Dr Michael Green Explains the Link Between Monocyte-Like Cells, Neurotoxicity After CAR T Therapy

Immune-associated neurotoxicity in patients following chimeric antigen receptor (CAR) T-cell therapy may be due to monocyte-like cells in infusion products, explained Michael R. Green, PhD, University of Texas MD Anderson Cancer Center.

The cells associated with neurotoxicity syndrome following chimeric antigen receptor (CAR) T-cell therapy were most like conventional monocytes, explained Michael R. Green, PhD, associate professor of lymphoma and myeloma and director, Translational and Laboratory Research, Department of Lymphoma/Myeloma, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, when discussing study results on the use of Yescarta (axicabtagene ciloleucel) for diffuse large B-cell lymphoma.


What did your studies show about predicting neurotoxicity and cytokine release syndrome following CAR T-cell therapy?

So I think we were underpowered to address cytokine release syndrome [CRS], and this is partially due to the fact that it can be effectively managed in the clinic now. So we did not have a large number of patients that had grade 3 or 4 CRS. We did find some signal there within the CD4 T-cell compartment, but it wasn't so significant.

Really, I think the most important results in terms of adverse events were found in relation to immune effector cell-associated neurotoxicity syndrome, otherwise known as ICANS. And there we took exactly the same approaches that we took to identify T-cell populations that are associated, as we did with looking at response, and we were surprised to see really no signal within the basic CD4/CD8 T-cell compartments. But what we did identify was a quite a small cluster of cells, only a few hundred cells amongst the over 100,000 that we profiled that were significantly associated and overrepresented amongst the infusion products of patients that had high-grade ICANS.

And when we looked further into the characteristics of those cells, they had a very surprising transcriptional signature that was very much like a monocyte. So when we took the signature genes from the cells that we coined “ICANS-associated cells” and compared it across normal cell subsets, they were most similar to conventional monocytes. However, they didn't have some of the traditional characteristics that we expect to see from monocytes—CD14, CD16 expression, for example—so we couldn't really nail down this specific cell type. So we referred to them as being monocyte-like cells within the infusion products that are associated with neurotoxicity.