ACR Convergence 2020—Because B cells play many roles in autoimmune diseases, rheumatologists have long explored B cell depletion as a reasonable strategy for the treatment of autoimmune diseases. The problem with the currently available strategies for B cell depletion, however, is that they are only partially effective, perhaps because they leave behind persistent autoimmune long-lived plasma cells.
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In healthy individuals, when inflammation resolves, these plasma cells regress, diminish in number and survive in niches in previously inflamed tissue where they are immobile. Some rheumatologists wonder if these cells may be one potential source of pathogenic autoantibodies that can contribute to humoral immunity in refractory autoimmune diseases.1
On Sunday afternoon at last fall’s conference, experts convened to discuss the future of B cell depletion given the controversy about whether pathogenic autoantibodies are produced by these cells or, alternatively, by plasmablasts and short-lived plasma cells.
B Cell Biology
Richard John Looney, MD, a professor of medicine at University of Rochester in New York, set the stage by reviewing B cell biology and identifying the problems with current B cell depleting therapies that have difficulties reaching these long-lived plasma cells.
Rheumatologists often think of B cells, explained Dr. Looney, as production factories for antibodies. But B cells have many other functions, including antigen presentation to T cells, secretion of cytokines and organization of tissue inflammation.
Antibodies, including autoantibodies in lupus, can be made by short-lived or long-lived plasma cells. Currently approved B cell depletion therapies all target CD20, a marker on naive and memory B cells, that is not on long-lived plasma cells. Not surprisingly, these therapies affect B cell functions such as antigen presentation, cytokine production and organization of tissue inflammation, and they have the potential to eliminate autoantibodies made by short-lived plasma cells that are continually derived from B cells. Unfortunately, they do not affect long-lived plasma cells.
Consequences of Depletion
Marko Radic, PhD, an associate professor of microbiology, immunology and biochemistry, University of Tennessee Health Science Center, Memphis, then spoke about the consequences of this incomplete depletion of memory B cells and short-lived plasma cells. He also described CD19-specific chimeric antigen receptor (CAR) based T cell therapy, an antibody-based immunotherapy primarily used for the treatment of B cell lineage malignancies, and its remarkable ability to deplete all CD19+ cells, including naive and memory B cells as well as short-lived plasma cells.
Although CD19 therapy eliminates many antibodies, there are certain antibodies it does not eliminate, perhaps because those antibodies are produced by long-lived plasma cells known to be CD19 negative.
Dr. Radic explained that even when patients responding to anti-CD19 therapy experience highly effective B cell depletion in secondary lymphoid organs, they continue to have persistent long-lived plasma cells and humoral immunity.2 These findings have raised awareness that therapies designed to eradicate pathogenic humoral immunity will likely need to address the CD19-negative, long-lived plasma cells.
Dr. Radic then described his laboratory’s research using anti-CD19 CAR T cells in the MRL-lpr strain of mice that develops lupus-like disease, predominantly in female mice. He and his colleagues depleted CD19 B cells in NZB/W and MRL-lpr mice using anti-CD19 CAR T cells and were able to achieve B cell depletion for more than one year.
When the researchers compared CAR-treated and control MRL-lpr mice, they found that CAR-treated mice had decreased anti-DNA antibodies and decreased anti-histone antibodies. Depletion of CD19+ B cells not only significantly reduced serum anti-DNA titers, it also decreased glomerular immune complex deposits, reversed proteinuria, healed skin lesions and extended lifespans. Moreover, anti-CD19 CAR T cells were effective in animals that had developed progressive disease, even after six weeks of high-grade proteinuria.
When the investigators further examined the IgG serology of CAR-treated MRL-lpr mice, they found that although anti-ribonucleoprotein (RNP) autoantibody-producing clones remained in CAR-treated mice, mice with anti-RNP autoantibodies did not show any detectable pathology. It thus appeared that CAR T cells efficiently depleted pre-B cells in the bone marrow while at the same time allowing long-lived anti-RNP plasma cells and immunization-elicited B cells (such as to ovalbumin) to remain functional.
Although CD19 therapy eliminates many antibodies, there are certain antibodies it does not eliminate.
An important implication of these results is that secretion of anti-DNA autoantibodies may depend on continuous production of CD19+ plasmablasts.
When Dr. Radic and colleagues performed flow cytometry of CAR-treated MRL-lpr mice as well as tissue histochemistry, they found consistent improvement in tissue pathology in mice receiving anti-CD19 CAR T cell treatment, and overall the pathologists saw a much worse presentation of disease in the control mice. Moreover, the researchers found that the CAR T cells could be serially transferred to naive mice to ameliorate lupus.
Dr. Radic concluded his presentation by suggesting there are certain disease conditions for which rituximab (an antibody against the B cell marker CD20) is in clinical trials, but for which CAR T might offer certain advantages. He believes anti-CD19 CAR T cells represent an attractive therapy for lupus. He noted, however, that patenting and intellectual property issues may sideline investors.
Falk Hiepe, MD, a professor of medicine at the Charité University of Medicine, Berlin, Germany, concluded the session by describing two promising strategies to deplete long-lived plasma cells: proteosome inhibitors and anti-CD38 antibodies.
He suggested that proteosome inhibitors, such as bortezomib, would be able to effectively target plasma cells and explained how bortezomib treatment, while associated with fever and allergic skin reaction, was able to deplete plasma cells in refractory lupus.
He also highlighted results from a multicenter double-blind randomized controlled trial of bortezomib in refractory anti-N-methyl D-aspartate (NMDA) receptor (anti-NMDAR) encephalitis and in other refractory antibody-mediated diseases that suggested the therapeutic effect of bortezomib is not only due to plasma cell depletion, but also blockade of nuclear factor kappa B (NF-κB). Dr. Hiepe cautioned that although these preliminary results are promising, use of the novel proteosome inhibitors remains limited by their toxicity.
All told, the new data have implications for the treatment of diseases mediated by B cells.
Lara C. Pullen, PhD, is a medical writer based in the Chicago area.
- Radbruch A, Muehlinghaus G, Luger EO, et al. Competence and competition: The challenge of becoming a long-lived plasma cell. Nat Rev Immunol. 2006 Oct;6(10):741–750.
- Bhoj VG, Arhontoulis D, Wertheim G, et al. Persistence of long-lived plasma cells and humoral immunity in individuals responding to CD19-directed CAR T-cell therapy. Blood. 2016 Jul 21;128(3):360–370.