CD19-targeting CAR T cell therapy in five patients with systemic sclerosis unsuitable for autologous stem cell transplantation.

Objectives: The efficacy of chimeric antigen receptor (CAR) T cell therapy in patients with systemic sclerosis (SSc) has been substantiated by a small number of case reports and series. An established treatment option for severe SSc is autologous stem cell transplantation (HSCT). The objective of this analysis was to assess the feasibility and safety of CD19-targeting CAR T cell therapy in patients with SSc who are unsuitable for HSCT. Methods: Five patients with SSc were treated between July 2023 and July 2024 with CAR T cells. The cells were produced in our academic Good Manufacturing Practice laboratory with a human anti-CD19 lentiviral construct and amplification in a CliniMACS Prodigy. The CAR T cells (1 Mio per kg) were reinfused on day 0, following lymphodepletion with fludarabine and cyclophosphamide. Results: All patients exhibited robust expansion of CAR T cells and B-cell depletion. No imminent cases of severe cytokine release syndrome, infection, or immune effector cell-associated neurotoxicity syndrome were recorded, and patients were treated as inpatients for a period of 2 to 3 weeks. Two patients were observed for a period of up to 12 months, 1 patient for 10 months, and 1 patient for 5 months. The observed outcomes indicated the presence of highly promising efficacy on the skin, lung, and gastrointestinal manifestations. One patient developed a fatal secondary haemophagocytic lymphohistiocytosis probably due to herpes simplex virus infection after an allergic reaction to acyclovir and consecutive massive CAR T expansion 2 months after therapy. We hypothesise an association with an underlying mutation in ten-eleven translocation methylcytosine dioxygenase 2, a protein that is mutated in various haematopoietic malignancies. Conclusions: The analysis of our 5 patients suggests that CD19-targeting CAR T cells are a feasible treatment option that can be used in patients who are ineligible for HSCT. Nevertheless, fatal side effects can occur, and we suggest a careful patient selection and screening for gene alterations in patients with abnormal blood count.