CAR-T Meeting 2024 | Factors contributing to the pathogenesis of ICAHT

So, we’ve learned more about the factors that are associated with the pathogenesis of ICAHT in the last few years.

Broadly, I would separate these into sort of the role of the hematopoietic stem cell reserve of a patient. Each patient presents to CAR T-cell therapy with a unique history of genotoxic chemotherapy, also aging-related changes in some patients, and even clonal hematopoiesis changes, and these all contribute to the functional hematopoietic stem cell reserve in a patient.

The second factor relates to the local bone marrow reserve. We know that underlying extranodal manifestations of lymphoma in the bone marrow can predispose to transmigration of CAR T-cells to the bone marrow, and this can predispose to local inflammatory processes.

The third is the CRS-related changes in the inflammatory mediators, though it’s still sort of unclear if this is really induced by the CAR T-cells, or if the immune dysregulation is already present prior to infusing the CAR T-cells.

And then the last, which is sort of emerging, is the role of clonal expansion phenomena and what their role is in inducing and relating to the hematopoietic stem cell repertoire and T- and B-cell imbalances.

So that is broadly our current understanding of the pathogenesis of ICAHT.