Effects of B Cell Depletion by CD19‐Targeted Chimeric Antigen Receptor T Cells in a Murine Model of Systemic Sclerosis

Objective Our goal was to study the tolerance and efficacy of two B cell depletion strategies, including one with CD19‐targeted chimeric antigen receptor (CAR) T cells, in a preclinical model mimicking the severe lung damages observed in systemic sclerosis. Methods B cell depletion strategies were evaluated in the Fra‐2 transgenic (Tg) mouse model. We considered a first group of 16 untreated mice, a second group of 15 mice receiving a single dose of anti‐CD20 monoclonal antibody (mAb), and a third group of 8 mice receiving CD19‐targeted CAR‐T cells in combination with anti‐CD20 monoclonal antibody. After six weeks of clinical evaluation, different validated markers of inflammation, lung fibrosis, and pulmonary vascular remodeling were assessed. Results CD19‐targeted CAR‐T cells infusion in combination with anti‐CD20 mAb resulted in a deeper B cell depletion than anti‐CD20 mAb alone in the peripheral blood and lesional lungs of Fra‐2 Tg mice. CAR‐T cell infusion worsened the clinical score and increased mortality in Fra‐2 Tg mice. In line with the above findings, CAR‐T cell infusion significantly increased lung collagen content, the histological fibrosis score, and right ventricular systolic pressure. CAR‐T cells accumulated in lesional lungs and promoted T activation and inflammatory cytokine production. Treatment with anti‐CD20 mAb in monotherapy had no impact on lung inflammation–driven fibrosis and pulmonary hypertension. Conclusion B cell therapies failed to show efficacy in the Fra2 Tg mice. The exacerbated Fra‐2 lung inflammatory burden stimulated accumulation and expansion of activated CD19‐targeted CAR‐T cells, secondarily inducing T cell activation and systemic inflammation, finally leading to disease worsening.