November, 2023
At the recent ACR Convergence 2023, the annual meeting of the American College of Rheumatology, important lupus clinical trial data and breakthrough foundational research were presented. Following are highlights of work funded by the Lupus Research Alliance or supported in partnership with industry through our clinical affiliate Lupus Therapeutics.
CAR-T Cell Therapy is Showing Great Promise
The Lupus Research Alliance (LRA) is particularly excited about the results of clinical research presented at the meeting that builds on foundational work LRA funded with a grant to Dr. Marko Radic on CAR-T cell therapy in lupus back in 2015. A study presented by Professor Georg Schett, evaluating the safety and effectiveness of anti-CD19 CAR-T cell therapy in patients with refractory lupus (resistant to available treatment) showed favorable safety along with effectiveness in depleting B immune cells up to 24 months.
More studies on the effectiveness and safety of CAR T cell therapies in lupus patients is needed – and Lupus Therapeutics, the clinical affiliate of the Lupus Research Alliance, is currently working in collaboration with several organizations on cell therapy clinical research.
Lupus Therapeutics Supported Data Presented at ACR
Data related to an important initiative supported by Lupus Therapeutics and LuCIN, its prestigious network of lupus clinical investigators, were presented at the ACR meeting — focused on increasing underrepresented participants in clinical trials:
- Lupus Clinical Investigators Network (LuCIN) representatives presented the greatest barriers to lupus clinical trial participation. The three top barriers included restrictive criteria (what patients should or should not be included) from a trial (89.1%), participant mistrust in research (38.2%), and a lack of referrals from healthcare providers (32.7%). Almost 50% of sites reported that they had not received training on recruitment of underrepresented patients in clinical trials. The findings underscore the need to increase provider-patient communication and engagement between academic and community practices to improve access and referrals to lupus clinical trials.
Clinical Trial Highlights from Industry Partners of Lupus Therapeutics
Several presentations shared data from studies aimed at advancing clinical research so that all people with lupus have faster, more equitable access to safe and effective therapies.
- Improvements in cutaneous lupus were observed in a study in patients treated with deucravacitinib. Data presented demonstrated that among patients with moderate to severe skin involvement, more patients treated with deucravacitinib, a selective TYK-2 inhibitor from Bristol Myers Squibb, were able to achieve improvements in skin overall and sustain a CLASI-50 response compared to placebo. CLASI is a validated tool used to measure cutaneous or skin related manifestations of lupus.
- Improved symptoms and quality of life were observed in a Phase 2 PAISLEY trial in SLE. Patients receiving the investigational drug deucravacitinib reported greater improvements in pain, fatigue, and health-related quality of life at Week 48, compared with patients who received placebo.
- Reductions in flares and disease activity was seen among adults with moderate to severe active SLE in a Phase 2 clinical trial combining two drugs. Of patients given ABBV-599 (combining elsubrutinib and upadacitinib) in addition to standard therapy, 33% were able to lower their steroid dose and showed an improvement in lupus symptoms. In development by AbbVie, upadacitinib is now being evaluated in Phase 3 for the treatment of lupus.
- A Phase 2 clinical trial with the novel investigational drug ianalumab improved lupus symptoms according to the standard SRI-4 measurement tool and reduced the need for steroids for 34.5 percent of patients. Among patients given ianalumab, a monoclonal antibody being developed by Novartis, in addition to the standard treatment everyone received, there were a significantly lower incidence of moderate to severe flares – 44 percent compared with 64 percent who received placebo plus standard of care.
Spotlight on Foundational Research Funded by the Lupus Research Alliance
The unwavering commitment of the LRA to advancing the understanding of lupus and identifying new and improved treatment approaches was evident in the more than 30 LRA-funded presentations at ACR Convergence 2023. Here are just a few highlights:
- Growth of a specific gut bacteria may contribute to heterogeneity in lupus nephritis: Abhimanyu Amarnani, M.D., Ph.D., presented exciting findings from the lab of Gregg Silverman, M.D., that showed the complex relationship between SLE and naturally occurring bacteria in the gut. In SLE, imbalances in the gut microbiome can coincide with lupus nephritis (LN) flares, and the impairment of the gut barrier allows for the leak of gut microbes or microbial toxins out of the intestines. To better understand how gut microbial alterations contribute to flares, the team investigated changes in gene expression, or the levels of genetic information that encodes biological processes and molecular functions, in individuals with active LN and a surge in a specific gut bacterium called Ruminococcus gnavus (RG), known to cause gut leakiness. The team found that individuals with LN experiencing this surge of RG showed a higher level of genes associated with the activation of platelets–small cell fragments in the blood– which causes a release of inflammatory molecules called cytokines and chemokines. The data suggest that RG blooms may contribute to the heterogeneity (how lupus differs from person to person) seen in LN. These results also highlight a potential role for platelet activation in the development of LN, offering insights into the complexities of autoimmune disease.
- Deep learning model shows promise for the development of a diagnostic tool for childhood-onset SLE: Santiago Arciniegas, MSc, a member of the lab of Andrea Knight, M.D., MSCE, presented work that offers a promising avenue for the development of a novel diagnostic tool for neuropsychiatric lupus in Childhood-onset SLE (cSLE) is often associated with greater neuropsychiatric symptoms, including psychosis, headache, cognitive dysfunction, and acute confusional state. Identifying biomarkers of neuropsychiatric SLE (NPSLE) has been a major challenge, and more than half of conventional MRI reports in individuals with NPSLE appear normal, confounding diagnosis. The team developed a type of machine learning, called a deep learning model, capable of using brain images to identify distinguishing structural brain features of individuals with cSLE. The model also highlighted specific brain regions as the most helpful in distinguishing people who were diagnosed with lupus during childhood from those who were not.
- Harnessing T cells (Tregs) to suppress immune cell activity and offer a promising therapy for lupus nephritis (LN): Eric Morand, M.D., Ph.D., presented groundbreaking work led by his colleague Joshua Ooi, Ph.D., focused on developing a potential treatment for lupus nephritis by harnessing the power of regulatory T cells (Tregs), an immune cell type that plays an important role in maintaining immune system regulation. Tregs potently suppress autoimmunity and are lower than normal in people with SLE, suggesting their potential to be redesigned to treat autoimmune diseases. The team designed Tregs that specifically target an important protein in lupus called Smith. In a humanized mouse model, (a mouse that has been given human cells from people with SLE) the generated Smith-targeting Tregs effectively halted disease progression and lessened kidney damage. These results highlight the potential of engineering targeted Tregs as a promising therapy for LN.
- Heat is a pro-inflammatory factor that plays a critical role in the control of immunity: Jeffrey Rathmell, Ph.D., discussed his recent research on the effects of fever on T cells, an immune cell type that plays a critical role in SLE. Heat is a defining feature of inflammation, and individuals with SLE often experience fevers. Dr. Rathmell and his team found that increased temperature causes T cells to produce more inflammatory molecules. Additionally, increased temperature induces metabolic stress and death in some T cell types. In these cells, mitochondrial stress, which occurs when there is an imbalance between the energy demands of the cell and the ability of the mitochondria (the powerhouse of the cell) to produce energy, results in the generation of highly reactive chemicals called reactive oxygen species, causing irreversible DNA damage. Rathmell’s finding that fever induces stress and cell death in specific immune cell subsets highlights the important effects of fever on the immune system.
- UV light triggers skin inflammation through inflammatory immune cell types in individuals with lupus: Mitra Maz, from the lab of J. Michelle Kahlenberg, M.D., Ph.D., presented recent findings on what causes photosensitivity and how targeting important players in photosensitive responses may prevent and treat cutaneous lupus – when the skin is affected by lupus. Individuals with lupus often experience rashes after sun exposure, and significant sun exposure can lead to flares, more symptoms throughout the body, and lower quality of life. Analyzing skin cells from healthy individuals and individuals with SLE and cutaneous lupus exposed to UV light, Mitra and colleagues identified a mechanism in which UV light induces a subtype of skin cells, called keratinocytes, to produce more inflammatory molecules called cytokines. These inflammatory keratinocytes then recruit other immune cells to coordinate a targeted defense. Targeting these inflammatory cells may be beneficial for the prevention and treatment of cutaneous lupus.
