Meet the 2024 Lupus Insight Prize Honorees

Drs. Marko Radic and Georg Schett receive the 2024 Lupus Insight Prize from LRA Chief Scientific Officer Dr. Teodora Staeva.

On June 20 in San Francisco, the Lupus Research Alliance (LRA) honored Marko Z. Radic, PhD, professor at the University of Tennessee Health Science Center, and Georg Schett, MD, director of Department of Medicine 3 and vice president research at Friedrich-Alexander-Universität, Erlangen-Nürnberg, with the 2024 Lupus Insight Prize. The prize was awarded during a ceremony at the Federation of Clinical Immunology Societies (FOCIS) meeting and acknowledged the two researchers for their pioneering discoveries in using chimeric antigen receptor (CAR) T cell therapy in lupus patients for whom rituximab therapy had proved ineffective.

Targeting Depletion of B Cells

The LRA had partially funded a previous study by Dr. Radic, initiated in 2014, which allowed him to pursue a line of investigation that he had been following since his time as a post-doc at the Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia. During his 30 years of studying lupus, Dr. Radic explained, the basic questions of understanding the drivers of the disease have gone hand in hand with thinking about the molecular interactions that form its basis. While he had been initially intrigued with DNA interactions and chromosome structure during his PhD studies (under the mentorship of Barbara A. Hamkalo, PhD, professor of molecular biology and biochemistry at the UC Irvine Dunlop School of Biological Sciences), he was exposed to the intricacies of immunology during his post-doc training, facilitated by Martin G. Weigert, PhD, Professor Emeritus in the biological sciences division at the University of Chicago and a member of the National Academy of Sciences. Dr. Weigert, he says, “took me under his wing.” Once established in his own laboratory, Dr. Radic continued to follow the work of people such as Carl H. June, MD, the Richard W. Vague Professor in Immunotherapy at the Perelman School of Medicine of the University of Pennsylvania, who was “trailblazing the CAR approach in cancers.” Dr. Radic began to wonder how the work with immunotherapies in oncology might translate to testing an approach with an autoimmune disease such as lupus. “Patients,” he noted, “understood that discovering the causes of lupus might be a curiosity, but they would much rather know how to get rid of this disease.”

Patients’ concerns and the inroads being made with immunotherapies in oncology created a confluence in his mind to attempt an approach to deplete B cells, which are key orchestrators of lupus disease. Using a mouse model of lupus, Dr. Radic and his team were able to show that CAR-T cell-treated mice experienced a depletion of CD19 B cells. That B cell depletion was sustained, and the treated mice had fewer manifestations of disease as well as extended life spans. The results were published in Science Translational Medicine in March 2019.¹

Building on Mouse Model

Dr. Schett and his team, building on these foundational findings, moved the approach to the clinical arena. In August 2021, they published a report of a 20-year-old woman with severe refractory SLE treated with autologous CD19 CAR-T cells who experienced rapid remission of her disease.² This was followed by a small case series in which patients treated with anti-CD19 CAR-T cells showed a reduction of lupus features, including presence of autoantibodies, nephritis and other manifestations. Four of the five study participants saw a reduction of their SLEDAI (Systemic Lupus Erythematosus Disease Activity Index) score to 0, and all five were able to stop taking immunosuppressant therapy. About 100 days after CAR-T cell therapy, B cells remained, although symptoms of lupus were absent.

An Immune System Reboot?

From these clinical study results, there is some hope, the researchers agree, that the patients’ immune systems were reset by the therapy. How lasting that effect will be remains to be determined. Dr. Schett has now embarked on an effort to determine whether some self-reactive B cells remain in patients’ tissues. This, of course, could result in continued immune system malfunction. His Lupus Insight Prize award will be used to obtain tissue samples to assess the extent of B cell depletion.

The LRA funding will allow the team to assess patients sequentially and to compare their B cell depletion trajectory with other patients on rituximab. Dr. Schett also notes that patients in the case study have been eager to sign up for this second part of the study. The fast feedback on B cell depletion is reassuring for the patient, and the other component for participation is that they believe they are contributing to better understanding of this therapy.

As a provider, Dr. Schett sees this type of therapy as a paradigm shift, especially for patients with very severe and refractory disease. “The idea that you can actually reset the immune system and not just suppress it is something new and revolutionary. I think the CAR experience tells us that this is at least possible in some patients.”

‘Endless Possibilities’

Dr. Radic notes that the findings of the CAR-T studies open up a wide range of additional questions to be explored—for example, what other cell types, targets and biological functions beyond cytotoxicity could be brought to bear in the fight to curb autoimmune diseases. The Radic lab intends to use the award to learn more about the inner working of CAR T cells.

Of his foundational study on chimeric antigen receptors, Dr. Radic says the results were “quite astounding and broadly positive.” Now that those results are mirrored in patient studies, the bottom line is that there are more techniques in the treatment armamentarium for improving quality of life for patients.

For the present, both Drs. Radic and Schett are pleased to be honored by the LRA in this manner. “If you read the names of people honored [by the Lupus Insight Prize], it’s the cream of the crop of immunologists,” says Dr. Radic, “So I’m particularly honored and humbled by being included in this group.”

References

1. Kansal R, Richardson N, Neeli I, et al. Sustained B cell depletion by CD19-targeted CAR T cells is a highly effective treatment for murine lupus. 2019 Mar;11(482):eaav1648.
2. Mougiakakos D, Krönke G, Völkl S, et al. CD19-targeted CAR T cells in refractory systemic lupus erythematosus. 2021 Aug;385(6):567–569.