ASH 2025 | Studying progression from CLL to Richter’s transformation in immunocompetent mouse models

This is a study that I have started back when I still was a post doc with Cathy Wu, and we’re trying to wrap the manuscript together soon. So essentially, we interrogated the tumor microenvironment of mouse models that I have built through CRISPR-Cas9-based gene editing that mimic disease evolution from CLL to Richter’s. And because these models are immunocompetent, we also interrogated the impact of immune checkpoint blockade with PD1.
So one of the main findings is that convergently, Richter’s transformation cases were characterized by abundant presence of cytotoxic exhausted T-cells, which are a subset of T-cells that retain effector properties, but also express exhaustion markers that can be somehow reverted and become effector and cytotoxic in the context of PD-1 blockade. These T-cells show killing capacity in vitro, we see that in mouse models. They do show polyfunctional features, that is expression of multiple cytokines, and we do see these features to be associated with their ability to respond to checkpoint blocking. The study was built on the models. We’re, of course, trying to validate it in human samples. We’re lucky enough to have collaborative efforts with colleagues that can provide us with clinical trial specimens. And so we hope to confirm that actually our findings in mouse models are valuable for human disease.

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