Developments in the design of processes for cell therapy

Dr. Peter Zandstra, PhD, FRSC, founding director of the School of Biomedical Engineering and director of Michael Smith Laboratories at the University of British Columbia, talked to writer Tanuja Koppal, Ph.D. about the new developments in the design and manufacturing of processes for cell therapy.

He discussed the use of new technologies for engineering cells, monitoring key cellular attributes, and accelerating manufacturing are leading to better and safer cell therapy products.

Can you share your perspectives on Quality by Design (QbD) and the response to your work on this topic?

Quality by Design has been around for a while in other manufacturing sectors. However, in the cell therapy area we haven’t yet had, until recently, technologies that have allowed us to do design-based manufacturing and process development. At first, we didn’t have the right reagents and later we did not have the right bioreactors or sensors. A few things have now made this possible. We have more confidence that the cells that we are manufacturing have the required therapeutic effect. We are seeing that with CAR-T cells and others, which is very motivating.

We also have a better understanding of the types of signatures that we want these cells to have, and the link between those signatures and what is happening in vivo. The understanding is not complete yet, but it certainly allows us to do more defining in the design space. Lastly, we can now engineer cells using gene editing techniques like CRISPR/Cas9 and other technologies that not only increases the functionality but also the manufacturability of these cells. With these new technologies we can reduce costs, as well as increase the efficacy of cell therapy products.

What do you refer to as the top-down approach and how does it work?

In a top-down approach we decide the characteristics or critical quality attributes of the cell types we want to make and then find a way to design the system or design the cell to meet those attributes. Controlling the microenvironment around the cell very closely using niche engineering is one way to do that or there are other ways to design the cell.

Previously there was no motivation to do this, nor did we have the biological understanding to figure out what was needed. Now the integration of new technologies with new biological information has really opened a lot of opportunities for bioengineering. Some of the big device and manufacturing companies are getting interested in the opportunity to bring their products from other large-scale manufacturing processes into the manufacturing of living cell products. For instance, they are thinking about how controlled rate freezers can be integrated into the automated manufacturing process for living cell products.

You recommend the use of synthetic biology tools and in silico predictions as opposed to the classical analytical techniques for measuring and controlling cell state. Why?

We are all excited about the interface between computational biology, machine learning and simulations, and many fields are now starting to look at that. In biology we are dealing with complex systems and there are many factors that can affect the outcome of the cellular product. If we can use in silico biology and simulations to categorize and prioritize what factors control cell fate and what parameters are important then, we can accelerate the development of manufacturing solutions. It’s at an early stage but people are doing it. Unlike other types of biologics manufacturing, in the cell therapy the process affects the quality of the cells.

This understanding of the cellular phenotype and function and the parameters that control it is much more important in cell therapy. Hence, what we need are reporters or sentinel systems that allow us to accurately predict when and whether the cell function is appropriate or not. Currently people are using combinations of cell surface antigens, secreted cytokines or gene expression profiling that may or may not report cell function, rather than using better engineered reporter systems for monitoring cell state during the manufacturing processes. However, we are starting to use this new approach in pluripotent stem cells.

How have the regulatory agencies responded to these new developments in cell therapy?

Both our recent papers have been written with input and consultation with the regulatory agencies. In the 2016 Nat. Biotech paper, we had discussions with members of the cell products division of the National Institutes of Health (NIH), and in the 2017 paper we worked closely with people from Health Canada. The section on regulatory perspectives in the latter paper points out that regulators are rightly, primarily concerned with patient safety. If we can prove that the additional burden that we are putting on the cells, due to the engineering, actually improves safety (and efficacy), then they are very open to it.