PHILADELPHIA — A new discovery might help explain the cause of neurotoxicity in patients undergoing CD19 directed CAR T cell immunotherapy.
A report in the journal Cell discussed how new research uncovered the previously unknown presence of CD19 — a B cell molecule targeted by chimeric antigen receptor (CAR) T cell immunotherapy to treat leukemia, lymphoma, and multiple myeloma — in brain cells that protect the blood brain barrier.1
“Our work has revealed that there is CD19 expression in a subset of cells that are, one, not B cells, and two, potentially related to the neurotoxicity we observe in patients treated with CAR T cell therapy targeting CD19,” explained Avery Posey, PhD, an assistant professor of Systems Pharmacology and Translational Therapeutics in the Perelman School of Medicine at the University of Pennsylvania and Research Health Science Specialist at the Corporal Michael J. Crescenz VAMC, both in Philadelphia. “The next question is, can we identify a better target for eliminating B cell related malignancies other than CD19, or can we engineer around this brain cell expression of CD19 and build a CAR T cell that makes decisions based on the type of cell it encounters—for instance, CAR T cells that kill the B cells they encounter, but spare the CD19 positive brain cells?”
Background information in the report noted that CD19-directed immunotherapies are clinically effective for treating B cell malignancies but also cause a high incidence of neurotoxicity. The result is that a subset of patients treated with chimeric antigen receptor (CAR) T cells or bispecific T cell engager (BiTE) antibodies display severe neurotoxicity, including fatal cerebral edema associated with T cell infiltration into the brain.
The authors reported that that mural cells, which surround the endothelium and are critical for blood-brain-barrier integrity, express CD19. They identified CD19 expression in brain mural cells using single-cell RNA sequencing data and confirmed perivascular staining at the protein level. CD19 expression in the brain begins early in development alongside the emergence of mural cell lineages and persists throughout adulthood across brain regions.
The study pointed out that mouse mural cells demonstrate lower levels of Cd19 expression, suggesting limitations in preclinical animal models of neurotoxicity.
“These data suggest an on-target mechanism for neurotoxicity in CD19-directed therapies and highlight the utility of human single-cell atlases for designing immunotherapies,” the authors concluded.
A discovery by a PhD student at Stanford University, study co-author Kevin Parker, put the research into motion. He found CD19 expression in a data set of fetal brain samples, even though CD19 was thought to only exist in B cells. His lab sought help in understanding the discovery from Penn Medicine researchers, who pioneered CAR T cell immunotherapy.
“I suggested we test this as a preclinical model. When we treated the mouse model with CAR T cells targeting the mouse version of CD19, we found what looks like the start of neurotoxicities,” Posey said.
The researchers said their discovery of CD19 molecules in the brain provides evidence that this increase in neurotoxicity is due to CD19-directed CAR T cell immunotherapies. Posey advised that neurotoxicity tends to be temporary and patients generally recover.
- Parker KR, Migliorini D, Perkey E, Yost KE, et. Single-Cell Analyses Identify Brain Mural Cells Expressing CD19 as Potential Off-Tumor Targets for CAR-T Immunotherapies. Cell. 2020 Oct 1;183(1):126-142.e17. doi: 10.1016/j.cell.2020.08.022. Epub 2020 Sep 21. PMID: 32961131.
