CAR-T cells as 'bait' show promise in autoimmune diseases

This is a photo of the Clinical Research Building of the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, PA
University of Pennsylvania scientists developed chimeric autoantigen receptor T cells cells to treat antibody-mediated autoimmune diseases. (Hazmat2)

Chimeric antigen receptor (CAR) T cells have become powerful treatment options for blood cancers. By using the same idea of modifying T cells to target diseased cells, scientists at the University of Pennsylvania have developed chimeric autoantigen receptor (CAAR) T cells to specifically eliminate B cells that are responsible for autoimmune diseases.

The team designed CAAR T cells to treat myasthenia gravis (MG), a disease that in some cases is caused by rogue antibodies against the muscle-specific kinase (MuSK). In lab dishes, the CAARs successfully directed T cells to destroy B cells expressing anti-MuSK antibodies, according to an abstract to be presented at the American Neurological Association 2019 annual meeting.

Penn’s Aimee Payne, M.D., Ph.D., and Michael Milone, M.D., Ph.D., a co-inventor of Novartis’ CAR-T cancer therapy Kymriah, pioneered the CAAR-T idea and have founded biotech Cabaletta Bio, hoping to bring their therapies through clinical studies to the market. The MuSK-CAAR-T is the second candidate in its pipeline; the company has already received FDA clearance to test its lead project, DSG3-CAAR-T, in patients with mucosal pemphigus vulgaris (PV), and a phase 1 trial is expected to start in 2020.

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CAR-T cells are genetically modified T cells with artificial CARs on their surface that allow them to recognize and attack cancer cells. In a 2016 Science paper, Milone, Payne and colleagues described engineering CAR-T cells to express the desmoglein (Dsg) 3 protein.

In PV, autoreactive B cells produce antibodies against Dsg3, disrupting its adhesive function and causing skin blistering. By expressing Dsg3 on their surfaces, the CAAR-T cells lure those B cells in and kill them. The Dsg 3 CAAR-T cells eliminated Dsg3-specific B cells in lab dishes and in mice, the researchers reported at the time.

RELATED: A CAR-T approach to lupus

To further validate the idea, the team generated CAARs expressing MuSK as the “bait” on the surface of T cells. In about 6% to 7.5% of MG cases, rogue antibodies could target MuSK, a protein that’s essential for neuromuscular junction development and function.

“The pathogenic antibodies that cause MuSK MG are well-defined suggesting that this disease is an ideal candidate for our CAAR T approach,” Payne said in a statement. The researchers observed that in lab dishes, the CAAR T cells specifically targeted the anti-MuSK antibody-expressing B cells.

Several research teams have adopted a cell therapy approach to treating autoimmune diseases. In a recent study, scientists at the University of Tennessee found CAR-Ts could delete harmful CD19 B cells, relieve symptoms and extend life spans in mouse models of lupus.

RELATED: Sangamo strikes TxCell takeover to gain CAR-Treg pipeline

Last year, Sangamo Therapeutics shelled out €72 million to acquire TxCell, which developed regulatory T cells modified with a CAR to achieve local—versus whole-body—immunosuppression to prevent graft rejection in organ transplant. TxCell is also developing the treatment for autoimmune diseases such as Crohn’s and multiple sclerosis.

Current treatment for MG requires immune suppression, which raises the risk of lethal infections. Because CAARs are designed to only target the B cells that express disease-causing autoantibodies, these cells “represent a novel strategy for targeted B cell depletion in MG, and may ultimately prove to be valuable for the treatment for a broad range of antibody-mediated diseases,” the Penn researchers said in the study.

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