Manuel Carrondo on Innovation Trends on Cell and Gene Therapy

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Manuel Carrondo, Vice-President of iBET, shared expert insight on Cell and Gene Therapy in an interview to Cell & Gene Therapy Insights:

• Current cutting edge in cell and gene therapy
• Current and future innovation trends in the cell and gene therapy field
• Main priorities of iBET Research & Development

Full interview – Keys to remaining at the forefront of innovation in cell and gene therapy

Q1: Tell us about iBET and your role there

I founded iBET over 30 years ago, and for the last 7 years I have been Vice President in charge of business development. As we have been growing, I have been focusing on business and corporate development on behalf of the board of directors. I’m working to expand the network of partnerships and collaborations iBET has throughout the world, and enlarging our footprint in terms of collaborations with both large pharma companies and small start-ups. 

At iBET, we started working in gene therapy back in the 1990s when it was really nobody’s field yet. This has given us extensive experience with viral vectors as the field developed. Since the early 2000s we have also been working with stem cells growing into cell therapy and we have experience in creating 3D cell models – initially for toxicology and preclinical use, but these are now becoming more relevant for immunology studies in cell and gene therapy. We are in a very fortunate position as we have been around for a long time and have had the opportunity to work with a lot of players in the cell and gene therapy space.

Q2: In your view, where is the current cutting edge right now in cell and gene therapy?

Companies in this space are growing and so are the potential markets for cell therapy products, as the shift from autologous to allogeneic continues. A lot of the associated scaling-up of processes requires much improved technology. For example, improved tangential flow filtration, which is still relatively new in terms of application in this field. We are seeing additional chromatography steps now, too – it’s the same thing that we saw in the late ‘80s and early ‘90s with antibodies: people had to use chromatography techniques that had been developed for much smaller products than antibodies, which subsequently drove the development of dedicated downstream processing tools for the protein therapeutics field. Today, we are in the process of transferring some of those competencies and technologies to cell and gene therapy applications.

I do not think there are a lot of brand new approaches in cell and gene therapy right now. Instead, we are trying to adapt and improve all of these existing steps, not only to fit our current needs but in order to be able to operate under continuous manufacturing, and to finally integrate everything – the pumps, filters, chromatography, bioreactors, and so on. In a way, this is typical process development for engineers, continuous integrated processes, facilitating aseptic operation. We are also having to do this for newer modalities. The mesenchymal stem cells of the past still work, but we’re now seeing not just the CAR T cell therapies coming in, but also natural killer cells, tumor infiltrating lymphocytes, and more. These all require new tools. I wouldn’t yet call them platforms as they are not at that stage, but they are very much in demand. 

It’s a phenomenal time where you’re both developing new modalities and improving the tools at hand for the processes. For some of this development work, we are in collaboration with the tool providers and in some instances, we are creating or optimizing newer tools for the newcomers in the field. We’ve done this sort of work before with adenoviruses and then for adeno-associated virus (AAV). These aren’t ground-breaking changes; instead, we are just continually improving operations and deciding which direction to go next. 

Q3: How do you expect iBET’s activities to evolve in step with current and future innovation trends in the cell and gene therapy field?

I anticipate that eventually, viruses will slowly fall out of favor for use in CAR T-like applications. However, if you can lower the cost of the viruses for these current cell therapies to perhaps a tenth of what it is now, the advancement of non-viral options may become less attractive. And of course, as in any industry, once people are used to a given tool and a given system, change requires everybody to learn new tricks. Not just the scientists, not just the researchers, but also the people on the shop floor: the technicians and the analysts. You only want to replace things when the advantages are substantial. For this reason, one of the areas on which we have been betting is to work on producing viral vectors for CAR T applications more cheaply, better, and in much larger batches. I think there will be a fight for balance between viral and non-viral vectors in the coming decade. But oncolytic viruses will survive for much longer! 

You have got to look also at cell therapy for solid tumors. As mentioned earlier, this is where natural killer cells (NK)s, tumor infiltrating lymphocytes, and more new cell types will come in, and we’ll be looking at a whole new field. There may be some things that remain analogous, but the cells are different, so a lot of our approaches will need to be revisited. And as we have so many different potential cells, we expect to not only see new modalities but also combined modalities becoming more popular. This is something that’s already happening to some extent. 

A lot of clinical trials are no longer done with just a CAR T cell therapy or just a gene therapy – they are done with the addition of antibodies, cytokines, or nanopeptide particles, and so on. It’s like painting; the palette of colors is growing richer all the time, and the opportunities for personalized medicine are increasing in number and effectiveness. These areas will continue to grow for at least the next 10 years. And of course, in between, some of the applications will become more mature. There is still so much to explore – I don’t think we’ll be out of work in the next 10–20 years! It’s a phenomenal field to be in and I sense that there are a lot more opportunities and options to be found and a lot more tools to be developed.

Q4: What are the main priorities both for yourself and for iBET as a whole over the next 12–24 months?

One key area of focus for us at the moment is the immune aspects of AAV vectors. We need to understand better what the immune effects are from using these vectors in different organs. We have 3D cell models for some of these organs and we hope to partner with companies to combine their knowledge of immunological aspects with our 3D cell models, our viral production capacity, and our tools and analytics. 

At the same time, by understanding this better we are also exploring the immune aspects of the viral gene therapies that are essentially targeting cancer. Immunology is a new area for us and frankly, we’re not experts, but we believe we have skills and tools we can apply to this area. For example, artificial intelligence and machine learning can be applied to the large amounts of complex data being generated by our omics tools. 

If you’re a small team like us, you can only grow from your strengths. There’s no way that you can pay for entry into a new area where you need 10 million just to reach entry level. So that’s what we do: grow from knowledge, grow from strength. By being in that position, we get more partners to come on board. Our business model is to network and link to biopharmaceutical organizations in both Portugal and around the world, and in this way enlarge the footprint of Portuguese science. 

We are expanding from systems biotechnology to big data and artificial intelligence, which is required to work with the data being produced by the immunology field. It’s a slow process, but these areas are becoming more and more relevant. We hope to reinforce these critical skills now as we expect them to become even more important in the future. And hopefully, to enjoy ourselves along the way, as that’s how you keep your motivation to work hard and develop new scientific knowledge!