New Innovations and Technology for T cell and Viral Vector Manufacturing

Podcast: Discover technological innovations addressing cell & gene therapy's most pressing needs

Transcript

Interviewer: BioPharm International

Interviewee: Xavier de Mollerat du Jeu, Director of Cell and Gene Therapy at Thermo Fisher Scientific

BioPharm:

What are the major issues in clinical T-cell manufacturing?

de Mollerat du Jeu:

Cell therapy has shown incredible promise, but the main issues are around manufacturing those cells, which are very different from classic therapeutics like antibodies or small molecules to manufacture. Because of the viability of the product and the volumes involved, there aren’t clear cell-therapy-specific equipment and products to make them. The available technology was essentially developed for large-scale antibodies, which can be problematic.

Another issue is that cell therapy is very labor intensive. There’s a lot of hands-on work, which can lead to errors and issues. When you’re dealing with patients’ cells, you must have zero-failure tolerance.

Last, development and QC testing is a long and expensive process. When a patient needs cells to treat dire conditions, they can’t afford to wait.

BioPharm:

How is Thermo Fisher Scientific addressing these issues?

de Mollerat du Jeu:

We’re looking at the cell therapy market as a workflow and identifying gaps or issues in different areas. For example, when isolating white blood cells from blood, many processes are done in open environments—meaning you’re using a centrifuge and have an open cap. All of that makes manufacturing more complicated. So, we’re developing much smaller instruments in closed systems. While it’s true that to produce commercial volumes, we do a lot of development on a large scale, but now we need to go to a smaller size and work in smaller volumes. We’re also looking at closed systems using bags, tubes, and welding that allow you to contain material across the process and avoid those open processes and labor.

Finally, we’re trying to automate the process so that you cannot make a mistake around cell counting or adding the right ratios. That brings speed and consistency to the process which, of course, reduces costs.

To assist with these processes, we recently developed the benchtop Gibco CTS Rotea Counterflow Centrifugation System, which can be used for many cell processing steps such as cell isolation and cell washing. It is completely closed and can be programmed and automated to reduce both contamination risks and user variability. The CTS Rotea system can deliver an output as small as 5 mL, which is a clinically relevant output size for cell therapy, especially autologous therapies when the starting volume might not be very high.

Cell therapy shouldn’t be the third line of defense against cancer. It should be the first line because it’s easy to manufacture, affordable, and can be used widely to treat cancer. That’s our goal.

BioPharm:

What are the major issues in viral vector manufacturing today?

de Mollerat du Jeu:

Viral vector manufacturing is all about scale—producing enough viral particles to address the needs. Most gene therapies are intended to address rare diseases. But once you move to a broader disease like hemophilia, many more viral particles are needed, which is challenging because there is currently not enough capacity across the globe to produce them.

Much effort is being devoted to increasing the square footage of available capacity. We’re investing in new buildings and capabilities to address these needs. Most importantly, we are investing in new technologies to develop novel cell lines and media that can support high growth and, therefore, make bioreactors more productive. If production can be improved by 10- to 20-fold, the yield will be much higher. By doing all this within the same square footage, many more viral particles can be produced.

We’re also working on new technology around manufacturing such as continuous-flow purification and new, faster QC methods. The goal is letting innovation drive production yields of these particles.

BioPharm:

What is your company working on to address these issues?

de Mollerat du Jeu:

We recently invested in growing our CMO capabilities with new buildings, new capacity, and entering new markets for viral production services. We’re also developing media that can sustain very high growth so that we can grow cells at a higher density. Again, a higher cell density per bioreactor means higher yields. But if you work with high-density cells, transfection can be an issue. Therefore, we’re developing a new set of reagents that allow high transfection efficiency and higher yields.

In addition, we’re developing new purification systems. When you make viral particles like lentivirus, for example, there’s a lot of loss during purification—you can lose as much as 50%. We want to make sure that by developing a system like resin, or specifically vinyl LV, along with the way you package and process things, you maximize lentivirus recovery without the loss.

All these efforts—increased square footage, new cell lines, and new purification systems—have the same goal: minimize loss, maximize results.

BioPharm:

What might be the future of cell therapy manufacturing?

de Mollerat du Jeu:

Right now, we’re using patient cells to develop personalized cell therapy, but we think the future will be using healthy cell donors for multiple doses for patients. It’s a more scalable approach than autologous therapy and we believe the results of the heterologous model will mature and improve in the future. We’re already thinking ahead to what we’ll need and what the volumes will be as this field develops. In the longer term future, we can leverage the capability of stem cells. iPS cells, for example, can be grown pretty much indefinitely. One day, developers might be able to use those cells to target a specific disease or dose. So as we’re developing the technology for today’s needs, we’re also preparing for how the same technology can be taken into tomorrow.

BioPharm:

What do you think will be the future of gene therapy?

de Mollerat du Jeu:

With the results we’ve seen so far, gene therapy really addresses the needs of rare diseases. Once gene therapy shows an ability to treat more common disease like hemophilia, it will be an incredible therapeutic modality. Addressing larger populations brings with it the need to produce as many viral assays as possible, and because there’s not enough capacity in the world to address those needs yet, innovation will have to drive this.

For example, many methods are transient, which can be costly and hard to scale. We believe stable cell lines (i.e., those that consistently produce viral vectors) are the way of the future. That’s what’s being done in the bioprocessing world for antibodies, and we think viral will follow the same path. Of course, it takes a lot of development and effort to develop the cell line, and that’s something we’re working on as well.