B cells produce antibodies that target foreign invaders like viruses and bacteria to protect us from infections. In people with lupus, B cells can become self-reactive, producing autoantibodies that mistakenly target a person’s own cell contents. These autoantibodies, which target a wide variety of molecules, bind to their targets and can move to the kidney or other organs, where they cause inflammation and damage. Endogenous retroviruses (ERVs) are like ancient records of viruses our ancestors were exposed to that have become part of our DNA over millions of years. ERVs are known to play a role in lupus, and many mouse models of lupus have high levels of autoantibodies against an ERV protein. Dr. Tokuyama and her colleague Dr. Laura Evgin will develop a novel cell therapy, called CAAR-T cell therapy, that targets and destroys B cells that produce disease-causing anti-ERV autoantibodies.

Chimeric antigen receptor (CAR)-T cell therapy (re-engineering a person’s own T cells to target and eliminate specific cell types) has shown promising effects in people with lupus. Many existing CAR-T cells target all B cells, both healthy and harmful, which can leave the person susceptible to infections. Dr. Tokuyama and Dr. Evgin will first develop and optimize an alternate approach using chimeric autoantibody receptor (CAAR)-T cells that target and eliminate B cells that produce anti-ERV autoantibodies. She will then test whether the CAAR-T cells can prevent disease development, progression, and kidney inflammation in a mouse model of lupus.

What this study means for people with lupus

While CAR T-cells have shown promise in both cancer and lupus treatment, this new type of CAAR-T cell therapy has not yet been explored in lupus, and further research is needed to understand its potential. Findings from this study could unlock a new treatment that can benefit people with lupus by targeting harmful B cells while sparing healthy B cells.

The development of novel biologics to treat systemic lupus erythematosus (SLE) has been slow and existing biologics suffer from the lack of broad efficacy within the patient population. Chimeric antigen receptor (CAR) T cells are promising next generation tools to treat autoimmune diseases; in fact, multiple clinical trials are underway using B-cell maturation antigen (BCMA) or CD19 CAR T cells for SLE. However, the use of chimeric autoantibody receptor (CAAR) T cells to target antigen-specific B cells in SLE has not yet been explored. The proposed innovation project seeks to design a novel CAAR T cell therapy for SLE that builds on decades of research implicating antibodies against ERVs in SLE. This is in addition our recent work showing the pathogenic potential of anti-ERVK envelope antibodies on neutrophil activation and inflammation in SLE. Leveraging our collective expertise in ERVs and CAR T cell therapies, we propose a proof-of-principle study to design a novel CAAR encoding the gp70 ERV envelope protein to target anti-gp70 specific B cells in mice. The therapeutic potential of these CAAR T cells to prevent development and progression of disease will be assessed in established mouse models of lupus. We anticipate that the proposed study will facilitate the development of similar CAAR T cells to target ERV-specific B cells in SLE patients. Given that a clinical translational path for CAAR T cell therapy has been forged for the treatment of mucosal-dominant pemphigus vulgaris with DSG3-CAAR T cells, the proposed work can build on this existing path from research to clinical translation. Moreover, we anticipate that our interdisciplinary approach will further elucidate fundamental mechanisms of disease and address the age-old question of whether the ERVs are cause or consequence of disease pathobiology.