Anti-CD20 failures
B-cell depletion with the anti-CD20 monoclonal antibody rituximab has been shown to be an effective therapeutic strategy for patients with rheumatoid arthritis and multiple sclerosis, but was ineffective in two separate clinical trials for SLE.
“Incomplete B-cell depletion of tissue-resident B cells, or the transient nature of the treatment, may have contributed to the failure of the initial rituximab trials to attain satisfactory outcomes,” Dr. Radic and coauthors wrote.
In patients with severe lupus, autoreactive B cells may lurk in lymphatic organs and/or inflamed tissues. Alternatively, CD20-negative plasma cells, which are unaffected by rituximab, could also be a source of SLE autoantibodies, Dr. Schett and coinvestigators said.
Case details
As noted before, the 20-year-old patient described by Dr. Schett and colleagues presented with World Health Organization class IIIA active lupus nephritis, indicating focal proliferative disease. In addition, she also had nephritic syndrome, pericarditis, pleurisy, rash, and arthritis, and had a history of Libman-Sacks endocarditis.
Her disease was refractory to treatment with all the usual suspects, including hydroxychloroquine, high-dose glucocorticoids, cyclophosphamide, mycophenolate mofetil, tacrolimus, rituximab, and belimumab, another B-cell targeted agent.
The T cell collection, transduction, expansion, and infusion were all successfully performed. By day 9 following infusion, CAR T cells comprised nearly one-third of her total circulating T cells, and then began to decrease, but remained detectable in circulation for the ensuing 7 weeks.
Levels of anti–double-stranded DNA decreased from above 5,000 U/mL to 4 U/mL within 5 weeks, and her complement levels (C3 and C4) normalized.
“These signs of serologic remission were paralleled by clinical remission with proteinuria decreasing from above 2,000 mg of protein per gram of creatinine to less than 250 mg of protein per gram of creatinine,” the investigators wrote.
The patient’s SLE Disease Activity Index score with SELENA (Safety of Estrogens in Lupus National Assessment) modification dropped from 16 at baseline to 0 at follow-up.
The patient did not experience any of the adverse events that are commonly seen in patients treated with CAR T therapy, such as the cytokine release syndrome, neurotoxic adverse events, or prolonged cytopenias.
Unanswered questions
Dr. Radic said that it was unclear from the brief case report whether Dr. Schett and colleagues considered including a “kill switch” in their CAR T construct, which could be activated in the case of serious toxicities.
In addition, their use of both CD4-positive T cells in addition to CD8-positive cells in their construct raises some concern, because in patients with SLE there is evidence that CD4-positive helper T cells can be autoreactive, he noted.
The work by Dr. Schett and colleagues was supported by grants from the German government, European Union, and the Innovative Medicines Initiative. Dr. Schett reported having no conflicts of interest to disclose. Dr. Radic is listed as inventor on a patent for anti-CD19 CAR T cells in lupus.