Evidence continues to grow that KRAS, once considered an “undruggable” target, can be targeted successfully in non–small cell lung cancer. In a phase I trial, the KRASG12C inhibitor sotorasib elicited responses in about a third of patients with the disease and was generally well tolerated.
Non-B cells in the brain called mural cells unexpectedly express CD19—and thus may contribute to neurologic side effects associated with CD19-targeted chimeric antigen receptor (CAR) T-cell therapies—according to recently reported findings (Cell 2020;183:126–42). The research, which relied upon single-cell RNA-sequencing data, might also aid in the development of cell-based therapies that target other antigens.
CAR T-cell therapies targeting CD19 have dramatically improved survival for patients with hematologic malignancies, such as B-cell leukemia and lymphoma. However, up to 50% of patients develop neurologic side effects—ranging from headaches and confusion to cerebral edema and seizures. This neurotoxicity has previously been attributed to an inflammatory side effect called cytokine release syndrome, yet it remains poorly understood, prompting Kevin Parker, PhD, and Ansuman Satpathy, MD, PhD, of Stanford University in California, and their team to reexamine patterns of CD19 expression.
“Now that CAR T therapies have been shown to work, one problem that needs to be solved is understanding off-tumor antigen expression,” Satpathy explains. “We wanted to ask, ‘Are there cells in the human brain or elsewhere in the human body where we could find unexpected expression of CD19?’”
To this end, the researchers analyzed several large sets of single-cell RNA-sequencing data from human brain cells and performed immunohistochemistry with CD19 antibodies on human brain tissue. They established that CD19 is expressed on brain mural cells, which help maintain the integrity of the blood–brain barrier. They also found that these CD19-expressing cells are present from early development through adulthood and occur across multiple brain regions, although expression levels vary. Finally, they confirmed that the CD19 isoform expressed in the brain contains the epitope targeted by CD19 CAR T cells.
The CD19-expressing brain mural cells “fit the clinical effects you see in patients of blood–brain barrier leakiness and edema,” Satpathy says. However, whether CD19 expression in brain mural cells causes neurotoxicity remains unclear. “This provides another piece of the puzzle, and we're hoping that the field continues to investigate cytokine release syndrome–related adverse effects, and their interaction with CD19 mural cell expression,” he says. “Many studies need to happen in human patients to really see to what extent this does contribute to clinical neurotoxicity.” Follow-up research could also explore differential CD19 expression across brain mural cells, as well as how expression varies among individuals and how it changes with age.
“We don't really understand the big driver in causing neurotoxicity with these CD19 CAR T cells, and this paper provides a potential explanation for that—it's something that is really novel, and I think not a lot of people would have necessarily predicted it,” says Lawrence Fong, MD, of the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, who was not involved in the research. Fong agrees that more questions need to be answered to understand the causal link between CD19 expression in brain mural cells and neurotoxicity. For example: Do CAR T cells lodge near CD19-expressing brain mural cells? Do CAR T cells damage brain mural cells and lead to an inflammatory cascade?
Beyond CD19, the team's single-cell RNA analysis approach could improve the design and development of antigen-targeting cell therapies. “This paper shows that you can use these unbiased approaches to predict off-tumor toxicities for a particular target antigen,” Satpathy says, “and, on the flip side, maybe nominate better target antigens that have less off-tumor expression across the human body.” –Catherine Caruso
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