Definition and application of good manufacturing process-compliant production of CEA-specific chimeric antigen receptor expressing T-cells for phase I/II clinical trial.

Adoptive cell therapy employing gene-modified T-cells expressing chimeric antigen receptors (CARs) has shown promising preclinical activity in a range of model systems and is now being tested in the clinical setting. The manufacture of CAR T-cells requires compliance with national and European regulations for the production of medicinal products. We established such a compliant process to produce T-cells armed with a first-generation CAR specific for carcinoembryonic antigen (CEA). CAR T-cells were successfully generated for 14 patients with advanced CEA(+) malignancy. Of note, in the majority of patients, the defined procedure generated predominantly CD4(+) CAR T-cells with the general T-cell population bearing an effector-memory phenotype and high in vitro effector function. Thus, improving the process to generate less-differentiated T-cells would be more desirable in the future for effective adoptive gene-modified T-cell therapy. However, these results confirm that CAR T-cells can be generated in a manner compliant with regulations governing medicinal products in the European Union.

Sources and fate of nitrosodimethylamine and its precursors in municipal wastewater treatment plants.

To assess the occurrence and fate of nitrosodimethylamine (NDMA) and its precursors in wastewater treatment plants, samples from wastewater treatment plants and industrial sources were analyzed for NDMA, total NDMA precursors, and dimethylamine (DMA). The median concentration of NDMA in untreated wastewater was approximately 80 ng/L, with maximum concentrations up to 790 ng/L presumably occuring because of sources unrelated to domestic wastewater. Concentrations of DMA in untreated wastewater ranged from approximately 50 to 120 microg/L and accounted for a majority of the NDMA precursors. The removal of NDMA during secondary biological treatment exhibited considerable variability, with overall removal ranging from 0 to 75%. In contrast, removal of NDMA precursors and DMA generally exceeded 70%. The median concentration of NDMA in secondary effluent before disinfection was 46 ng/L. Although DMA was removed during secondary treatment, other NDMA precursors in wastewater effluent will result in formation of additional NDMA upon disinfection with chloramines.