Integrated Clinical and Proteomic Profiling of CD19 Chimeric Antigen Receptor T Cell Therapy in Progressive Systemic Sclerosis.

OBJECTIVE

To characterize the clinical, immunologic, and proteomic changes associated with CD19 chimeric antigen receptor T cell therapy in patients with progressive systemic sclerosis (SSc).

METHODS

Patients with progressive SSc received CD19 chimeric antigen receptor (CAR)-T cell therapy and were observed longitudinally for safety, clinical efficacy, immune reconstitution, and plasma proteomic changes. Clinical assessments included skin, pulmonary, vascular, patient-reported, and physician-reported outcomes. Plasma proteins were profiled at baseline and serial post-treatment time points using the SomaScan platform. Differential protein abundance and pathway-level changes were analyzed to explore treatment-associated molecular remodeling.

RESULTS

CD19 CAR-T cell therapy was associated with manageable safety profiles and sustained clinical improvement across multiple SSc disease domains, including skin involvement and patient- and physician-assessed disease activity. Treatment induced rapid B cell depletion followed by immune reconstitution. Longitudinal proteomic profiling revealed coordinated changes in proteins and pathways related to inflammation, fibrosis, vascular remodeling, and immune regulation. At day 180, differential protein analysis identified treatment-associated shifts in multiple systemic sclerosis-relevant proteins, including down-regulation of proteins linked to profibrotic or inflammatory activity and up-regulation of proteins potentially associated with vascular repair or immune regulation. Pathway-level analyses further supported broad attenuation of inflammatory and fibrotic programs with relative enhancement of repair-associated biologic processes.

CONCLUSION

Relma-cel therapy in patients with SSc led to early clinical improvement, supported by CAR-T cell expansion, B cell depletion, and a favorable safety profile. Proteomic alterations were associated with the observed clinical improvements and suggested broad remodeling of inflammatory and fibrotic pathways. Further studies with larger sample sizes are warranted.