Developing therapeutic regulatory T cells: an interview with Leonardo Ferreira
Leonardo Ferreira is an Assistant Professor of Microbiology and Immunology at the Medical University of South Carolina and the Hollings Cancer Center (SC, USA).
At Phacilitate’s Advanced Therapies Week 2023 (17-20 January 2023; Miami FL, USA), we spoke to Leonardo about his lab’s work developing regulatory T cell-based therapies and how he sees the immunotherapy landscape changing over the coming years.
How has the immunotherapy landscape evolved over the past 10 years?
It’s been really fascinating to see how the field has developed from when I first started my PhD in 2011. We used TALENs to edit the genome when I initially started, then a couple of years later, CRISPR-Cas9 came out. I was among the first people to use CRISPR-Cas9 in human T cells. The improvement in cell viability and efficiency of gene editing has been a game changer. One example can be seen with T cells. We’ve gotten really good at isolating, purifying and genome editing the cells. Before, we used to use plasmid DNA, then came viruses. And now, we can take the Cas9 protein and use a synthetic single guide RNA to deliver that directly to the T cells, which results in viral-free genome-edited human T cells that can be scaled up. Several companies are focusing on scaling up human T cells, and there are already six FDA-approved CAR-T therapies. The past 10 years has been an inflection point and I’m looking forward to the next 10 years.
Could you tell us more about your work on the design and development of therapeutics using engineered T cells?
My goal in science is to understand and control how the immune system defines self and non-self. For example, in autoimmune diseases, some tissues are easily attacked because they’ve been seen as non-self. I want them to be seen as self again. In cancer, you have altered malignant cells that are still being seen as self, even though they’ve become non-self.
One way that we’re going about this is to focus on regulatory T cells (Tregs). In summary, it’s a subset of T cells whose job is to regulate the immune system. You can use Tregs to re-educate someone’s immune system. Let’s say that you get an organ transplant. The organ is going to be from someone else so there’s going to be some incompatibilities, it will be recognized as non-self, but you can engineer Tregs to re-educate the recipient’s immune system to accept this new organ as if it were self. Unlike conventional T cells, Tregs can sometimes become unstable as their phenotype can change after prolonged growth in the lab. My lab’s main interest is finding ways to better obtain Tregs and modify them, whilst keeping their primary function.
You spoke about developing CAR-Tregs as a therapeutic for Type 1 diabetes. Are there any further diseases that you think this technology may be used to treat?
Type 1 diabetes has been a big focus of my research over the last few years. It’s an autoimmune disease that results in the loss of insulin-producing beta cells. So you could imagine that if you can re-educate the patient’s immune system to stop attacking the beta cells, the problem will go away. One way to do that is by engineering Tregs to create tolerance toward pancreatic islets – where beta cells are located.
There are many diseases out there that arise due to the loss of a specialized cell type. In many of those cases, the immune system is involved. So many processes in the body can go wrong due to dysfunctional immune regulation. I believe that with the right targets and the right quality of the cells, you can use Tregs for a broad range of diseases, including Alzheimer’s Disease and amyotrophic lateral sclerosis. I will end by saying, I think even aging itself can be helped with Tregs because aging is a slow accumulation of inflammation. Tregs fight inflammation and so if we could somehow target these cells to low-grade damaged tissues, I think it could help in that as well.
Get more content from Advanced Therapies Week 2023
Check out Leonardo Ferreira’s Advanced Therapies Week 2023 conference report, which was published in Volume 18 of Regenerative Medicine!
Find Leonardo’s highlights from the week and insights into some of the topics covered by speakers and panelists, including cell and gene therapy for autoimmune diseases, gene delivery technology, chimeric antigen receptor T-cell therapy in oncology and more.
How do you envision your work with regulatory T cells changing the landscape of cell and gene therapy?
I believe that our work with Tregs is going to help push the field forward because we’ve learned so much about conventional T cells and CAR-T cells for cancer that now we can expand the field to also include other diseases, such as autoimmune diseases and organ transplant rejection. I hope that my work and the work of others brings these cells into the limelight. It’s not going to be as easy, because Tregs are much rarer, accounting for only 1% of white blood cells. They also divide much less than conventional T cells do, and the targets are not always immediately obvious. So if you have a CAR-T cell for a tumor cell, you target the tumor cell that you want to kill. But if you want the Treg to protect a tissue from an ongoing immune attack, what do you target? Do you target the tissue itself? For example, you can have Tregs that target beta cells, you could target killer T cells, or you can target the antigen presenting cell. There are a couple of additional layers of complexity in using Tregs compared to conventional T cells and so my lab and others are addressing these issues by finding new and better targets and more efficient ways to obtain Tregs.
What has been your highlight from Advanced Therapies Week 2023?
I’ve been mesmerized by the latest developments that I’ve seen here at ATW. Whilst walking around, I saw that there are now so many closed-loop sterile circuits to grow cells. You have your leukopak — your blood product — and you can isolate cells and purify your cell subset of interest. Sometimes you can even have gene modification built in, you have an electroporator device inside the same closed machine and then your modified cells come out the other end. I think that these technologies are important because cell culture is so variable.
I’ve also attended some excellent talks, including one on how best to cryopreserve cells. If you think about it, the United States is a big country and not every town in the country has the facilities to have a cell therapy formulation and production center. If we get better at storing the cells and shipping them, that could make a big difference to cell and gene therapy.
Every year, at conferences such as ATW, you see new and improved technologies addressing important issues in the field. It gives me hope that over the next ten years we’ll see more approved therapies because in the end, it is for the patients’ benefit that we’re creating, testing, and having these therapies approved.
Disclaimer
The opinions expressed in this interview are those of the interviewee and do not necessarily reflect the views of RegMedNet or Future Science Group.
