Please can you introduce yourself and tell us a little bit about your research and professional background?
I am a bioprocess engineer by training, and I have spent 13 years building devices and processes for cell and gene therapy across academia, industry and startups.
Image Credit: Nemes Laszlo/Shutterstock.com
You will be presenting a seminar at the 7th Annual Allogeneic Cell Therapies Summit later this year. Can you give us a sneak peek at what you’ll be discussing during your talk?
I will be talking about ImmuneBridge and how we have used our proprietary technology to develop a rapid, affordable, and impactful preclinical development process to evaluate drug candidates. This process directly reflects the clinical manufacturing process and can even use the same starting material. ImmuneBridge and our partners can save time, money, and patient lives using this approach. Our advantage is due to our proprietary HSC expansion molecule, IBR403, which enables us to generate large numbers of HSCs that are further expanded and differentiated into many kinds of immune cells. For this talk, I will be focusing on our HSC expansion and NK differentiation processes.
What are some key steps involved in turning stem cells into natural killer (NK) cells for medical use?
The first step is expanding the cord blood HSCS to generate a screening-scale HSC bank or a manufacturing-scale HSC bank. The frozen HSC vials can then be differentiated into NK cells in multiple runs, both for screening and for manufacturing. The HSC to NK differentiation is a two-part process where we first generate lymphoid progenitors and then mature the cells into NK cells. All these steps are done in well-mixed bioreactors, so the 10 ml bioreactor screening scale translates easily into the litre scale required to reach thousands of doses for commercial-scale manufacturing. In the screening process, after NK cells are differentiated, they are tested and filtered in multiple levels of in vitro and in vivo assays that yield the top 1-10% of indication-specific drug candidates. The CBUs of these candidates are then used for the clinical and commercial manufacturing scales, such that the same donor is used from preclinical to commercial stage.
Why is large-scale manufacturing important for cell-based therapies, and what are some common challenges in scaling up production?
Part of the importance of scale up relates to COGS reduction – larger batch sizes minimize the cost impact of labor, facility usage and the QC sample “tax.” Most of the challenges come from going to clinical trials with a process that is difficult to scale and will need a lot of changes after Phase I. The first challenge is to choose a cell source that can be scaled, i.e. it has the potential to expand and deliver the final quality, such as IBR403 expanded cord blood HSCS.
Another scale-up challenge is that even for scalable processes, there is a need to confirm that the equipment that is used in smaller scales (fit for Phase I trials) has a scaled version for commercial manufacturing. For instance, stirred tank scale-up has a low risk of not having a larger version for commercial scale. On the other side of the spectrum, static culture equipment does not scale volumetrically and requires additional surface area and scale out, which will hurt the manufacturing costs in the end.
At what stage in the development process should manufacturers finalize their production methods, and why is this decision important?
Manufacturers will finalize their production methods before commercialization through validation. What is important is not to finalize the process too early and leave room for changes that might be required as the product’s clinical data becomes available. It might be necessary to change the process to adjust the product quality to the new clinical data. The challenge with changes during the clinical stage of development is that they are hard to make, from the regulatory point of view. Now imagine doing these clinically relevant process changes while you are also figuring out how to make enough of your product – it is a very hard challenge. This is why any developer should have scalability and donor selection solved from the preclinical stage.
Why have we been seeing headwinds in the allogeneic cell therapies space for the past several years?
Allogeneic cell therapies have been affected by a pressure to reduce the price tag of cell therapies, while delivering the same quality as autologous cell therapies. But is it reasonable to expect the same persistence from an allogeneic CAR T therapy as from an autologous CAR-T therapy? Certainly not in all indications. I would expect allogeneic cell therapies to deliver the same effect as their autologous counterparts across multiple doses, which need a lower price point.
The scalability of allogeneic cell therapies holds the key to offering these affordable products to the masses, where we know that autologous cell therapy is unlikely to deliver. Scalability means equipment size, production capacity, and donor selection. In the allogeneic space, developers can select donors by avoiding “bad donors”, or they can select the best donors empirically. This is why ImmuneBridge addresses donor selection in scale-down bioreactors, together with other process parameters and cell engineering strategies. As more donor data is collected, an ML/AI supervised analysis of the data will make donor selection easier.
What are the most exciting advancements you’re seeing in the allogeneic cell therapies space that are turning the field around?
Cell engineering strategies have been advancing at a good pace. Besides the TRAC locus KO, there are several strategies that allogeneic companies have been developing, such as b2m KOs or HLA-E expression to cloak the cell product from the host immune system. On this note, I would like to see a better integration of allogeneic therapies with the host immune system. For instance, an NK cell product would kill enough tumor cells to trigger the host’s immune system via cytokine secretion and antigen presentation. In this way, we would move from a pharmacokinetic driven persistence (where cell products last longer in the body) to a pharmacodynamic driven persistence, where what lasts is the effect.
Where do you see the allogeneic cell therapy space in the next 5 years?
A more futuristic example of what the future might hold is the use of allogeneic NK cells to prevent cancer - by clearing transformed cells that the patient’s own immune system would otherwise let proliferate. One challenge with an approach like this is the definition of medical need, which might arise as molecular diagnostics and imaging technologies continues evolving to detect earlier stages of cancer. This is the type of scenario that requires improvements to cost and manufacturing scale but also other technological and regulatory innovations.
What are you looking forward to most at the 7th Annual Allogeneic Cell Therapies Summit?
Any good clinical news from any company would be perfect. I expect to hear a lot about manufacturing-aware preclinical development, new cell types such as gamma delta T-cells and innovative cell engineering that address cancer cell targeting and the host immune system interactions. I am particularly interested to hear new developments in NK cell manufacturing, given that this is our most advanced product.
What are the next steps for you and your research? Do you have any exciting projects coming up?
We have two defined goals that contribute to our mission of making affordable and accessible cell therapy cures: partner with other immune cell therapy developers and develop our internal pipeline. To enable these goals, we are exploring our competitive advantage of using our proprietary molecule, IBR403, for HSC expansion in a new perfusion process, and we are continuing our work to make higher yields of the most mature NK cells possible.
On the partnership angle, we are talking to potential partners that would either add a new cell engineering strategy to our cells and processes or anyone who wants to develop a more scalable version of their allogeneic HSC, T, gamma delta or NKT cell therapy, among others. We are really looking to offer scalable cell therapy manufacturing to the entire industry.
Where can readers find more information?
About Rui Tostoes
I have been at ImmuneBridge for nearly 3 years, most of these as VP of CMC, and I am currently Chief Technology Officer - overseeing our technical strategy and roadmap, as well as managing the technical team and program execution.
Before ImmuneBridge, I worked for 5 years on the design, testing, and validation of equipment, consumables, and reagents for cell therapy manufacturing at MilliporeSigma and FloDesign Sonics. Outside of the US, I worked as a scientist at CCRM (Toronto, CA) and did 5 years of postdoc work at University College London in the UK.
My doctoral program was in Bioengineering, and most of the work was done at IBET, Portugal, in collaboration with the chemical engineering department of MIT.
The focus of my career has been on making cell and gene therapy manufacturing simpler and more affordable, whether that is by inventing new equipment, assembling new processes or developing new cell therapy products, at ImmuneBridge. My main acquired taste is people development and mentoring – the only path to doing great work is with teamwork.