A CAR-T approach to lupus

Scientist at the University of Tennessee Health Science Center have shown that depleting harmful B cells with CAR-T cells could be a promising strategy to treat lupus. (Nephron/Wikimedia Commons)

B cells play a key role in lupus, an autoimmune disease that occurs when a patient’s antibodies mistakenly attack the body’s own tissues and organs. Could CAR-T cell therapies, which have shown strong efficacy in B-cell cancers, also be used in lupus? A team of scientists at the University of Tennessee Health Science Center thinks so, and they’ve turned up some positive early evidence to support the approach.

The team, led by Marko Radic, Ph.D., associate professor at the University of Tennessee, created T cells that express chimeric antigen receptors (CARs) against CD19. The CAR-Ts bind to the B-cell surface marker and kill the targeted cells. When administered to mice, the modified T cells improved lupus symptoms and extended the animals' lifespans, according to a study published in the journal Science Translational Medicine.

The researchers believe their findings could extend the use of CAR-T cells beyond cancer, offering a more stable and effective strategy to treat lupus than what can be achieved with monoclonal antibodies. The cells may work for other autoimmune diseases as well.

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When B cells produce autoantibodies against DNA and other targets, they cause inflammation and damage to organs such as the kidney. They can also influence antigen presentation and cytokine secretion, which worsens the inflammatory immune response. Therefore, B cells have been a popular target in lupus research.

For example, GlaxoSmithKline’s Benlysta, approved by the FDA in 2011 as the first new drug for lupus in about 50 years, is a monoclonal antibody that inhibits B-lymphocyte stimulator (BLyS), a B-cell survival factor.

In their study, the University of Tennessee researchers tested CAR-Ts in two mouse models of lupus. They found that the CAR-Ts depleted harmful CD19 B cells, which prevented autoantibody production.

The rodents also showed improvements across several lupus indicators, including increased protein in the urine (proteinuria) and skin lesions. What’s more, most mice given the therapy lived for one year after treatment, while others in the control group died much earlier or had been euthanized because of advanced disease.

RELATED: Xencor’s lead lupus antibody misses phase 2 endpoint

Antibodies are currently the mainstay of lupus pipeline, but they’ve seen their fair share of failures. Last August, AstraZeneca said its experimental lupus treatment, anifrolumab, missed the mark in the first of two phase 3 trials.

That drug works by inhibiting certain interferons—proteins that are key in cells’ anti-viral defenses but that also contribute to inflammation. Previously, Roche’s anti-CD20 blockbuster Rituxan failed to demonstrate efficacy in large phase 3 lupus trials, even though the drug has been approved to treat other autoimmune diseases such as rheumatoid arthritis. More recently, Xencor’s lead candidate, XmAb5871, which also targets CD19, didn’t meet the primary endpoint in a phase 2 clinical trial in lupus patient.

While more research is needed to validate the University of Tennessee team’s CAR-T before it can enter the clinic, Radic and his colleagues said their therapy might be better than monoclonal antibodies.

In addition to eliminating B cells from a variety of tissues such as the spleen and bone marrow, the CAR-T cells proliferated in the host and remained active for one year after the initial infusion, Radic's team reported. In comparison, monoclonal antibodies require repeated administrations to maintain a therapeutic dose, according to the scientists.

“Over time, resistance to the treatment arises in the host and further limits use,” they wrote in the study.

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