Investigation of effect of nintedanib in experimental uveitis model.

PURPOSE: This study aims to investigate the protective efficacy of nintedanib in experimental uveitis induced by endotoxins. MATERIALS AND METHODS: In this study, 24 Wistar albino rats were randomly divided into three groups: Group I was the healthy control with no uveitis that did not receive any treatment, Group II (sham) group did not receive treatment, and Group III (nintedanib) received oral nintedanib for 10 days. On the 10th day, endotoxin-induced uveitis (EIU) was induced by lipopolysaccharide (LPS) injection in Groups II and III. The clinical activity score was evaluated in all groups at the 24th hour, when uveitis formation was thought to be the most intense after LPS injection. All rats were then killed via anaesthesia. Tumour necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) levels were measured in their right eyes using the enzyme-linked immunosorbent assay (ELISA) method. Further, histopathological examinations were performed on their left eyes. RESULTS: For Groups I, II, and III, the IL-6 levels were 30.88 ± 1.79, 36.77 ± 1.21, and 30.93 ± 3.96 mg/pr, respectively, and TNF-α levels were 50.20 ± 3.24, 59.87 ± 2.98, and 50.23 ± 4.83 mg/pr, respectively. IL-6, TNF-α levels and clinical activity score were higher in the sham group compared to the other groups, and it decreased significantly in the treatment group (p < 0.05). Intense inflammatory cell infiltration of the ciliary body, edema and hyperaemia were evident in the sham group compared to the healthy control group (p < 0.05). These pathological findings were significantly decreased in the treatment group compared to the sham group (p < 0.05). CONCLUSION: Nintedanib may be preferable as a new agent for treating non-infectious uveitis. However, further studies are needed to evaluate its long-term effects, effects on other antiinflammatory pathways, side-effects, and ideal dose optimization.

Thiol/disulfide homeostasis in patients with ocular-active and ocular-inactive Behçet disease.

PURPOSE: To evaluate thiol/disulfide homeostasis in ocular-active (OA) and ocular-inactive (OI) Behçet disease (BD) patients and compare the data with healthy subjects. METHODS: Twenty OABD patients, 20 OIBD patients and 20 healthy control subjects were included into the study. The BD ocular attack score 24 (BOS24) scoring system was used to assess the activity of disease in ocular BD patients. Systemic activity was also evaluated using BD current activity form (BDCAF). The native thiol (NT), total thiol (TT) and disulfide levels and NT/TT, disulfide/NT and disulfide/TT ratios were measured via using an innovative and automated method. RESULTS: BOS24 and BDCAF scores were 13.25 ± 2.32 and 4.18 ± 2.06 in OABD patients and 0.31 ± 0.47 and 2.14 ± 1.98 in OIBD patients, respectively. The NT, TT levels and NT/TT ratio were significantly reduced; in contrast, the disulfide levels, disulfide/NT and disulfide/TT ratios were significantly increased in OABD and OIBD patients compared to the healthy control subjects (p < 0.05). Moreover, while the levels of NT and TT were significantly reduced, the disulfide levels as well as disulfide/NT and disulfide/TT ratios were significantly elevated between OABD and OIBD patients (p < 0.05). However, the ratio of NT/TT did not significantly differ between OABD and OIBD patients (p = 0.449). The multiple regression model including BOS24 and BDCAF score statistically significantly predicted NT level, TT level and disulfide level (p < 0.001 for all). CONCLUSION: Thiol oxidation in BD patients resulted in a change of the thiol/disulfide balance. Therefore, thiol/disulfide homeostasis in BD patients can be used an innovative oxidative stress marker.

Stressed target cancer cells drive nongenetic reprogramming of CAR T cells and tumor microenvironment, overcoming multiple obstacles of CAR T therapy for solid tumors.

The poor efficacy of chimeric antigen receptor T-cell therapy (CAR T) for solid tumor is due to insufficient CAR T cell tumor infiltration, in vivo expansion, persistence, and effector function, as well as exhaustion, intrinsic target antigen heterogeneity or antigen loss of target cancer cells, and immunosuppressive tumor microenvironment (TME). Here we describe a broadly applicable nongenetic approach that simultaneously addresses the multiple challenges of CAR T as a therapy for solid tumors. The approach massively reprograms CAR T cells by exposing them to stressed target cancer cells which have been exposed to the cell stress inducer disulfiram (DSF) and copper (Cu)(DSF/Cu) plus ionizing irradiation (IR). The reprogrammed CAR T cells acquired early memory-like characteristics, potent cytotoxicity, enhanced in vivo expansion, persistence, and decreased exhaustion. Tumors stressed by DSF/Cu and IR also reprogrammed and reversed immunosuppressive TME in humanized mice. The reprogrammed CAR T cells, derived from peripheral blood mononuclear cells (PBMC) of healthy or metastatic breast cancer patients, induced robust, sustained memory and curative anti-solid tumor responses in multiple xenograft mouse models, establishing proof of concept for empowering CAR T by stressing tumor as a novel therapy for solid tumor.

CAR T Cell-Based Immunotherapy for the Treatment of Glioblastoma.

Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary brain tumor in adults. Current treatment options typically consist of surgery followed by chemotherapy or more frequently radiotherapy, however, median patient survival remains at just over 1 year. Therefore, the need for novel curative therapies for GBM is vital. Characterization of GBM cells has contributed to identify several molecules as targets for immunotherapy-based treatments such as EGFR/EGFRvIII, IL13Rα2, B7-H3, and CSPG4. Cytotoxic T lymphocytes collected from a patient can be genetically modified to express a chimeric antigen receptor (CAR) specific for an identified tumor antigen (TA). These CAR T cells can then be re-administered to the patient to identify and eliminate cancer cells. The impressive clinical responses to TA-specific CAR T cell-based therapies in patients with hematological malignancies have generated a lot of interest in the application of this strategy with solid tumors including GBM. Several clinical trials are evaluating TA-specific CAR T cells to treat GBM. Unfortunately, the efficacy of CAR T cells against solid tumors has been limited due to several factors. These include the immunosuppressive tumor microenvironment, inadequate trafficking and infiltration of CAR T cells and their lack of persistence and activity. In particular, GBM has specific limitations to overcome including acquired resistance to therapy, limited diffusion across the blood brain barrier and risks of central nervous system toxicity. Here we review current CAR T cell-based approaches for the treatment of GBM and summarize the mechanisms being explored in pre-clinical, as well as clinical studies to improve their anti-tumor activity.

Anti-inflammatory effect of cortistatin in rat endotoxin-induced uveitis model.

PURPOSE: To evaluate the anti-inflammatory effect of cortistatin (CST) in endotoxin-induced uveitis (EIU) model and to compare the results with corticosteroid treatment. METHODS: A total of 35 healthy Wistar albino rats were randomly divided into five groups. EIU was induced by a single subcutaneous injection of lipopolysaccharide (LPS). Group I received intraperitoneal (ip) normal saline (NS), Group II received ip 150 µg LPS plus NS, Group III received ip 150 µg LPS plus 250 µg/kg CST, Group IV received ip 150 µg LPS plus 1mg/kg dexamethasone, and Group V received ip 250 µg/kg CST only. The aqueous humor was collected 24 h after injection and the infiltrating cells were determined. Moreover, histopathological and immunohistochemical examinations were also performed. RESULTS: The clinical score and infiltrated cell count were reduced in Groups III and IV compared with Group II (P < 0.001). The pathological findings of Groups III and IV were significantly reduced compared with Group II (P < 0.001). These findings were similar between Groups III and IV (P = 1.000). Tumor necrosis factor-alpha (TNF-α) and interleukin 1 beta (IL-1ß) immunoreactivity in the ciliary body of Group III and Group IV were significantly reduced compared with Group II (P < 0.001). TNF-α and IL-1ß immunoreactivity in the ciliary body of Group III and Group IV were similar compared with Group I and Group V (range of P values was 0.539-0.958). CONCLUSION: CST administration as a therapeutic agent might ameliorate the severity of intraocular inflammation in uveitis patients. In conclusion, effect of CST and dexamethasone in EIU model was comparable.