Cell: Car-T therapy is highly neurotoxic? The latest Cell reveals key breakthroughs!

CD19 targeted immunotherapy is clinically effective in treating B-cell malignancies such as leukemia, lymphoma and multiple myeloma, but compared to treatments targeting other B-cell proteins such as CD20, patients treated with CAR-T cells or biscommunicated T-cell convergence (BiTE) antibodies with a higher incidence of neurotoxicity may cause cerebral edema and death.
that CD19's accidental expression in non-B cells in the brain is a possible mechanism.
in a new study published September 21 in Cell, researchers from Stanford University School of Medicine and the Perelman School of Medicine at the University of Pennsylvania found expressions of CD19 in brain cells that protect the blood-brain barrier, which may be the cause of neurotoxicity in patients receiving CD19 targeted immunotherapy.
discovery stems from an accident. Dr. Kevin Parker, the first author of the
paper, analyzed previously published single-cell sequencing data sets and found the expression of CD19 in a "strange" fetal brain sample dataset, but cd19 has only been detected in B cells.
, the team set out to explore the mechanism behind the discovery.
first, the researchers analyzed single-cell RNA sequencing data from 2,364 human pre-cortogenic cells and identified CD19 expressions in wall cells that are critical to regulating the integrity of the blood-brain barrier.
further studies have observed CD19 expressions in human brain wall cells that span multiple data sets, brain regions, and developmental points in time.
important is that CD19 isomer expressed in the brain contains clinically targeted antigen espressos of CAR-T cells and Bite antibodies.
the expression of CAR-T-recognizable CD19 isomer (Source: Cell) in the brains of adults, the researchers analyzed whether CD19 expression in mouse wall cells was conservative.
showed that there were relatively few wall cells expressing CD19 in the mouse brain compared to the human brain.
Given the presence of non-B cell expression CD19 in mice, the researchers used immunodeficiency, tumor-free NSG mice (NSG mice that did not develop B cells) to detect whether CD19 CAR-T cells could lead to observable neurotoxicity.
results after 7 days of infusion of CAR-T cells showed an increase in the permeability of the blood-brain barrier in mice receiving CAR-T cells that targeted ROD19 instead of human CD19 (mice did not express human CD19).
suggests that neurotoxicity already exists in preclinical animal models, and that car-T cell studies originally conducted in mouse models did not predict the extent of neurotoxicity in human clinical trials.
the injection of CD19 CAR-T cells into mice (Source: Cell) In general, these findings provide a possible strategy for further research on wall cell targeting in human clinical trials and for the development of next-generation therapies with improved safety. Lead researcher Dr Avery Posey,
, said: "The next question is whether, in addition to CD19, we can identify a better target to remove B-cell-related malignancies, or whether we can engineer around cd19's brain cell expression mechanism to build a CAR-T cell that functions according to cell type."
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