820 million write-down a year earlier as the company downgraded the value of Yescarta and Kite’s CAR-T pipeline.

With Gilead chief executive Daniel O’Day talking about a looser relationship with Kite – perhaps with its own CEO – suggesting Gilead is looking elsewhere for growth potential.

Tecartus is the first CAR-T to be approved for MCL, a rare and aggressive form of NHL, and had been awarded breakthrough status by the FDA based on results of ZUMA-2, an open-label study that found an 87% response rate with the CAR-T including 62% complete responses. That’s considered an impressive level of efficacy considering the hard-to-treat patient population.

In autologous CAR-T therapy, the patient’s T cells are harvested and genetically modified to include a new gene that helps then target and kill lymphoma cells, and the modified T cells are then infused back into the patient.

It’s a process that can take at least a couple of weeks, and carries a risk of side effects including cytokine release syndrome (CRS), which can cause fever and flu-like symptoms and can be life-threatening.

Tecartus has a boxed warning on the label for CRS, as 18% of patients treated with the therapy in the ZUMA-2 trial developed the side effect at a level of grade 3 or higher. The warning also covers neurological toxicities, which were seen in 37% of patients.

The CAR-T is currently under review in the EU and has been granted priority medicines (PRIME) designation by the EMA for relapsed or refractory MCL, so could get approval there before year-end.

Meghan Gutierrez, chief executive of the Lymphoma Research Foundation, said that the approval builds on progress in the treatment of MCL with an increase in clinical trials for the blood cancer that “we hope will continue to improve treatment strategies” for patients.

Recent approvals for MCL include AstraZeneca’s Calquence (acalabrutinib) and BeiGene’s Brukinsa (zanubrutinib), two BTK inhibitors used as second-line therapies after initial therapy chemotherapy or proteasome inhibitors such as Takeda’s Velcade (bortezomib).

Meanwhile, Gilead/Kite is also looking ahead to the readout later this year of ZUMA-7 – a trial that could advance Yescarta up the treatment pathway for diffuse large B cell lymphoma (DLBCL) and – they hope – restore some sales growth.

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