Innovation Needs Infrastructure

Like many people in the CGT field, any opportunity we get to hear Dr Bruce Levine speak, we take it! At the recent Terrapinn meeting, Bruce gave an inspiring keynote address detailing the innovation that bubbles and erupts out of UPenn. What struck us was how crucial the infrastructure is to take this science and turn it into clinically relevant, patient-serving and life changing therapies.

Translation, tech transfer and scale-up are the three cornerstones of converting academic innovation into clinical applications and, ultimately, a commercially successful therapy. Pennsylvania has created the perfect conditions to support all three of these factors, and as Bruce said in his keynote, ‘it takes a village’. He describes the University of Pennsylvania Centre for Cellular Immunotherapies as a biotech embedded within academia.

“We have research labs, we have translational facilities for scale up manufacturing, quality control, and QA of the regulatory infrastructure that allows us to conduct first in human clinical trials [to generate data that is] attractive to licensing and partnership with industry.”

The University, tech transfer office, spin-off biotechs all contribute to building a world-class innovation cluster. A global network of these clusters that can further facilitate collaboration and innovation is key to getting science to patients.

There were many examples of innovative science during the presentations in London. Here’s are some that stood out to us:

1. Dr Ioaannis Papantoniou: automated organoid production at KU Leuven

Dr. Papantoniou gave us amazing detail into the approach to the fully automated organoid production research that’s going on at KU Leuven. This approach to organoid production moves away from large, contaminated structures towards microtissues that are developmentally engineered. The micro tissue model allows more efficient purification.

When microtissues are contained in multiwell plates, they require more media change processes, which Ioannis and his team have automated, combining a new, ‘mono well’ plate design with one outlet, one gas exchange etc and the media can be changed using a liquid exchange robotic system. Software is used to detect empty and full plates as a target for optimization.

All these highly purified microtissues are then built into one final product, but the next stage of the development process is how to maintain the fully built tissue until it is needed for transplant. Ideally, manufacturing will occur at the point of care, a more centralised operation may be possible in future with the right shipping technologies, but a system to maintain the fully built tissue is still required. Ioannis is developing a prototype that is fully controlled and can be operated on a bench – We will be following his progress with much interest!

2. Dr Ander Izeta: infrastructure and therapeutic innovation at BioDonstia University Hospital

Picking up Bruce Levine’s theme of infrastructure, we found Dr Izeta’s presentation very informative. He described a hospital-based infrastructure programme developed by the Spanish Ministry of Health. The Spanish strategy for advance therapies launched in 2018 and has three main objectives. First, to organize the use of CAR-T cell-based medicine products in a safe and efficient manner. Second and third it aims to promote public-based research and public manufacturing. This is a great idea in principle, but the challenge in achieving this is being able to do this from a public hospital setting. There are around 500 products a year in clinical trials in Spain, with most outsourced to CDMOs, so the government is aiming to bring this manufacturing to the hospital system.

Ander walked us through the strategy: the first thing that the Ministry of Health did was to set up a network of hospitals that are designated ‘reference centres, with 14 hospitals authorised in the first year, followed by 28 the next that are allowed to use the CAR-T cells drugs in their settings, including Biodonostia.

There are similar initiatives across the EU, it would be great to hear more about these at future meetings.

Ander is also leading an exciting organoid project similar to Ioannis, there is some real momentum happening in this space. Anders’ cartilage product, is based on a bioprinted PCL scaffold, seeded with chondrocytes under low oxygen conditions. A proof of concept has been established with rabbit peripheral chondrocytes grown on the culture system for 20-21 days, and then grafted to rabbits for another 12 weeks. He has documented evidence of cartilage-like differentiation and the project is progressing.

Simultaneously, the challenge of how to put bioprinted products into the surgery room is one Anders is also facing. The bioprinting setup is very difficult to introduce into a GMP facility, to combat this, his team has developed and patented a solution that will permit bioprinting in a box that is fully transportable from one place to the other. This technology will permit gas exchange, as such it can be put into an incubator for a few weeks if needed, and it can also be transported to, to the surgery room, so that the bioprinted tissues can be ready for the patients.

A patent was filed two years ago, and the product is very much still in development, but it is an exciting advancement we hope to hear more about in future.

3. Kikuo Yasui: next-generation iPSC purification at HeartSeed

Our third innovation pick comes from Kikuo Yasui, COO at HeartSeed, who shone a light on the purification advancements that are enabling next-generation iPSC-derived therapies to advance into the clinic. The company is recognized as one of the top players developing cardiovascular drugs with a pipeline focused on cardiomyocyte spheroids aka “microtissues of the heart”.

To improve the efficacy and safety of their therapies, HeartSeed is using the concept of metabolic selection for cell purification. The selective differentiation into ventricular cardiomyocytes, is essential for successful cardiovascular therapy, as it reduces the potential risks of arrythmia. Moreover, all potential remaining iPSCs must be removed as they have the risk for teratoma formation.

The metabolic selection process is based on a better understanding and use of the metabolic differences and energy sources differences between stem cells and differentiated cells. For cardiomyocytes, by changing the cell culture media in which the glucose is depleted but the lactate is added, the cell populations can be purified for the cell type of interest, as all other residual cells die. This is then translated into an increased engraftment of the cardiomyocyte spheroids. The scientific principles behind the metabolic selection process, mimic the natural events and tissue environment present during heart development.

 In terms of cell phenotype, the cardiomyocytes obtained through the metabolic selection process present a modular mature profile, which resembles more to stages of low cell maturation. This also improves the feasibility for cell therapy applications, as low mature phenotypes have several advantages for optimal cell transplantation and host tissue engraftment. Continued studies have shown a terminal cardiomyocyte maturation after engraftment, followed by the development of sarcomere structures.

 HeartSeed have initiated a phase one to study in Japan where 10 patients (5 low dose and 5 high dose) will be enrolled and selected on the basis of ischemic heart failure who will be indicated for microsurgery with epicardial cell injection.

Preliminary results show how one year after transplantation, you can see the muscle cells beating and the tissue with vessel formation, coming from the neovascularization. The end point showing the benefits of these phase I/II trials is the efficacy measured by the heart ejection fraction, which allows to determine the improvement on the damaged tissue function.

 Without a doubt, the company is seeding new iPSC based technologies and therapeutic approaches that are setting the bases of regenerative medicine, not only for cardiovascular diseases, but also for other tissues, as the metabolic selection process can be also applied to other cell types as neurons. We will follow up very closely the advancements of this smart and amazing technology.


There was so much more innovation on show in London, showing so much promise for the advanced therapies field and, most importantly, for patients with rare or incurable conditions.

Getting this science to patients is still a huge challenge, however, and while infrastructure and innovation clusters are beginning to ease some bottlenecks, the high costs of translation and materials still needs to be addressed if these therapies are to be commercially viable.

More importantly, we can see more and more how the field is arriving at an excellent equilibrium between robust and well-established therapies as CAR-Ts, together with more innovative approaches tackling a wide range of disease conditions such as heart failure, hearing loss, liver disfunction, urinary incontinency, or muscle injuries. Commonly, innovation comes from small groups that were fantastically represented at the Innovation zone of Terrapinn ATMPs. Despite the size of these companies compared to large biopharma corporations, the years of experience accumulated in the cell therapy and regenerative medicine fields behind the founders, board, and technical members is a key driver for translating their innovative technologies into therapies. However, for such successful translation, there must be accessible and consistent materials, together with standardized protocols and regulatory guidelines, that make the manufacturing process easy, instead of presenting additional challenges to the field.