Human Studies
Dr. Jackson further shared how he and others in the field began to study B cell mechanisms in lupus nephritis through human studies. It was challenging to make this move because they were attempting to understand the role of B cells in lupus nephritis on a very mechanistic level. They began to make progress with a new technique, single cell resolution spatial transcriptomics, which allowed them to visualize specific RNA molecules in cells in kidney samples from controls and from children with lupus nephritis.10
“The spatial data seem to imply that there’s a role for an ongoing adaptive immune response in lupus nephritis, and, at least based on what we see, the activated B cells seem to be at the center of that,” shared Dr. Jackson. He noted that this data mirrored what they’d seen in animal models on the key role for B cells in orchestrating the immune response.
Circling back to the question of rituximab’s failure, Dr. Jackson discussed a case report of a refractory pediatric patient with lupus nephritis. On biopsy, Dr. Jackson and colleagues found that the patient’s kidneys were full of B cells and plasma cells post-rituximab treatment, even when her blood levels of B cells were undetectable. “That implied that one of the reasons why rituximab was not working was because it doesn’t deplete B cells very well in the secondary lymphoid organs, and in this case, the [kidney] as well,” he explained.
CAR T Cell Therapy
This finding is consistent with Dr. Schett et al.’s paradigm-shifting work with CAR T cell therapy. Instead of depleting B cells via a monoclonal antibody, an individual’s T cells are removed and then genetically modified to target the CD19 antigen (naturally occurring on B cells). After chemotherapy, infusion with the modified T cells has resulted in profound depletion of circulating B cells, with much greater reductions in B cells in lymphoid tissue compared with rituximab. This approach has yielded remarkable patient outcomes that have been sustained in some patients for many months, even after the B cells repopulate.3,4
Seattle Children Hospital is also pursuing the first U.S. CAR T cell trial for children with lupus in their ongoing REACT-01 trial (Reversing Autoimmunity through Cell Therapy). Initial results have been encouraging, Dr. Jackson noted. Their first patient, who has successfully come off immunosuppressive therapies, reports feeling remarkably better; her laboratory markers are much improved, although she may have sustained some degree of permanent kidney damage during her long and refractory disease course.
