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

Abstract

ObjectiveTo 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 (SSc).MethodsB 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 6 weeks of clinical evaluation, different validated markers of inflammation, lung fibrosis and pulmonary vascular remodeling were assessed.ResultsCD19‐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 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, 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.ConclusionB‐cell therapies failed to show efficacy in the Fra2 transgenic 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.

Soquelitinib, A Selective Inhibitor of Interleukin-2-Inducible T Cell Kinase (ITK), is Active in Several Murine Models of T Cell-Mediated Inflammatory Disease

“…Disease severity was assessed using a ten point scale as previously reported 19,20 . One point was given for the presence of blepharitis, alopecia, skin lesions, abnormal fur texture, hepatomegaly, hunched posture, or impaired mobility.…”

“…This mutation results in widespread inflammation, vasculopathy, pulmonary fibrosis, and pulmonary hypertension. The mice develop vascular injury which precedes fibrosis as is seen in systemic sclerosis 19,20 . The model and techniques for its assessment have been previously described 19,20 .…”

“…The mice develop vascular injury which precedes fibrosis as is seen in systemic sclerosis 19,20 . The model and techniques for its assessment have been previously described 19,20 . In the description of results, we refer to these mice that over express Fra-2 simply as Fra-2 mice.…”

Chimeric antigen receptor T cell therapy: a new emerging landscape in autoimmune rheumatic diseases

“…The ASyS case mentioned earlier [ 13 ] exemplifies this complexity, wherein enhanced CD8 + T cells were detected in circulation following CAR-T treatment, leading to the incorporation of additional T cell suppressive drugs due to concerns about potential relapse. A recent report of the failure of murine CD19-targeted CAR-T therapy on an SSc animal model also suggested that CAR-T design should be consistent with disease pathogenesis [ 49 ]. The study used a Fra-2 transgenic mouse model, which could well mimic the fibrosis and vasculopathy of SSc but lacks the typical autoimmune response [ 50 , 51 ].…”

“…The study used a Fra-2 transgenic mouse model, which could well mimic the fibrosis and vasculopathy of SSc but lacks the typical autoimmune response [ 50 , 51 ]. Although CD19-targeted CAR-T combined with anti-CD20 monoclonal antibody achieved deeper B cell depletion in the peripheral blood and lungs of Fra-2 mice than anti-CD20 monoclonal antibody alone, it did not improve overall outcomes, and even worsened the pulmonary fibrosis and pulmonary hypertension [ 49 ]. This is partly because B cells do not play a key role in the pathogenesis of Fra-2 transgenic mice, verified by the result that the anti-CD20 monoclonal antibody group did not show a significant difference compared with the control group.…”