The Lupus Research Alliance (LRA) announced the recipients of the 2024 Lupus Insight Prize to Marko Radic, Ph.D., The University of Tennessee Health Science Center, and Georg Schett, M.D., Friedrich-Alexander-Universität Erlangen-Nürnberg, for their groundbreaking discoveries in utilizing CAR T cell therapy to potentially revolutionize lupus treatment. Drs. Radic and Schett were honored at a celebratory award ceremony during the Federation of Clinical Immunology Societies (FOCIS) 2024 meeting.
The Lupus Insight Prize is awarded to outstanding investigators who have made a significant discovery in the last five years that will advance our understanding of the development, diagnosis, or treatment of lupus.
Revolutionizing Lupus Treatment Through CAR T Cell Therapy
T cells are an essential pillar of the immune system— they mount a response against harmful invaders, targeting and eliminating pathogens like viruses and bacteria to protect us from infection. Chimeric antigen receptor (CAR) T cell therapy involves reprogramming a patient’s own T cells to target and eliminate cells contributing to the disease. CAR T cell therapy has garnered significant attention and success in cancer treatment. Drs. Marko Radic and Georg Schett have made pioneering contributions to the field of CAR T cell therapies for lupus, charting a new course in the treatment landscape and offering hope for individuals with this complex condition.
“We are thrilled to award Drs. Marko Radic and Georg Schett the 2024 Lupus Insight Prize for their groundbreaking contributions to engineered cell therapies in lupus,” noted Teodora Staeva, Ph.D., Vice President and Chief Scientific Officer at the LRA. “Their innovative application of CAR T cell therapy offers unprecedented hope for a cure for individuals living with lupus.”
Pioneering CAR T Cell Therapy in Mouse Models of Lupus
Dr. Marko Radic’s seminal study, partly funded by the LRA, highlighted the profound efficacy of CAR T cells targeting CD19, a protein found on B cells. By using CD19-targeted CAR T cells to deplete B cells, which serve as key orchestrators of lupus disease, Dr. Radic’s innovative approach reduced disease progression in two mouse models of lupus. The CAR T-treated mice lived longer, and several features of lupus were eliminated or reduced substantially, including autoantibodies, proteinuria (excess protein in the urine), and markers of inflammation. Notably, the CAR T cells continued working several months after administration. Dr. Radic’s work laid the cornerstone for exploring CAR T cell therapy as a promising avenue for treating lupus in human patients, offering a glimpse into the potential of immunotherapy for autoimmune diseases.
Dr. Radic will use his Lupus Insight Prize to study how a process called trogocytosis affects the success or failure of CAR T cell therapy. In some cases, when a CAR T cell attaches to its target antigen (CD19 on the surface of B cells, in this case), the CAR T cell can take in a piece of the target cell’s membrane, including CD19, without killing the target B cell. This process, called trogocytosis (also known as “cell nibbling”), may lead to exhaustion and death of the CAR T cells, potentially impacting the effectiveness of CAR T therapy. Dr. Radic’s proposed study will guide the development of more effective cell therapies for people with lupus.
Translating CAR T Cell Therapy to Clinical Success
Building upon Dr. Radic’s foundational research, Dr. Georg Schett made significant strides in translating CAR T cell therapy from preclinical studies to clinical application. In his groundbreaking publication and follow-up study, Dr. Schett and his team reported compelling outcomes from a single patient followed by a small case series involving individuals with refractory (resistant to treatment) lupus. Infusing CAR T cells that target CD19 eliminated B cells from the blood by the second day after CAR T administration. All individuals treated with anti-CD19 CAR T cells showed a reduction in or disappearance of lupus features including the presence of autoantibodies, nephritis (kidney inflammation), and other manifestations such as arthritis, fatigue, and lung issues.
In addition, four of the five patients reached a SLEDAI score (a commonly used tool to measure disease activity) of 0, indicating no detectable disease activity, and all five were able to stop taking immunosuppressive drugs, achieving drug-free remission. Notably, although their B cells returned about 100 days after CAR T cell therapy, lupus remained absent, raising the possibility that the immune system has been “rebooted” by the treatment, offering hope for transformative treatments for people with lupus who are resistant to conventional therapies.
CAR T cell administration effectively eliminated B cells from the individuals’ blood. However, if some self-reactive B cells remain in the body’s tissues, such as the lymph nodes, the immune system may continue to malfunction. Dr. Schett has recently developed a method to take tissue biopsies from people with lupus to assess the extent of B cell depletion in their lymph nodes, which are small lumps of tissue that are critical components of the immune system. He will use his Lupus Insight Prize to analyze these biopsies to assess how well the CD19-CAR T cell therapy was able to eliminate B cells from this tissue. These findings could inform and optimize treatment strategies, leading to improved long-term disease management and better patient outcomes.
The groundbreaking use of CAR T cell therapy represents a convergence of cutting-edge science and clinical innovation, signaling a major shift in our approach to lupus management. As we celebrate the remarkable achievements of both Drs. Radic and Schett, we eagerly anticipate the continued advancements that will emerge to unravel the complexities of lupus and improve outcomes for people with lupus.
