ASH 2025 | A novel cell model of pirtobrutinib-tolerant persister cells in mantle cell lymphoma

Perhaps the most exciting abstract that I presented was from my lab. I have four presentations, three are regarding novel agents in clinical trials, but this is a phenomenon cell model that we discovered. So, and as you know that I had the fortune of leading the pirtobrutinib FDA approval two or three years ago, and in anticipation of this emerging resistance, I wanted to, in my lab, we wanted to make a cell line that’s resistant to pirtobrutinib so that we can study the mechanisms, whether it’s mutations or biopathways, upregulation, so that the cells become resistant to pirtobrutinib. Therefore, we culture the cell lines in the culture, and we put the concentration of pirtobrutinib. Instead of seeing the cells gradually die off, those cells have become larger and larger, like four or five, even 10 times larger than the cells. They do not die. They become larger. We call the giant cells. The giant cells, once they become giant cells, no matter how high a concentration of pirtobrutinib you use, they are not responding. So it’s pirtobrutinib resistant. And then if you take the drug off, two weeks later, the giant cells become regular cells again, and the size and morphology, and it starts to respond to pirtobrutinib again. So this is very, very exciting, right? We also tested in organoid models that not only pirtobrutinib can cause this. Other BTK inhibitors, ibrutinib and acalabrutinib can also cause the thing. So we said, well, if it’s BTK inhibitor can cause, what about the other agents? We use a monoclonal antibody called [inaudible], it’s a monoclonal antibody against a surface antigen. So this antibody can also induce the giant cells. So we dig in the literature. We finally found that actually there’s a description in 2010 in a very famous journal called Cell by Sharma et al. They proposed this model in cancer therapy, 2010, but not very much happened after that. So then the cells, giant cells, the reversible giant cells are called DTP cells, drug-tolerant persisters. So this drug are famous, although no breakthroughs happen, but many want to recapitulate the DTP cells in their system. So there’s a review about all these progresses. And the concept is the cells are around having randomly there’s a great heterogeneity there’s…depends on very much on the metabolism and they have stem cell properties. So our giant cell is a reversible cell model actually fit in exactly like the DTP cells, in morphology, cell cycle, and proliferated features and all that. So we call our giant cells now DTP cells. So DTP cells have never been described in mantle cell lymphoma. This is the first time ever. And we’ve discovered those cells can be reversible. And that could be the generation you put drug on giant DTP cells, drug off normal cells. This can be repeated for many generations. So the actual clinical tumor we have in patients are a mixture of the cells in different phases of their DTP cycle. And so the tumor are very heterogeneous. They do not respond to their therapy. And we also found our DTP cells have stem cell properties. The RNA biosensors increased, mitochondria increased. We find that the TCA cycle, you know, in all our biochemistry, we all have to pass the examination. Every examination of biochemistry has something on the TCA cycle, also called the tricarboxylate cycle or Krebs cycle. So, and we found that the alternative pathway of this mitochondria, the Krebs cycle explained this very fitting into the mechanisms. So we think really that it is the acetylcholine that controls the fate of the cells, whether they are large or they’re small and drug resistant and so forth. And it is an elegant study. It published in the very recent Blood, journal of blood, you know, a very famous time. We all read Blood in hematology. And one of the figures that stayed positive for the ribonucleogenesis is a beautiful grain victor. And it becomes the current Blood cover.

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