Abstract Presenter: Daniel Brown, PhD, graduate student in the Pharmacology Graduate Group at the University of Pennsylvania

Abstract Title: Cytokine-Mediated Expansion of Clonal Hematopoiesis after CART Cell Therapy

Session: Late Breaking Abstracts, 3:15 – 4:10 p.m. on Feb. 15, Ballroom B

Presentation Time: 3:51 – 4:09 p.m.

What is your presentation/abstract about?

“We’re focused on the effects of cytokines produced by CAR T-cell therapy and how that can lead to the expansion of certain hematopoietic stem cell clones, specifically ones that harbor mutations that can then lead to secondary malignancies.

“After the CAR T-cell therapy is administered for one cancer, some patients can actually develop a secondary cancer, and that may be caused by these individual clones. Our hypothesis is that the inflammatory environment produced by the CAR T cells facilitates and promotes this expansion.”

How did you first become interested in this topic?

“I’m a grad student at the University of Pennsylvania, and my project has involved looking at clonal hematopoiesis in general and clonal hematopoiesis of indeterminate potential (CHIP) specifically. This is a condition that has been characterized for a little over a decade, so it’s relatively new. It’s associated with the development of hematologic malignancies, but the mechanisms of how that happens aren’t clear.

“My background has been trying to develop humanized mouse models and engineering stem cells to express certain mutations to try to assess mechanisms. In the past couple years, there has been clinical evidence of patients developing secondary cancers after CAR T-cell therapy, and that these cancers seem to have these mutations we’ve been looking at, DNMT3A2, for example. We became interested in this specific topic since it was a natural progression from what we had been doing from a more basic science standpoint. It seems to be a more clinically relevant application and can potentially help us understand what’s happening with these patients down the line. We didn’t initially set out to look at this, but this has been a natural progression of what we’ve been doing.”

What are you working on next related to this topic?

“This is a pretty new direction for us, establishing that the cytokines from CAR T cells can actually lead to clonal expansion. The next big thing is to figure out what the specific mechanisms are, which specific cytokines are predominantly responsible. We think it’s interferon-mediated, but we need to figure out what the actual mechanism is and whether there can be some sort of therapeutic intervention.”

How do you hope your work influences the field?

“We hope that by delineating the mechanisms that this can be informative for identifying patients who are at greater risk of developing secondary malignancies.”

What excites you most about transplantation and cellular and gene therapy today?

“I’m excited about our work and what it means for CAR T-cell therapy in general. With my gene editing background, I’m also excited about seeing gene-editing therapies translated into the clinic and the development of curative therapies that are gene editing-based, such as for sickle cell beta thalassemia. I’m primarily excited about those because during the course of my graduate school experience, I’ve seen those therapies develop from the lab into the clinic.”

Is there anything else you would like Tandem Meetings attendees to know about your abstract?

“This is pretty preliminary work. We have some conclusive results, and we’re very excited about that, but there is still a good amount of follow-up work that needs to be done, like figuring out the specific mechanisms and investigating additional mutations beyond the ones that we’ve looked at. Within the next couple of months, we hope to have some exciting data to build out the  story a little bit more.”