B-cell depletion works in a variety of rheumatologic diseases, but not always over the long term.
Current approaches such as anti-CD20 therapy have four key problems, explained R. John Looney, MD, Stephen and Elise Rosenfeld Distinguished Professor of Allergy and Clinical Immunology at the University of Rochester. Dr. Looney described the promise and the problems of B-cell therapy during the basic science session A 2020 Vision of B-Cell Depletion. Registered ACR Convergence 2020 attendees have on-demand online video access to watch a replay through Wednesday, March 11, 2021.
Anti-CD therapy has been approved for rheumatoid arthritis, ANCA-associated vasculitis, and multiple sclerosis and is being used off label in a wide variety of conditions, including autoimmune hemolytic anemia, lupus nephritis, neuromyelitis optica, and pemphigus vulgaris.
Current approaches have four problems, Dr. Looney said.
- Long-lived autoimmune plasma cells are persistent and can rebound within days or weeks of treatment.
- Treatment may not adequately deplete B cells in tissue.
- Residual populations of autoimmune memory B-cells and T helper cells can survive treatment.
- Current B-cell depletion agents cannot target pathogenic B cells while sparing regulatory and anti-inflammatory B-cell populations.
“The holy grail of B cell therapy has been to induce and maintain a long-term, robust, and highly specific autoimmune response,” Dr. Looney said. “The problems are many and so are the new approaches.”
CAR-T for Autoimmune Diseases
Chimeric antigen receptor T-cell therapy (CAR-T) is transforming cancer treatment. CAR-T targets long-lived cells that can cause disease rebound after more ephemeral cells are depleted.
“B cells may be the culprit in SLE, but rituximab trials failed,” said Marko Radic, PhD, associate professor of microbiology, immunology, and biochemistry, University of Tennessee Health Science Center. “So we took a different approach, cell-based immunotherapy. There was very consistent improvement in tissue pathology in treated mice with much worse disease in control mice.”
Dr. Radic’s lab developed a chimeric antigen receptor T cell to CD19, a pan-B cell surface marker that is expressed on early precursor B cells but is turned off in plasma cells. In a mouse model of systemic lupus erythematosus (SLE), mice treated with CAR-T showed improved renal function, almost no alopecia, and dramatic improvement in bloody skin lesions compared to sham-treated control mice.
CAR-T treated mice showed depletion of CD19+ B cells for over a year, Dr. Radic reported, and treatment was effective in animals that had developed progressive disease, including renal dysfunction. The clinical potential of CAR-T is clear, he said, but continuing patent and intellectual property issues may complicate funding for clinical development.
Proteasome Inhibitors
Immunosuppression targeting activated B cells can suppress autoimmune disease and flares, but long-lived memory plasma cells in bone marrow and inflamed tissue can escape treatment. One way to prolong disease remission is to deplete the long-lived plasma cells that trigger recurrence of disease.
“We know that bortezomib, a proteasome inhibitor, works over the long term in mice and in humans,” said Falk Hiepe, MD, Senior Professor of Rheumatology and Clinical Immunology, Charité – Universitätsmedizin Berlin and German Rheumatism Research Center. “A single cycle of treatment can have significant depletion of plasma B cells. The problem is toxicity.”
Bortezomib, like other proteasome inhibitors, can trigger severe allergic reactions, gastrointestinal upset, infection, myalgia, thrombocytopenia, neuropathy, and other adverse events leading to discontinuation. One potential solution is more selection inhibition.
The problem is depleting plasma cells that secrete pathogenic antibodies while sparing cells that contribute to humoral immunity. Preclinical data suggest that a conjugate combing ovalbumin and anti-CD138 antigen-specific plasma cell targeting could help.
“A single injection of the conjugate reduced precursor B cells by more than 70%,” Dr. Hiepe said. “Selective immunoproteasome inhibitors is a promising approach.”