Few studies have described chimeric antigen receptor–modified T cell (CAR-T) therapy for central nervous system (CNS) B-cell acute lymphocytic leukemia (B-ALL) patients due to life-threatening CAR-T-related encephalopathy (CRES) safety issues. In this study, CAR-Ts targeting CD19 with short hairpin RNA (shRNA)-IL-6 gene silencing technology (ssCART-19s) were prepared. We conducted a phase 1 clinical trial ( ClinicalTrials.gov number, NCT03064269 ). Three patients with relapsed CNS B-ALL were enrolled, conditioned with the fludarabine and cyclophosphamide for lymphocyte depletion and infused with ssCART-19s for three consecutive days. Clinical symptoms and laboratory examinations were monitored. After ssCART-19 treatment, three patients' symptoms resolved almost entirely. Brain leukemic infiltration reduced significantly based on magnetic resonance imaging (MRI), and there were no leukemic blasts in cerebrospinal fluid (CSF), which was confirmed by cytological and molecular examinations. Additionally, increases in the levels of cytokines and immune cells were observed in the CSF of all patients. Only grade 1 cytokine release syndrome (CRS) manifesting as fever was noted in patients. In conclusion, CAR-Ts with shRNA-IL-6 gene knockdown migrated into the CNS, eradicated leukemic cells and elevated cytokines in CSF with mild, acceptable side effects.

Neuromyelitis optica spectrum disorder (NMOSD) likely results from humoral immune abnormalities. The role that helper T cells play in the pathogenesis of this disease is not fully understood. To ascertain the clinical significance of two important costimulatory molecules required for T-cell activation in the peripheral blood of patients with NMOSD, we examined the expression levels of a membrane- and soluble-type inducible costimulatory molecule (ICOS), its ligand (ICOSL), programmed death-1 (PD-1), and its ligand (PD-L1) in the peripheral blood of 30 patients with NMOSD and compared these levels with those in patients with longitudinally extensive transverse myelitis (LETM), those with optic neuritis (ON), and healthy controls (HCs). Our results showed that the ICOS/ICOSL and PD-1/PD-L1 pathways may play important roles in the early stages of NMOSD pathogenesis. ICOS and PD-1 are potential therapeutic targets and valuable biomarkers for the differential diagnosis of early-stage NMOSD.

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Background. A previous study on thymomas in myasthenia gravis (MG) patients indicated that OX40 expression may be upregulated in thymic tissues adjacent to germinal centers (GCs) and thymomas, and OX40 may interact with OX40L in GCs to enhance anti-acetylcholine receptor antibody production. However, little is known about the clinical significance of the expression of OX40 and OX40L in the peripheral blood of patients with MG. We aimed to characterize the expression of membrane-bound and soluble OX40 and OX40L in the peripheral blood of patients with MG and to identify their clinical significance. Methods. For membrane molecules, we collected peripheral blood (PB) from 39 MG patients at baseline, 22 patients in relapse, and 42 patients in remission, as well as from 36 healthy participants as controls. For soluble molecules, plasma from 37 MG patients at baseline, 34 patients in relapse, and 30 patients in remission, as well as plasma from 36 healthy controls (HC), was retrospectively collected from the sample bank of the First Hospital of Soochow University. The expression of membrane-bound OX40 and OX40L (mOX40 and mOX40L) by immune cells was measured using flow cytometry. Plasma levels of soluble OX40 and OX40L (sOX40 and sOX40L) were measured by ELISA. Results. (1) The expression of OX40 on CD4+ T cells and that of OX40L on B cells and monocytes were significantly increased, and the levels of sOX40 were significantly decreased in MG patients at baseline compared with HC, while the expression of sOX40L was not significantly different between the two groups. (2) Dynamic observation of the molecules showed significantly higher expression of OX40 on CD4+ T cells and higher levels of sOX40 in MG patients in relapse than in MG patients at baseline and MG patients in remission. Furthermore, the expression levels of sOX40 were significantly elevated in MG patients in remission compared with MG patients at baseline, and the expression of sOX40L was significantly lower in MG patients in remission than in MG patients at baseline and MG patients in relapse. (3) Plasma levels of sOX40 and sOX40L were significantly decreased in 13 patients with relapsed MG after immunosuppressive treatment compared with those before treatment. (4) Correlation analysis showed that the expression of OX40 on CD4+ T cells in patients with relapsed MG was positively correlated with the concentration of acetylcholine receptor antibodies (AchR-Ab), whereas the expression of OX40L on CD19+ B cells and CD14+ monocytes was negatively correlated with disease duration. (5) Binary regression analysis showed that patients with high CD4+ OX40 expression and high sOX40L levels had an increased risk of relapse. Conclusions. OX40 and OX40L are abnormally expressed in the peripheral blood of patients with MG and may be closely associated with disease status and treatment. The OX40/OX40L pathway may be involved in the immunopathological process of MG and may play a role mainly in the later stage of MG.