The long-term effects of CAR-T cell therapy with David Porter 

During this interview we discussed CAR-T cell therapy with David Porter, the Jodi Fisher Horowitz Professor in Leukemia Care Excellence, Director, Cell Therapy and Transplantation at the Abramson Cancer Center at the University of Pennsylvania (PA, USA), who – along with others – published the findings of a study focused on patients a decade on from treatment. He provides the motivation behind the study and explores how the findings will affect cancer treatment going forward. 

It’s fantastic to be discussing patients who remain in remission a decade after treatment with CAR-T cell therapy. What was the motivation behind the study? 

The original motivation was to develop a novel therapy for patients with B-cell malignancies such as leukemia and lymphoma with few – if any – treatment options left. Patients who have multiply relapsed and/or refractory diseases such as chronic lymphocytic leukemia, acute lymphoblastic leukemia and non-Hodgkin’s lymphoma tend to have a very poor prognosis with limited options. In an approach developed by Carl June – professor of immunotherapy at University of Pennsylvania – the concept was to remove a patient’s own immune cells, called T-cells, and then genetically modify them in the laboratory so they could recognize and kill leukemia and lymphoma cells by targeting a protein called CD19 on the surface of the cancer cells. Then, they were further grown in the laboratory, and infused back into the patient. 

There are now patients who remain in remission beyond 10 years after first receiving CAR-T cell therapy. The motivation for the recent study was to try and better understand what was working so well in the first two patients we treated, who had been in remission since 2010. We were able to collect T-cells from their blood 10 years after their first treatment, to understand their characteristics and activity. The hope is that if we understand what kind of cells survive and continue to function, we will better understand how this therapy works, and then will be able to design even better more effective therapies for future use.   

How was the study conducted? 

For the current study, our two longest responding patients had agreed to donate samples periodically over time including — most recently — 10 years after their treatment. Their T-cells were isolated and studied in the lab. We learned that the genetically modified CAR-T cells had survived in both patients, and we could determine that they still were functional, meaning they still had the ability to kill CD19 expressing tumor cells. We were able to study the characteristics of these cells and see how their properties changed over time. By identifying and characterizing these cells over time, the properties of effective CAR-T cells will be better understood. This can then aid the development of newer, more effective approaches. 

What is your reaction to the results? Did you expect CAR-T cells to be detectable this long after treatment? 

The clinical results, apparently eradicating far advanced extensive leukemia and lymphoma, at least in some patients, was tremendously exciting. We knew the cells could survive for long periods of time and continue to provide anti-cancer activity, but we did not know how long the cells could survive. Most of us did not expect that they would persist for over a decade and remain active and functional. 

What were the characteristics of the CAR-T cells that remained in the patients’ systems? 

The most important characteristic is that even 10 years later the cells could still recognize and kill tumor cells. In other words, they were not just present, they were still functional. 

Does this research give any information that will assist at the point of first treatment? 

This research helps us identify the properties of the T-cells when therapy is successful. If we can learn more about what makes a successful CAR-T cell treatment, we may be able to modify the cells at the point of first treatment to increase the chances of successful outcomes. 

Conversely, what does this research tell us about the longer-term effects of CAR-T therapy? 

There have been very few long-term side effects, despite the fact that T-cells survive up to a decade. However, this long-term persistence does result in one important long-term issue. CD19, which is the target of the CAR-T cells, is also on normal B-cells. As long as these CAR-T cells persist and are functional, patients may not be able to make normal B-cells, so may not be able to make normal antibodies. That could put them at higher risk of certain infections, and they may not respond normally to vaccines. This of course has been particularly important during the pandemic, and we have a number of strategies to try and make sure these patients are as safe as possible. 

What kinds of strategies can be used to keep these patients safe? 

For one, patients are advised more carefully about their risks, and clinicians can react to possible infections earlier and more aggressively than they might in other patients. In addition, patients who do not make normal antibodies are treated with intravenous immunoglobin preparations to provide some antibody immunity. 

Specifically for COVID-19, there are emerging therapies to treat exposed patients, and new antibody preparations, which are being used to prevent severe infection, specifically in patients who don’t respond well to vaccination.   

How will this research affect the use of CAR-T cell therapy for other cancers? 

These studies help us understand what makes a potent, functional and long-lasting CAR-T cell. As we learn more about the properties of a successful treatment, hopefully this approach can be applied to other types of cancers as well. There is a great deal of work being done to develop CAR-T cell therapy for many different kinds of cancers. Those studies are very early in development, but I am optimistic that the information we have gathered about successful CAR-T cells can be applied to make CAR-T cell therapies function more effectively in other situations as well. 

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.