Penn Autoimmunity Center of Excellence (ACE)
Precision medicine for B cell-mediated autoimmune diseases
Funded by the National Institute of Allergy and Infectious Diseases (NIAID), the Penn Autoimmunity Center of Excellence (ACE) is one of five clinical and translational research centers in the United States, connected to an additional five basic research centers. ACEs conduct clinical trials and collaborate to perform basic and translational research to better understand why autoimmunity occurs and how we can develop safer and more effective therapies for autoimmune diseases. Information about the ACE program can be found here.
The Penn ACE focuses on B cells as drivers of autoimmunity for three debilitating and potentially life-threatening autoimmune diseases—multiple sclerosis, pemphigus vulgaris, and type 1 diabetes. Prospective randomized clinical trials have shown that B cells are established drivers of autoimmunity in these conditions, but the diseases differ in the ways in which B cells contribute to disease. The Penn ACE aims to better understand causes and mechanisms of autoimmunity, accelerate clinical research, and increase interdisciplinary collaborative research across these and other B cell-mediated autoimmune diseases.
Multiple sclerosis: Time-limited B cell depletion with ocrelizumab
Amit Bar-Or, MD, Principal Investigator
This Penn ACE clinical project is based on the observation that a subset of patients who stop treatment with anti-CD20 monoclonal antibodies such as rituximab or ocrelizumab may have lasting disease remission. This observation leads to the critical question: Can anti-CD20 therapy be safely withdrawn in some multiple sclerosis patients and what biomarkers might predict such long-term tolerance induction? Recent work by Dr. Bar-Or and others have identified unique molecular profiles during immune reconstitution in multiple sclerosis that differ from the immune profiles during active disease. Frequent brain imaging and molecular profiling in multiple sclerosis patients after anti-CD20 discontinuation will be performed to determine if long-term remission with effective restoration of tolerance can be defined and predicted. The results of this clinical trial will be potentially paradigm-shifting for the treatment of multiple sclerosis, which currently relies on continuous targeting of the immune system to limit further disease activity and central nervous system damage.
Pemphigus vulgaris: Targeted B cell depletion with DSG3-CAART
Aimee Payne, MD, PhD, Scientific Advisor
This clinical project also addresses the ultimate challenge in autoimmune disease therapy: Is a safe and lasting remission of autoimmune disease possible? The inspiration for this clinical project is based on the lasting cures of cancer observed in refractory leukemia and lymphoma patients treated with tisagenlecleucel, the first FDA-approved, genetically-engineered, chimeric antigen receptor T cell (CART) therapy, which programs a patient’s own T cells to seek out and destroy cancerous B cells. Dr. Payne’s group re-engineered this powerful technology for autoimmune disease therapy by using the autoantigen targeted in pemphigus vulgaris (known as desmoglein 3 or DSG3) to program T cells to eliminate only the pathogenic autoimmune B cells. The proposed trial is a first-in-human phase 1 study to evaluate the safety and potential ability of DSG3 chimeric autoantibody receptor T cells (DSG3-CAART) to induce disease remission in relapsed or refractory pemphigus vulgaris. The translational research program will determine mechanisms of long-term immune tolerance induced by DSG3-CAART. If proven successful, DSG3-CAART has the potential to transform the therapy of autoimmunity away from the current model of chronic and generalized immune suppression toward a precision medicine approach that eliminates only the disease-causing immune cells.
Type I diabetes: a big data collaborative approach to better understand drivers of autoimmunity
Eline Luning Prak, MD, PhD, Principal Investigator
Type 1 diabetes (T1D) is an autoimmune disease caused by immune-mediated destruction of the insulin-producing beta cells of the pancreas. The inability to regulate blood sugar is associated with an increased risk of many serious conditions including cardiovascular disease, eye damage, kidney damage, foot ulcers and other problems. Autoantibody production by B cells precedes the development of overt clinical disease in T1D, and randomized clinical trials have shown that B-cell depletion therapy with rituximab can delay disease onset. Recent studies also suggest a role for intestinal microbiota and inflammation in T1D disease development. In conjunction with the other ACE institutions and the Human Pancreas Analysis Program (HPAP), the Penn ACE collaborative project will use cutting-edge techniques including B cell deep phenotyping, in situ imaging and computational analysis, antibody repertoire sequencing, and high-throughput screening of antigen arrays to investigate the factors contributing to disease development in T1D.
The Penn ACE faculty are internationally recognized physician-scientists with a strong commitment to mentoring clinical and research scientists in the field.
Aimee S. Payne, MD, PhD is the Director and co-Principal Investigator of the Penn ACE. Dr. Payne is the Albert M. Kligman Associate Professor of Dermatology and Associate Director of the Medical Scientist (MD-PhD) Training Program at the University of Pennsylvania. Dr. Payne also serves on the Medical Advisory Council of the International Pemphigus and Pemphigoid Foundation, a patient education and advocacy organization. Dr. Payne’s clinical and research expertise centers on pemphigus vulgaris, a rare but well-defined autoimmune blistering disease that is considered a paradigm for understanding antibody-mediated disease in humans. Her research has led to a better understanding of mechanisms of autoimmunity and how therapy works in pemphigus, with the goal of developing precision medicine therapies for disease.
Amit Bar-Or, MD is the Clinical Project Leader and co-Principal Investigator of the Penn ACE. Dr. Bar-Or is the Melissa and Paul Anderson President’s Distinguished Professor of Neurology, Chief of the Division of Multiple Sclerosis, and Director of the Center for Neuroinflammation and Experimental Therapeutics at the University of Pennsylvania. Outside of Penn, Dr. Bar-Or serves as President of the International Society of Neuroimmunology, on the Steering Committee for the Immune Tolerance Network, on the Board of Directors of the Americas Committee for Treatment and Research in Multiple Sclerosis, and on the Education Committee for the Federation of Clinical Immunology Societies. His research focuses on neuroimmune health and central nervous system autoimmune and inflammatory diseases, with a particular interest in developing clinically meaningful biomarkers and advancing precision medicine in neuroimmune disorders.
Eline Luning Prak, MD, PhD is the Collaborative Project Leader of the Penn ACE. At Penn, Dr. Luning Prak is Professor of Pathology and Laboratory Medicine and Director of the Human Immunology Core laboratory. Dr. Luning Prak also serves as Chair of the Adaptive Immune Receptor Repertoire (AIRR) Community, an international group of academic and industry experts that organizes and coordinates stakeholders in next generation sequencing technologies to study B and T-cell repertoires. Dr. Luning Prak’s research focuses on B-cell tolerance checkpoints and the characterization of B-cell repertoires in patients with autoimmune disease. Her commitment to mentoring has been recognized with the Peter C. Nowell Award for Excellence in Teaching and the Leonard Berwick Memorial Teaching Award, representing two of the highest awards for teaching bestowed by the Perelman School of Medicine.
For further information about the Penn ACE, please contact Insuk Choe, program coordinator.
A central component of the Penn ACE educational program is ME Time!, a program of Mentoring and Enrichment for early stage physician-investigators, including junior faculty and clinical and research fellows. ME Time! will synergize with other professional and scientific career development resources on campus, and will also offer grant application review and educational and travel fellowships. More information on ME Time! can be found here.