CAR T-Cell Therapy: New Frontiers in Diffuse Systemic Sclerosis Treatment

Systemic sclerosis (SSc) is an autoimmune disease characterized by widespread fibrosis, vasculopathy, and immune dysregulation. It has one of the highest mortality rates among autoimmune rheumatic diseases and significantly impacts patients’ quality of life due to skin thickening, vascular dysfunction, and progressive fibrotic damage to internal organs.

While immunomodulatory and antifibrotic treatments can slow disease progression, they often fail to provide lasting control. However, chimeric antigen receptor (CAR) T-cell therapy may offer new hope for patients with SSc.

Research on CAR T-Cell Therapy in SSc

B-cell dysregulation has been linked to fibroblast activation and the pathogenesis of SSc. By targeting CD19, a surface antigen on B cells, CAR T-cell therapy presents a new method of deep B-cell depletion with the goal of an immune reset.CD19-targeted CAR T-cell therapy has shown promising outcomes in systemic lupus erythematosus (SLE) and myositis.

A recent study in The Lancet Rheumatology reported the first evidence supporting the efficacy of CD19-targeted CAR T-cell therapy against the progression of fibrotic organ manifestations in SSc. Six patients with severe diffuse cutaneous SSc who had previously failed at least two treatments were enrolled at the University Hospital Erlangen, Germany. Primary outcomes included event-free survival or the need for treatment intensification, and secondary outcomes measured changes in modified Rodnan Skin Score (mRSS), modified American College of Rheumatology Composite Response Index in Systemic Sclerosis (ACR-CRISS), laboratory assessments, imaging, and patient-reported outcomes.

No progression of organ manifestations or new lung, cardiac, or renal events were observed during a median follow-up period of 487 days. Key findings included:

• Skin Improvement: Skin fibrosis, measured by mRSS—a tool assessing skin thickness—showed a median decrease of 8 points, or 31 percent, within 100 days.
• Lung Function and Imaging: Lung disease, as seen on CT imaging, decreased by a median of 4 percent. Forced vital capacity increased by a median of 195.
• Disease Activity: The ACR-CRISS score, a composite endpoint to evaluate the probability of improvement in SSc, showed a 100 percent median improvement at six months.
• Safety: Cytokine release syndrome was absent or mild. There were no cases of immune effector cell-associated neurotoxicity syndrome. All patients experienced an infection during the follow-up period, with one experiencing a bacterial superinfection.

Looking Ahead

This study suggested that CD19-targeted CAR T-cell therapy may halt fibrotic progression and improve both skin and lung involvement in diffuse SSc. While these case results were promising, extended follow-up studies are needed to validate sustained disease modification. Given that interstitial lung disease in SSc often alternates between periods of stability and progression, differentiating treatment effects from the natural disease course would be valuable.

As CD19-targeted CAR T-cell research advances as a treatment for rheumatic diseases, addressing implementation challenges observed with approved CAR T-cell therapies for hematological malignancies may provide valuable insights to support the development of this potential treatment option for SSc.

References:

Armanet, N., & A Montero Julian, F. (2024). Unleashing potential: tackling CAR-T cell production challenges to support the treatment of blood cancer. Cell and Gene Therapy Insights, 10(01), 149–157. https://doi.org/10.18609/cgti.2024.022

Auth, J., Müller, F., Völkl, S., Bayerl, N., Distler, J. H. W., Tur, C., Raimondo, M. G., Chenguiti Fakhouri, S., Atzinger, A., Coppers, B., Eckstein, M., Liphardt, A. M., Bäuerle, T., Tascilar, K., Aigner, M., Kretschmann, S., Wirsching, A., Taubmann, J., Hagen, M., Györfi, A. H., … Bergmann, C. (2024). CD19-targeting CAR T-cell therapy in patients with diffuse systemic sclerosis: a case series. The Lancet. Rheumatology, S2665-9913(24)00282-0. Advance online publication. https://doi.org/10.1016/S2665-9913(24)00282-0

Ayala Ceja, M., Khericha, M., Harris, C. M., Puig-Saus, C., & Chen, Y. Y. (2024). CAR-T cell manufacturing: major process parameters and next-generation strategies. Journal of Experimental Medicine, 221(2), e20230903.

Khanna, D., Furst, D. E., Clements, P. J., Allanore, Y., Baron, M., Czirjak, L., Distler, O., Foeldvari, I., Kuwana, M., Matucci-Cerinic, M., Mayes, M., Medsger, T., Jr, Merkel, P. A., Pope, J. E., Seibold, J. R., Steen, V., Stevens, W., & Denton, C. P. (2017). Standardization of the modified Rodnan skin score for use in clinical trials of systemic sclerosis. Journal of scleroderma and related disorders, 2(1), 11–18.

Khanna, D., Huang, S., Lin, C. J. F., & Spino, C. (2021). New composite endpoint in early diffuse cutaneous systemic sclerosis: revisiting the provisional American College of Rheumatology Composite Response Index in Systemic Sclerosis. Annals of the rheumatic diseases, 80(5), 641–650. https://doi.org/10.1136/annrheumdis-2020-219100

Lungova, K., & Putman, M. (2024). Barriers to CAR T-cell therapy in rheumatology. The Lancet. Rheumatology, S2665-9913(24)00240-6. Advance online publication. https://doi.org/10.1016/S2665-9913(24)00240-6