Accidental discovery of safety weaknesses in CAR-T therapy, where did the breakthrough point come from?

CAR-T is a revolutionary treatment for cancer.
principle, the therapy is genetically modified to ethloy "embedded antigens" (CAR) on T cells to identify antigen molecules on the surface of cancer cells, which in turn attacks cancer cells.
, CAR-T cells targeting CD19 molecules on the surface of B cells can effectively treat a variety of B-cell malignancies (e.g. acute lymphoblastic leukemia, lymphoma).
, however, this CAR-T therapy is not a one-of-a-kind drug.
the study authors note that some patients develop severe neurotoxicity after receiving CAR-T cell therapy, including fatal cerebral edema associated with T-cells invading the brain.
study, scientists found the underlying cause of the adverse reaction.
"Our work shows that in addition to B cells, there are some cells that express CD19.
neurotoxicity that we observed in patients receiving CAR-T therapy targeting CD19 is likely to be related.
," summed up Professor Avery Posey of the University of Pennsylvania.
CAR-T cells that target CD19, in addition to B cells, but also for other cell types? (Photo source: Resources) Interestingly, the discovery was quite accidental. Kevin Parker, a doctoral student at Stanford University and co-author of the study, noticed a strange thing when he looked at the previously published single-cell RNA sequencing dataset at home in his spare time: CD19 appeared in a group of fetal brain samples,
said.
the common understanding is that CD19 only exists in B cells.
young scientists didn't ignore the "abnormal" signal, and his lab contacted and collaborated with pioneers of CAR-T cell therapy at the University of Pennsylvania School of Medicine.
the single-cell map data and the staining experiments that bind protein levels, the researchers confirmed that CD19 expresses wall cells in the human brain.
these cells around blood vessels and are an important part of the blood-brain barrier.
complete blood-brain barrier prevents immune cells in the blood from "leaking" into nerve tissue.
wall cells are critical to the integrity of the blood-brain barrier (Photo: Source: Supplied) So what happens when CAR-T cells targeting CD-19 encounter these wall cells in the brain? Scientists are acutely aware that this may be related to the neurotoxicity of CAR-T cell therapy.
, they designed a group of animal experiments to verify.
when we treated mouse models with CAR-T cells that targeted the mouse version of CD19, we found what appeared to be neurotoxic phenomena," he said.
," the researchers said.
they found that when CAR-T cells targeted CD19 in mice, the blood-brain barrier became prone to "leakage."
In contrast, CAR-T cells targeted at human CD19 were injected into mice, and because cd19 was different in humans and mice, these CAR-T cells did not cause an increase in the permeability of the blood-brain barrier in mice.
, the team found that when CAR-T cells used different T-cells to stimulate the protein domain, the degree of leakage to the blood-brain barrier was different.
the severity of leakage of the blood-brain barrier was associated with the frequency of neurotoxicity associated with different CAR-T therapies observed clinically.
further suggests that the increase in neurotoxicity is caused by CAR-T cell therapy targeting CD19.
, Professor Posey says the neurotoxicity is usually temporary and patients can recover after timely treatment.
"The next question is whether we can find a better target than CD19 to eliminate B-cell-related malignancies, or whether we can build a new CAR-T cell that will make decisions based on the type of cells encountered, such as when B-cells kill them and CD19-positive brain cells," said Professor Posey.
" ability to identify cell types may be enhanced by distinguishing specific combinations of target antigens, the researchers note.
we look forward to the insights that this discovery will bring to the early realization of safer and more effective clinical treatments for the benefit of patients.
2020 Single-Cell Analytics Identify Brain Mural Cells Expressing CD19 as Potential Off-Tumor Targets for CAR-T Immunotherapies. Cell. DOI: .2) Penn researchers discover potential cause of immunotherapy-related neurotoxicity. Retrieved Sep. 22, 2020, from.