Penn Medicine Researchers Take Step Toward Development of Personalized, CAR T-like Treatment for Rare Form of Autoimmune Disease Myasthenia Gravis

PHILADELPHIA – The revolutionary chimeric antigen receptor (CAR) T cell therapy, used to treat patients with certain types of cancers, can be reworked to treat a form of the autoimmune disease myasthenia gravis (MG), according to a preclinical study conducted in a small animal model from the Perelman School of Medicine at the University of Pennsylvania and published in Nature Biotechnology. The product, known as MuSK chimeric autoantibody receptor T cells, or MuSK-CAART, is designed to precisely target the cause of muscle-specific tyrosine kinase (MuSK)-MG.

MG is a rare, chronic autoimmune disease that can cause severe muscle weakness and trouble breathing and swallowing. MG occurs when otherwise normal B cells—which typically produce antibodies that attack foreign antigens—instead produce antibodies that attack the body’s own connections between its nerves and muscles, damaging these connections and preventing muscles from working properly. MuSK-MG is a rare subtype of MG which often progresses more quickly and causes more extreme symptoms. The new research, conducted in cell and mouse models, found that the MuSK-CAART construct targets only a subpopulation of B cells that cause the autoimmune disease, leaving healthy B cells unscathed and functional. The new approach for potentially treating patients with MuSK-MG will now be evaluated for safety and tolerability in a phase 1 clinical trial, which recently opened for recruitment.

Although there are no FDA-approved therapies specifically for MuSK-MG, existing treatments include immunosuppressive drugs, steroids, and monoclonal antibodies. Each of these approaches has limitations and side effects. Medications that chronically suppress the immune system leave the body vulnerable to a host of infections, and prolonged steroid use can lead to weight gain, diabetes, and even bone thinning.

“The new approach we are developing is designed to program the patient’s immune system to kill only the autoimmune B cells that cause disease, while sparing healthy B cells that can protect patients from infection,”  said senior study author Aimee Payne, MD, PhD, a professor of Dermatology at Penn and director of the Penn Clinical Autoimmunity Center of Excellence. “We are hopeful that this precision-medicine approach with CAAR T cells may, if proven to be safe and effective, one day allow for a one-time infusion leading to long-term autoimmune disease remission.”

This technique is based off of CAR T cell therapy, which was pioneered by Penn’s Carl H. June, MD, the Richard W. Vague Professor in Immunotherapy and director of the Center for Cellular Immunotherapies. CAR T cell therapy was first approved in 2017 for use among patients with certain types of B cell cancer, spawning a new, highly personalized approach to treating certain blood cancers. The approach involves removing a person’s own T cells, engineering them in a laboratory to target their cancer, and then infusing them back into the body to fight the cancer cells that typically can evade the body’s immune defenses.

“Our preclinical research in cells and animals shows that we can take T cells, but instead of engineering them to attack cancerous B cells—as in the cancers for which CAR T cell therapy has proven effective—we can engineer them to attack the autoimmune B cells destroying neuromuscular junctions in MuSK-MG,” said Sangwook Oh, PhD, Senior Research Investigator and lead author of the study. “One important and interesting feature of CAAR T therapy is that, relative to CAR T, the protein interaction is flipped. In CAAR T, the antibody ligand is on the CAAR T cell, while the pathological antibody is located on the offending B cell. This is opposite to CAR T.”

Using cell cultures and mouse models, the research team showed in preclinical models that MuSK-CAART cells can kill autoimmune MuSK-reactive B cells, with no specific evidence of toxicity from the modified cells.

Additional Penn authors include Xuming Mao, Silvio Manfredo‐Vieira, Eun Jung Choi, Damian Maseda, Patricia Y. Tsao, Christoph T. Ellebrecht, Sami L. Khella, and Michael C. Milone. Yale University and University of California-Davis researchers also contributed to this study. The study was performed in collaboration with Cabaletta Bio, a biotechnology company co-founded by Payne, Milone, and the Wharton School’s Steven Nichtberger.

Editor’s note: Cabaletta Bio has licensed the MuSK-CAART technology from Penn and is sponsoring the Phase 1 clinical trial that recently opened for recruitment. Payne, Milone, and Nichtberger (who is the CEO of Cabaletta Bio) each hold equity stakes in Cabaletta Bio. Payne and Milone have also received significant sponsored research funding from Cabaletta Bio to support research in their laboratories at Penn, including funding for the preclinical MuSK-CAART studies. In addition, both Penn and the inventors of the licensed technology (including Oh) may receive additional financial benefits under the license in the future.