Single CAR-T cell treatment controls disseminated ovarian cancer in a syngeneic mouse model.

BACKGROUND: Treatment of some blood cancers with T cells that express a chimeric antigen receptor (CAR) against CD19 have shown remarkable results. In contrast, CAR-T cell efficacy against solid tumors has been difficult to achieve. METHODS: To examine the potential of CAR-T cell treatments against ovarian cancers, we used the mouse ovarian cancer cell line ID8 in an intraperitoneal model that exhibits disseminated solid tumors in female C57BL/6J mice. The CAR contained a single-chain Fv from antibody 237 which recognizes a Tn-glycopeptide-antigen expressed by ID8 due to aberrant O-linked glycosylation in the absence of the transferase-dependent chaperone Cosmc. The efficacy of four Tn-dependent CARs with varying affinity to Tn antigen, and each containing CD28/CD3ζ cytoplasmic domains, were compared in vitro and in vivo in this study. RESULTS: In line with many observations about the impact of aberrant O-linked glycosylation, the ID8Cosmc knock-out (ID8Cosmc-KO) exhibited more rapid tumor progression compared with wild-type ID8. Despite the enhanced tumor growth in vivo, 237 CAR and a mutant with 30-fold higher affinity, but not CARs with lower affinity, controlled advanced ID8Cosmc-KO tumors. Tumor regression could be achieved with a single intravenous dose of the CARs, but intraperitoneal administration was even more effective. The CAR-T cells persisted over a period of months, allowing CAR-treated mice to delay tumor growth in a re-challenge setting. The most effective CARs exhibited the highest affinity for antigen. Antitumor effects observed in vivo were associated with increased numbers of T cells and macrophages, and higher levels of cleaved caspase-3, in the tumor microenvironment. Notably, the least therapeutically effective CAR mediated tonic signaling leading to antigen-independent cytokine expression and it had higher levels of the immunosuppressive cytokine interleukin10. CONCLUSION: The findings support the development of affinity-optimized CAR-T cells as a potential treatment for established ovarian cancer, with the most effective CARs mediating a distinct pattern of inflammatory cytokine release in vitro. Importantly, the most potent Tn-dependent CAR-T cells showed no evidence of toxicity in tumor-bearing mice in a syngeneic, immunocompetent system.

An artificial neural network approach for predicting hypertension using NHANES data.

This paper focus on a neural network classification model to estimate the association among gender, race, BMI, age, smoking, kidney disease and diabetes in hypertensive patients. It also shows that artificial neural network techniques applied to large clinical data sets may provide a meaningful data-driven approach to categorize patients for population health management, and support in the control and detection of hypertensive patients, which is part of the critical factors for diseases of the heart. Data was obtained from the National Health and Nutrition Examination Survey from 2007 to 2016. This paper utilized an imbalanced data set of 24,434 with (69.71%) non-hypertensive patients, and (30.29%) hypertensive patients. The results indicate a sensitivity of 40%, a specificity of 87%, precision of 57.8% and a measured AUC of 0.77 (95% CI [75.01-79.01]). This paper showed results that are to some degree more effectively than a previous study performed by the authors using a statistical model with similar input features that presents a calculated AUC of 0.73. This classification model can be used as an inference agent to assist the professionals in diseases of the heart field, and can be implemented in applications to assist population health management programs in identifying patients with high risk of developing hypertension.