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We Need To Talk About Cell and Gene Therapy

When it comes to genomic medicine, do patients understand that they are consenting to a fundamentally different kind of treatment – one that may become part of their body for the rest of their lives? And are companies engaging all the relevant stakeholders early enough to avoid issues with commercialization down the line? Here, three industry leaders – Kelly Page, Head of Global Cell Therapy Commercialization at Takeda; Sandy Macrae, CEO of Sangamo Therapeutics; and David Meek, CEO of FerGene – explain what excites them most about cell and gene therapy today. And then kick off some crucial discussion topics for a field looking towards the future.

“It might not be glamorous, but improving how we culture and grow cells, how we mobilize them, and how we create space in the bone marrow to put them back are all crucial to ensuring that cell therapies work.”

Which areas of cell and gene therapy excite you the most?

Page: Overall, the story of our field has been the discovery of new ways to harness the immune system to fight cancer. The second chapter is going to be about optimization. We’re going to move cell therapy from just a few haematological indications to a broader range – perhaps including solid tumors. One issue we face is that many patients can’t get to an academic medical center – they often don’t even know these therapies exist. The next chapter will be about putting these therapies within the reach of the average patient. 

Starting with the first generation autologous CAR T cell therapies, the community has been dealing with very complicated products. Manufacturing delays are common, with patients’ diseases progressing and requiring bridging treatment. After treatment, patients can end up in intensive care or require close follow up in or close to a hospital. And sometimes the manufacturing fails altogether. 

With an allogeneic product, you aren’t having to take live cells and manufacture the therapy within a constrained time frame, which is the root cause of many manufacturing failures and delays. Plus, as these allogeneic therapies move forward, we should be able to expand the range of hospitals that are able to deliver them. Autologous therapies require specialized hospitals, but perhaps regional or larger community hospitals that are currently offering transplants could also offer allogeneic cell therapy – patients won’t have to live next door to an academic medical center to access a treatment. That’s an exciting development! 

Macrae: Cell and gene therapy is all about delivery; in the case of autologous therapies that includes the whole supply chain, and it includes the delivery of vectors for gene therapy. There tends to be a focus on the liver, because that’s where all the vectors go, but the next frontier is the brain. Everyone has been looking for a virus that can cross the blood brain barrier; and there have been some successes in small animals that have not been seen in primates. The field as a whole is getting more comfortable with neurosurgical interventions, which is opening up a whole range of diseases to new therapeutic intervention. Some companies are injecting into the cisterna magna – the reservoir for CSF in the brain. Another approach we’re interested in, pioneered by David Ojala,involves evolving viruses to select for their ability to reach the brain. Essentially, you perform targeted mutagenesis to create a library of barcoded viruses that you put into the brain. You can then use the barcode to track where each virus goes and select for the most effective ones. Do this enough times and eventually (in theory) you’ll find an effective vector for delivery across the blood brain barrier. It’s fascinating work and I believe David is on the threshold of succeeding with this approach.

With regard to cell therapy, there’s room for significant advances in process development. It might not be glamorous, but improving how we culture and grow cells, how we mobilize them, and how we create space in the bone marrow to put them back are all crucial to ensuring that cell therapies work. And if we listen to the people at Kite, a Gilead company, and Juno, a Bristol-Myers Squibb company, it’s all about the supply chain for autologous therapies. The real problem is in oncology, where there’s a danger that a patient may not survive the time it takes to manufacture the CAR T; I know Kite was pleased to be able to get the skin-to-skin time down to 17 days, for example. But that’s still too long for some patients. And that’s why I believe allogeneic is the right way to go (if we can figure out what allogeneic really means given the number of approaches today...). We use zinc finger nucleases to edit healthy donor cells and turn them into allogeneic therapies. We also have another program where we edit iPSCs and grow them up into allogeneic cell therapies. Finding allogeneic Tregs – particularly iPSC sourced – would be an enormous advantage because you would be able to treat anyone with an off-the-shelf product at any time; for example, during an acute multiple sclerosis flare up.

Meek: Cell and gene therapies provide an opportunity to potentially cure rare and chronic diseases that have lifelong debilitating effects for patients and families – I don’t think this can be said often enough! The pace of innovation is remarkable, particularly in areas like haemophilia. There are over 20,000 patients with this disease in the US and around 400,000 globally and it’s not inconceivable that we might be looking at a cure in the not-to-distant future. This opportunity alone is exciting enough, but there are many other indications that could be cured with cell and gene therapies. And I’m enormously proud and excited to be a part of this community.

Getting Everyone on Board

By Kelly Page

My dad is a cancer survivor. Twenty years ago, there weren’t many treatment options and it was also very difficult to find the information we needed. Today, patient advocacy groups do a great job filling that void and are becoming increasingly important in helping patients find what they need at the beginning of their journey. For cell therapies, there’s opportunity for this to continue through their treatment and recovery. These therapies are complex. It can be difficult to find out which treatments are relevant, where the treatment centers are located, and how to access them. In short, they have key roles in ensuring that patients are aware of – and can access – these therapies.

Patient advocacy groups also have a prominent part to play in ensuring cell therapies are developed with the needs of patients in mind. These groups are increasingly involved in clinical trial design – especially in helping to choose the endpoints that matter most to patients. A few years ago, we ran a study to compare the thoughts of Hodgkin lymphoma patients and physicians when it comes to therapeutic value. We found that patients and physicians had different criteria when selecting therapies. For example, a physician might have said that efficacy is what drives them to pick a particular treatment, whereas patients were more concerned with quality of life.

Similarly, we often find that regulators prefer a particular criterion of value (and with different endpoints) to a payer. It’s crucial that we initiate conversations between the various cell therapy stakeholders to ensure that we meet the needs of patients and run the best studies we can. We all want patients to get better and find treatments that work, but are we all defining “better” in the same way? Different payers may have different definitions of value, which may differ from what patient advocacy groups prioritize, which might not align with what the regulators are saying. 

Balancing all of these views when trying to determine what clinical study to run can be difficult, which is why getting together to discuss the best way forward is so important. 

“I remember when the first antibodies were under development and how complicated it was to manufacture them.”

Which programs at your company are you most excited about?

Page: In 2015, Takeda made the decision to focus on partnerships with a number of world class scientists, including with MD Anderson and Memorial Sloan Kettering; it is the MD Anderson partnership that brought about our lead candidate, a CD-19 directed CAR NK therapy. Natural killer cells are designed to kill and destroy cells that are foreign to the body, so harnessing innate immunity to fight cancer makes a great deal of sense – and that’s the line of development we’re taking with MD Anderson. Put simply, we took the collaborative approach to stay ahead of the curve – the rate of innovation in the field is rapid and we believe partnerships help open the doors to innovation that patients are waiting for. We also believe that academics at research hospitals maintain a real patient-focused perspective, which is crucial for the success of such therapies. It’s great to combine external innovation with our internal scientific experts and our ability to take a therapy through the approval and commercialization processes.

Macrae: In addition to our work in gene therapy delivery across the blood–brain barrier (which I’ve already touched on), I’m really excited about our work in Tregs. After our deal with Gilead, which took us into T cells and NK cells for oncology, it was obvious to us that Tregs (the cells that coordinate the immune response and regulate inflammation) were going to be next. The main advantage is that they localize to a certain antigen – but the antigen doesn’t have to be causative. For example, you could use a myelin binding protein to localize the Tregs to the myelin sheath to treat MS, without that particular antigen needing to be involved in the disease. Tregs are editable and we hope to soon be able to grow them up into allogeneic cells – even from iPSCs. There’s an emerging body of research accumulating to support their effectiveness and their ability to target areas of the body that could take us beyond the ultra-rare diseases. And that, I feel, is the next stage in cell and gene therapy. We’ve done a lot of preclinical work in this area and we’re hopeful of treating the first patient early next year.

Meek: Our lead program at FerGene is nadofaragene firadenovec – an investigational gene therapy for the treatment of high-grade, Bacillus Calmette-Guérin (BCG) unresponsive non-muscle invasive bladder cancer. This early form of bladder cancer presents in the superficial tissue of the bladder and has not yet spread to other parts of the body. In the US, there are approximately 81,000 cases of bladder cancer every year and 20 percent of those present as non-muscle invasive. BCG is the current recommended treatment, but in 30–50 percent of cases, high-grade disease reoccurs. In other words, there is an unmet need in a significant proportion of patients. Notably, patients that don’t respond to BCG are usually recommended for cystectomy (the removal of the bladder) – clearly, a life-changing procedure.

Nadofaragene firadenovec is an adenovirus containing the gene interferon alfa-2b, administered by catheter into the bladder every three months. The vector enters the cells of the bladder wall, where it breaks down and releases the active gene, which then causes the cells to secrete high quantities of interferon alfa-2b protein – a naturally occurring protein the body uses to fight cancer. The therapy essentially turns the patient’s own bladder wall cells into interferon microfactories, enhancing the body's natural defenses against the cancer. The Phase III study met its primary endpoint and we’re hoping for an FDA approval in the near future.

Understanding Consent

By Sandy Macrae

I am a physician and I’ve also worked in large pharma companies as the chair of the safety board, which helps decide whether a medicine is safe to be released into the population. And so understanding the benefit-to-risk ratio and how you transmit that information to the patient has been part of my life for some time. For example, imagine we were considering the release of tablets for diabetes; we knew that, if a patient had a bad reaction, they could stop taking the medication and would likely feel fine the next day. In contrast, genomic medicines potentially remain a part of the patient’s body for the rest of their days. And that means you need to think about the benefits and risks differently. I’ve come to realize that this is a conversation that isn’t happening enough.

I think it’s clear many people struggle with rationally evaluating benefit vs. risk – we see this with debates around masks and vaccines. In the case of a dying child with no alternative, it’s obvious that the benefit of a relatively safe and effective therapy far outweighs the risks. But when we’re talking about a patient with several alternatives, the answer is less clear. When a patient consents to a gene therapy, they are consenting for life (or a parent is consenting for the entirety of their child’s life).

The good news is that gene therapies appear to be remarkably safe. The biggest risk is usually at the moment of infusion (some patients can have a reaction to the virus) and inflammation or hepatitis of the liver (which can be treated with steroids). The vast majority of these therapies have had few adverse events. But we can’t be totally certain about the safety of gene therapies in the (distant) future. And that’s why it’s important that we follow patients over the course of their lives. And if something does happen to a patient many years down the line, we must be prepared by asking ourselves: what benefit did the patient receive over their lifetime? Were they properly informed of the potential (or unknown) risks of the therapy?

The FDA requires that we follow up with patients for up to 15 years. Is that enough? I personally think we should be following up with patients for their entire lives in some way. It won’t be easy, but we need to think about giving the patient a lasting form of certification that includes, for example: what treatment they had, when they had it, perhaps details of the DNA sequence that was changed, and contact details of the developers.

Another element of patient consent, as Kelly discussed, is involving patients in the development of these therapies. Fortunately, the voice of the patient has become increasingly heard by developers – especially in the cell and gene therapy industry. We understand their disease, but we also need to understand our responsibility to them as people – and that means taking the time to improve consent processes and better explain risk management. An analogy: before you buy a house, how much time do you spend thinking about it – and then filling out forms? Consenting to a gene therapy needs to be in the same bracket as these rare and big decisions – perhaps even in its own bracket; it truly could be once in a lifetime. We should be engaging with patient advocacy groups on how to get the right messages across to patients.

We’re a field that’s driven by the excitement of venture capital and groundbreaking science. And when you’re at the cutting edge, it’s like driving a car while simultaneously building the road in front… The key is to have essential conversations now to ensure we end up at the right destination. 

Do you think the cell and gene therapy field will follow the same trajectory as the monoclonal antibody field?

Macrae: I remember when the first antibodies were under development and how complicated it was to manufacture them. We’ve just begun to describe how to make cell therapies and therefore it’s going to take some years to perfect the processes. But there are now lots of people who used to work in monoclonals entering the cell and gene therapy industry (because that’s where the jobs are); and they talk about how monoclonals went from having many different specifications to a few specifications, and the important role that development played in the efficiency of manufacturing. We still have many specifications in cell therapy and we don’t quite know which ones are critical for efficiency. In short, I see many parallels with the monoclonal antibody field and I believe we are on an analogous journey.

“It’s certainly been an interesting year. But I would say that the pharma sector, and cell and gene therapy companies in particular, have been incredibly resilient.”

And finally, the question that we cannot avoid: How has the cell and gene therapy field coped with the challenges of COVID-19?

Page: Rather than “coped,” I’d say “pivoted,” as we’ve certainly had to pivot away from what we usually do to help our patients. We’ve seen a significant increase in digital and telemedicine approaches across the industry. Companies have also explored ways of treating patients at home – an especially complicated task for our industry given the nature of our therapies and the sometimes very ill patients we treat. There’s also been a push to make sure patients understand the importance of continuing with screening and treatments, which we’ve seen decrease due to COVID-19. Separately, we’ve been able to pivot through the opening of a new manufacturing facility in Boston to ensure we can continue providing treatments to our patients in ongoing and upcoming clinical studies. 

Macrae: If you’d have asked me eight months ago whether I could run a virtual business, I would have probably said, “No!” And yet our labs have stayed open throughout, with non-lab staff working effectively from bedrooms and kitchens – often taking care of children at the same time. As for the lab, anyone entering must have had a negative test within the last week, and we also arranged shifts – along with social distancing – to reduce person-to-person contact.

We’re lucky that, in California, our business has been considered a critical part of the healthcare system, so we were able to stay open. That being said, hospitals were understandably focused on treating COVID-19 patients during the pandemic, so it has been difficult to get new trials off the ground. One trial in Fabry disease was delayed by five months, for example. And I think this is a trend throughout the industry; existing trials, for the most part, have continued, but getting new trials underway has been difficult.

We’ve also seen a trend towards decentralized trials – even in the cell and gene therapy space. As an example, we worked out ways to send nurses out to patients in their homes to collect blood samples – saving them a trip to the hospital. Overall, I think the industry has done remarkably well given the circumstances. Necessity has indeed proved to be the mother of invention, and I can see some of these trends continuing post-COVID-19. However, I would like to get back to the office. Planned meetings are easy, but those chance occasions when you bump into someone at the coffee machine or in an elevator can’t happen virtually. And, in my experience, a great deal of progress and new ideas arise from those chance meetings and unplanned conversations.

Meek: It’s certainly been an interesting year. But I would say that the pharma sector, and cell and gene therapy companies in particular, have been incredibly resilient. Though operating norms and timelines have required adjustment, as in all industries, the innovation and patient focus – which is at the core of what we do – has not waned at all. If anything, COVID-19 has actually accelerated the focus on the patient, as we’ve found ways of keeping in touch and even treating patients within their own homes. The pandemic has also highlighted the real benefit of a once and done cure, as offered by many cell and gene therapies, given the risks to immunocompromised patients of having to regularly go into hospitals to receive treatment. And though we’ve had to adapt – especially in March, April and May, with hospitals and clinical trial sites closing – I would say we’re now back on track.

Kelly Page, Sandy Macrae and David Meek were all speakers at Reuters Cell and Gene Therapy USA 2020:

The Path to the Patient

By David Meek

The progress made in the gene therapy field over the past 20 years has been remarkable to watch, with a number of therapies steadily making their way through the FDA approval process to reach the patients that need them. Part of what makes gene therapies so transformative is their uniqueness – but that also brings new challenges. When Scott Gottleib was head of the FDA, he noted that, for small and large molecules, 80 percent of the FDA’s review was focused on clinical, with 20 percent on CMC and manufacturing. For cell and gene therapies, the weighting was reversed. I think that highlights the importance of focusing on manufacturing early to ensure launch and post-launch success. 

Scaling cell and gene therapy capacity is a clear and present challenge. Limited vector capacity is a real issue; with 39 new gene therapy approvals expected by 2022, companies must plan for potential capacity problems. The key to success is setting up a cross-functional team – characterized by open collaboration – early in the preclinical stage. Who should be in such a team? Well, medical affairs, patient advocacy, market research, operations planning, marketing, CMC, program management, policy, and patient access… Ensuring that these groups do not form silos is part of what you could call horizontal collaboration. But don’t forget that vertical collaboration is important too: your team leaders need to be speaking to their colleagues on the ground, who are working with customers day in, day out.

Listening to customers is something we take seriously – and we’ve been able to identify a number of issues that keep cropping up. For example, with treatment guidelines being relatively new, some healthcare professions have struggled to keep up with what the FDA is saying about first-line treatment unresponsiveness or understanding trial designs. We’ve also found that previous experience with high-cost “buy and bill” products has created skepticism of new treatments that require infrastructure and/or those that come with financial risk. Finally, differences in terms of patient care between regions, academic centers, and community-based practices has also been a challenge.

To address these problems, we’ve taken a number of approaches, including:

  • Analytics-driven segmentation of prescribers with early identification of early adopters.
  • Establishing a market development team to understand customer needs.
  • Sharing patient experiences and trial results with clinical stakeholders to demonstrate early impact.
  • Using real world evidence and education to address unmet needs and drive insight generation.
  • Segmenting payers to allow data-driven messages and evidence development for policies/guidelines.
  • Using prescriber and market insights to tailor payer-based responses and go-to market models.
  • Delivering a “white glove customer service experience” where you navigate the patient through the delivery of therapy, including support with the reimbursement process, if necessary.

My advice would be to begin these tactics two or three years before launch. And for complex diseases in particular, frequent and early engagement with payers is a must – we’ve found that payers are eager to learn more and to prepare for the introduction of new and innovative therapies. They want to understand the benefits of what your medicine offers, and that includes health economics and outcomes research, what it means for the patient, and the total value proposition. In the US, you might be speaking to different people, depending on the product – the government in the case of a Medicare patient or a private payer if not. But the fundamentals are the same for any payer, in any market – and the earlier you are able to have these conversations the better.

Companies are really charting their own paths and working out how best to commercialize these new and potentially revolutionary therapies. But we do now have the beginnings of a roadmap for ensuring the path to the patient is as smooth as possible.

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About the Author
James Strachan

Over the course of my Biomedical Sciences degree it dawned on me that my goal of becoming a scientist didn’t quite mesh with my lack of affinity for lab work. Thinking on my decision to pursue biology rather than English at age 15 – despite an aptitude for the latter – I realized that science writing was a way to combine what I loved with what I was good at.


From there I set out to gather as much freelancing experience as I could, spending 2 years developing scientific content for International Innovation, before completing an MSc in Science Communication. After gaining invaluable experience in supporting the communications efforts of CERN and IN-PART, I joined Texere – where I am focused on producing consistently engaging, cutting-edge and innovative content for our specialist audiences around the world.

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