‘Complete eradication’ of B cells drives remission after autoimmune CAR T-cell therapy
A “complete eradication” of B cells with chimeric antigen receptor T-cell therapy is responsible for the long-term, drug-free remission from autoimmune diseases observed after treatment, according to a speaker.
Georg Schett, MD, a pioneer of autoimmune CAR T-cell therapy at the Friedrich-Alexander University of Erlangen-Nuremberg, in Germany, outlined the treatment’s successes during a virtual talk hosted by Cleveland Clinic on Thursday, Feb. 27. He said his center has now used CD19-targeted CAR T-cell therapy to treat more than 40 patients with various autoimmune diseases, including systemic lupus erythematosus and systemic sclerosis, who have largely been able to maintain remission status without resuming their medications, over as many as 4 years.
“Why is this so effective, and why can we stop treatment? I think the reason for it is we have at one point in time completely eradicated the B cells in the bodies of these patients,” Schett said.
On a graph illustrating B cell counts over time after CAR T-cell therapy, the depletion appeared as a “deep, narrow valley,” dropping virtually to zero shortly after initiating therapy, according to Schett.
“At one point in time, you probably don’t have B cells in the body,” he said. “The only cell surviving that attack is actually the plasma cell, because the plasma cell has no CD19 on its surface, and therefore actually the CD19 CAR T cell cannot bind to the long-lived plasma cells in the bone marrow.”
This level of B-cell depletion is far superior to what can currently be achieved with current approaches, Schett said. He compared lymph node biopsy images demonstrating “complete eradication of the entire B-cell pool” after CAR T-cell therapy with those following rituximab (Rituxan, Genentech) use, in which B-cell follicles were “extremely maintained.” A type of T cell that helps B cells, the T-follicular helper cells, also disappeared with CAR T therapy, but were “perfectly fine” with rituximab, he added.
“The depth of this depletion is really amazing,” Schett said. “There is a lot going on — kind of a reset situation of the immune system.”
Later, as B cells repopulate after treatment, they show a fundamental shift, according to Schett.
“When the B cells come back, they are completely reset,” he said. “Almost all of them are naïve ... [and there are] very little memory B cells.”
There is also persistent reduction of DN2 cells, which are “intimately associated with lupus,” Schett said.
The process appears to leave vaccination antibodies relatively untouched.
“Classical vaccination antibodies, like measles, mumps, rubella, tetanus, pneumococcal and SARS-CoV-2, stay actually very stable after CAR T-cell therapy, suggesting that they are generated by the long-lived plasma cells in the bone marrow, which are CD19-negative and escape eradication by CAR T cells,” Schett said.
The advent of autoimmune CAR T-cell therapies in recent years is “a very exciting story,” he added.
“There are now more than 100 studies running,” Schett said. “I think we will hopefully see exciting news in the next years of how well this therapy works and how safe it is.”
Collapse
Schett G. CAR T-Cells in autoimmune diseases. Presented at: Basic and Clinical Immunology for the Busy Clinician: Special Series on CAR-T Cell and Advanced Immunotherapies for Autoimmune Diseases; Feb. 27, 2025.