Overcoming challenges in the safety and efficiency of cell manufacturing for the use of cell therapies in personalized medicine.
The potential of cell therapies hold great promise in the treatment of many diseases. From stem cell therapy for patients with diabetes,1 to mesenchymal cell therapy in stroke.2 However, there are still several prevailing issues and gaps before these therapies can be applied safely for broader patient use.
In an effort to boost research on cell therapies, the Singapore-MIT Alliance for Research and Technology (SMART) launched a new research group - Critical Analytics for Manufacturing Personalized-Medicine (CAMP). Focusing on development of innovative methodologies for cell manufacturing the research group aims to address challenges faced and bottlenecks in applying cell therapies in the treatment of medical conditions. SMART CAMP is part of Singapore’s National Cell Manufacturing Initiative led by SMART and Singapore’s Agency for Science, Technology and Research (A*STAR) with the support of Singapore’s National Research Foundation (NRF).
To learn more about the upcoming research efforts at SMART CAMP, our editor sat down with Professor Krystyn Van Vliet of the Massachusetts Institute of Technology, and the co – lead of SMART CAMP to understand how they will be contributing to bringing cell therapies to the masses.
1. Could you highlight to us some of the main goals and the motivation for SMART to invest in research related for manufacturing cells?
Cells are a very new kind of medicine, but in some ways, we have already been doing this for decades. For example, when people go for bone marrow transplant, that is a cell therapy. Because you are putting blood cells back into a person to regrow a new blood cell supply. We have been doing this for a long time for one particular cell type for one specific disease. But now the opportunities are really expanding for many different cell types to treat many different diseases. These diseases include cancer, knee repair, and even ageing of the brain. We see a lot of potential to have new kinds of medicine. But there are gaps in terms of quality control on that type of medicine to make sure it’s safe and effective. What CAMP is really about harnessing this potential and doing the quality control on the cells being safe and effective as well as being able to measure that in real time. Instead of making the medicine by a recipe, you're actually always measuring what you're making, so that you end up with a product for that person that will do the right job for that particular patient. Presently, the progress of biology and technology coupled with the clinical side of using cell therapies is the right moment to develop a team that can address those kinds of challenges. Singapore is a really great environment to bring together the people to work on these challenges.
2. Having mentioned about the environment in Singapore, what aspects of it do you find beneficial for having such a research facility here?
SMART is unique as it allows MIT and the researcher and hospitals and regulatory authorities in Singapore to work really closely together for a long period of time. This allows you to take risks in your research and it takes 15 minutes to sometimes travel from the research facility here to the hospital or to the Health Sciences Authority (HSA). The proximity and the ability to connect researchers form the U.S. with the researchers in Singapore makes it beneficial. On top of this, Singapore’s government is very interested in growing its medical technology and biotechnology workforce within is area of research. They have already seen benefits to working on problems like this in other kinds of biopharmaceuticals. For example, if you are going to do antibody production, they’ve worked on that for a long time in a collaborative fashion and seen success. They are able to see that as the way forward to doing that for cell therapy for the Asia Pacific region.
3. What specific methods will be employed in terms of critical analysis for manufacturing of cells?
First, we measure critical quality attributes, which is the industry term for the properties that the cells need to have for the cells to have the right quality to do their job. These critical quality attributes can include the types of proteins that the cell is secreting, or even the diameter of the cell, because there could be a one to one correlation between the size of the cell and what proteins its secreting. Any qualities that you can measure as fast as you can make the cells are the critical quality attributes. Certain methods that are used to measure are optics or microfluidics, or even the conductivity of the cell to infer the quality of the cell.
Second, is the analytics portion and how do we analyse the process in real time. As we grow thousands to millions of cells, we need to measure the characteristics like the size of the cells to check if the right cells are produced. From there we will be able to alter their nutrition intake to promote the properties and qualities desired of the cell.
Therefore, the two things we would need to employ is first the critical quality attributes, which are the properties we need the cells to have through our technologies. Secondly, is how to monitor and change the process to reinforce the properties that we want in a close loop feedback system. What we will be doing is drawing from our expertise in mechanics, optics, microfluidics, biology, and data analytics, as well as bioinformatics as it is not enough to just take the measurements, you have to develop a bioinformatics pipeline to connect the dots.
4. Would you say it’s more of a streamlining of the workflow in cell manufacturing?
Yes, it is definitely streamlining a workflow. However, many of the technologies that are required in the workflow do not exist right now. Those that are available operate on big volumes because they have been developed for antibody production. With cell production, you need to work on much smaller cell volumes.
Another challenge that we will face is the cost, some of the technologies that exist may work but at very high cost. As such, we are going to start doing this at production scale for patient medicine, we will also have to be cognizant of bringing down the cost.
5. Is there a main type of cell therapy technique that will be focused on or would it be in general for any type of cell therapy?
Ultimately it will be applicable to many different types of cell therapies and target diseases, but initially in the first year we are going to focus our efforts on mesenchymal stromal cells. So, these mesenchymal stromal cells from adults are used to treat diseases related to ageing, tissue regeneration, or even autoimmune disease. This presents one class of cell type and the range of indications which mesenchymal stromal cells might be useful or are already in clinical trials. Another cell type would be T-cells for indications like cancer.
The reason why we are going to focus those two broad classes of cells for the two classic groups of diseases, is because we are working within the Singapore ecosystem, with hospitals and other research teams are also focusing on those. But over time we will be working on for example, induced pluripotent stem cells as a source for even more diseases related to the central nervous system. They would be CRISPR edited. Also, it won’t just be utilising CAR T-cells but also edited and engineered cells with completely new approaches on measuring control and quality, which is very open for research now. In the future years we will be working on those more emerging technologies that are further for clinical trial.
6. In what ways in terms of manufacturing cells for cell therapy impact the developing field of personal medicine?
Ideally, if you could measure the quality of the product for every single patient, you will find out a lot more about the cells that are being used to generate the medicine, and it could be extracted from the patient who is already sick and has a lot of variability. The cells could also come from a family member or a cell bank. But you would now have the ability of generate the right medicine for that particular patient, in terms of dosage and characteristics and qualities that cell should have for that patient’s particular disease. That matching of the medicine to the disease and cell therapy we don’t really have that yet. However, it would be akin to picking the right aspirin for the right person’s dosage but much more powerful.
7. What challenges do you foresee in cell production during the research process?
One challenge is that the cell source is always going to be from a human, and human cells are quite variable even if they are from the same family. There is always this background of human biological variation in the starting material which will be a tough manufacturing problem that wouldn’t be present if you’re making for example, a biomedical device. Another challenge is that in order to compare data that has been gathered from many different companies or research teams, we have to make sure that we are recording metadata. Which means lots of detail about everything that influence the final cell product and having that data gathered in a way that can be transferred among researchers for better accessibility. As such this will be another challenge for our data pipelines and how we manage and share the information keeping in mind respecting patient privacy.
8. Besides manufacturing cells for personalised medicine, would there be a chance that SMART CAMP will be moving into research for gene therapy in the future.
I believe that this relates to the terminology, gene therapy used to mean trying to modify somebody’s genes by for example, introducing a vector to the patient and the vector would do the gene editing for you. Another example would be CAR T-cell therapy, some would refer to it as a cell therapy, while others call it a cell therapy because you are editing the genes of the cell. But at SMART CAMP we refer to that as a cell therapy. Even if you do genetic modification, the remedy is the cell, the genetically modified cell, we call that cell therapy. In fact, we are doing gene therapy and cell therapy at the same time at CAMP. Some of the cells we work with are not genetically modified, we just need to grow them up to large cell numbers. However, we are also including cells that are genetically engineered, because there’s more unknown about how to control the quality and how to define quality of the cell.
The world is still adapting to exactly what to call them, whether are they gene modified cell therapies, or are they gene therapies. In the U.S. we are adopting the term of advanced cell therapies or advanced medical products.
9. What are you most excited to see from the outcome of the research at SMART CAMP?
First, would be we are going to create some world changing technologies because we have such a great team that’s going to be able to work together for many years. We’re going to take some ideas that have never been applied to cell therapies before and develop and demonstrate them, making them available to companies that create them.
The second thing, which is probably more important in the long run, is the number of researchers and the interdisciplinary environment of these research teams we’re going to create so that companies out there will have much more diverse pipeline of scientists and researchers to hire. These would be the right people who understand cell therapy and cell manufacturing as well as the regulatory science. For the biotechnology industry, I believe is going to be increasingly important as with the demand for these technologies there should be a workforce and SMART CAMP will be able to contribute to the workforce development.
- Rahim, F., Arjmand, B., Shirbandi, K., Payab, M., & Larijani, B. (2018). Stem cell therapy for patients with diabetes: a systematic review and meta-analysis of metabolomics-based risks and benefits. Stem cell investigation, 5, 40. doi:10.21037/sci.2018.11.01
- Zheng, H., Zhang, B., Chhatbar, P. Y., Dong, Y., Alawieh, A., Lowe, F., … Feng, W. (2018). Mesenchymal Stem Cell Therapy in Stroke: A Systematic Review of Literature in Pre-Clinical and Clinical Research. Cell transplantation, 27(12), 1723–1730. doi:10.1177/0963689718806846
Krystyn J. Van Vliet, Ph.D.
Co-Lead PI, CAMP, SMART, MIT's Research Enterprise in Singapore
Associate Provost and Director of Manufacturing Innovation, MIT
Krystyn Van Vliet is the Co-Lead Principal Investigator of CAMP (Critical Analytics for Manufacturing Personalized-Medicine) at SMART, MIT's research enterprise in Singapore. Concurrently, she serves as the Associate Provost and Director of Manufacturing Innovation at MIT and is the Michael and Sonja Koerner Professor of Materials Science and Engineering and holds a dual appointment in the Department of Biological Engineering. Van Vliet earned her Sc.B. in Materials Science & Engineering from Brown University, and her Ph.D. in Materials Science and Engineering from MIT. Van Vliet also leads the MIT Laboratory for Material Chemomechanics, where her group has developed novel experiments and computational analyses to predict how the coupling between chemistry and mechanics at material interfaces can enable new material functions or failures.