Can chimeric antigen receptor T cells trigger long-term remission of autoimmunity?

By Abby S. Van Voorhees, MD, January 1, 2018

In this month's Acta Eruditorum column, Physician Editor Abby S. Van Voorhees, MD, talks with Aimee Payne, MD, PhD, and Christoph Ellebrecht, Md, about their recent Science article, "Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease." 

Dr. Van Voorhees: Remind us of what is now understood to be the cause of pemphigus vulgaris?

Drs. Payne and Ellebrecht: Pemphigus is an autoimmune disease caused when antibodies mistakenly attack a protein in the skin that’s responsible for holding skin cells together. As a result, patients can have severe blistering of the skin and mucous membranes. In pemphigus vulgaris, this protein is known as desmoglein 3 (or Dsg3 for short). In regard to why autoimmunity occurs, the exact mechanisms are not known, but we suspect that there may be different reasons in each individual as to why the body makes a mistake and begins to attack itself rather than foreign viruses and bacteria. We and others have shown that anti-desmoglein antibodies can cross-react with proteins from infectious agents, which could provide the initial stimulus for the break of tolerance in pemphigus, but there could likely be a variety of other triggers such as inflammation or cancer.

Dr. Van Voorhees: How does rituximab work?

Drs. Payne and Ellebrecht: The simplest explanation is that rituximab is an anti-CD20 monoclonal antibody that depletes B cells, which are the immune cells in the body that produce antibodies. Most of those antibodies are good and help to protect us against infections, but in the case of pemphigus, a few “rogue” B cells are making anti-desmoglein antibodies that cause skin blistering. By depleting B cells, rituximab eliminates the source of the anti-desmoglein antibodies, which is good for disease control, but it also eliminates the good B cells that make protective antibodies, which risks serious and even fatal infections.

The actual mechanism of action of rituximab in pemphigus is a bit more complicated, however. CD20+ B cells mature through a pathway where they are first “nave,” then become “memory” cells that activate against a particular antigen (such as Dsg3 in the case of pemphigus) by maturing into plasma cells. Antibodies are produced by these plasma cells, which are CD20 negative and can be either short-lived (meaning they are around less than a week and thus are dependent on the CD20+ B cell pool for replenishment) or long-lived (years to decades and hence are unaffected by CD20-mediated B cell depletion). In pemphigus, the autoantibodies are produced predominantly by short-lived plasma cells, because anti-Dsg3 antibody titers can fall to undetectable levels after rituximab therapy.

Dr. Van Voorhees: When patients relapse after taking this medication, why does this occur? How often does this relapse occur?

Drs. Payne and Ellebrecht: Not many studies have looked at the molecular mechanism of what causes relapse after rituximab therapy. One study in a few patients showed that relapse after rituximab is caused by recurrence of the identical B cell clones observed in active disease, indicating that relapse is due to incomplete B cell depletion. However, it is theoretically possible that relapse could be due to the ratio of short-lived to long-lived anti-Dsg plasma cells, the latter of which are not depleted by rituximab therapy. When you look at the published literature, relapse occurs approximately every one and a half years after rituximab therapy when using the lymphoma dosing regimen (four weekly infusions), and relapses may be more frequent when using the rheumatoid arthritis dosing regimen (two infusions separated by two weeks), which has led to the proposal that maintenance rituximab infusions every six months may be necessary to maintain disease control.

Dr. Van Voorhees: Chimeric antigen receptor technology has been used before. Where? Was it successful? Where has it been most successful up till now?

Drs. Payne and Ellebrecht: Chimeric antigen receptor (CAR) technology was first described in the late 1980s as a way of using an antibody variable region fragment to target T cell cytotoxicity against cells expressing the antigen targeted by the antibody fragment. In August 2017, the anti-CD19 CAR T cell technology tisagenlecleucel (see callout) became not only the first FDA-approved CAR T cell therapy, but also the first FDA-approved gene therapy. CAR T cells are now being trialed for a variety of cancers worldwide, but it has shown greatest success in B cell cancers, where approvals for other CAR T cell technologies for B cell leukemias and lymphomas are expected within the year.

Dr. Van Voorhees: Tell us about your study. What did you study and why?

Drs. Payne and Ellebrecht: We pay attention to therapies for B cell cancers since rituximab, one of the most effective therapies for pemphigus, was initially approved for use in B cell leukemias and lymphomas. The stunning initial reports of anti-CD19 CAR T cells leading to lasting cures of refractory B cell leukemias led Christoph Ellebrecht, the lead author on the study, to contemplate how to re-engineer the technology to treat antibody-mediated diseases such as pemphigus. B cells not only express CD19, but also express a B cell receptor, which is a surface antibody identical to the antibody that the B cell will secrete once activated to mature into a plasma cell. In the case of pemphigus, anti-Dsg3 B cells will express an anti-Dsg3 B cell receptor, so we designed a chimeric receptor that uses the disease autoantigen Dsg3 as the extracellular domain to target only these anti-Dsg3 B cells. We called this a chimeric autoantibody receptor, or CAAR. Our hope was that Dsg3 CAAR T cells could provide targeted and lasting remissions of autoimmunity in pemphigus.

Dr. Van Voorhees: What did you find? Were you able to adequately target Dsg3?

Drs. Payne and Ellebrecht: We first showed in vitro that Dsg3 CAAR T cells specifically killed anti-Dsg3 B cells, even in the presence of soluble antibodies that could theoretically neutralize CAAR-T function. Soluble antibodies can either stimulate CAAR T cells by inducing CAAR-T proliferation or can inhibit them by blocking the surface Dsg3 CAAR. However, because CAARs are continuously synthesized and only a few need to be available to trigger CAAR-T cytotoxicity, we still observed effective target cell killing at all of the soluble antibody concentrations we tested. We then tested Dsg3 CAAR T cells in an experimental pemphigus mouse model and showed that Dsg3 CAAR-T cells effectively eliminated anti-Dsg3 B cells, leading to histologic and serologic remission of disease (meaning no detectable epithelial blistering or serum autoantibody titers after treatment).

Dr. Van Voorhees: What are the clinical implications if this work is further substantiated?

Drs. Payne and Ellebrecht: We are very hopeful that the long-term remissions of cancer observed with anti-CD19 CAR T cells will also apply to CAAR-T therapy of autoimmunity. If that is the case, CAAR T cells may be able to provide lasting remissions of autoimmunity by eliminating only the autoimmune B cells while sparing the good B cells, which means that pemphigus therapy would no longer need to risk infections from generalized immune suppression. This would change the paradigm for how we treat autoimmune diseases from our current model of chronic immune suppression for disease control, to a one-time intensive disease treatment for disease cure.

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