FLT3-directed UniCAR T-cell therapy of acute myeloid leukaemia.

Adaptor chimeric antigen receptor (CAR) T-cell therapy offers solutions for improved safety and antigen escape, which represent main obstacles for the clinical translation of CAR T-cell therapy in myeloid malignancies. The adaptor CAR T-cell platform 'UniCAR' is currently under early clinical investigation. Recently, the first proof of concept of a well-tolerated, rapidly switchable, CD123-directed UniCAR T-cell product treating patients with acute myeloid leukaemia (AML) was reported. Relapsed and refractory AML is prone to high plasticity under therapy pressure targeting one single tumour antigen. Thus, targeting of multiple tumour antigens seems to be required to achieve durable anti-tumour responses, underlining the need to further design alternative AML-specific target modules (TM) for the UniCAR platform. We here present the preclinical development of a novel FMS-like tyrosine kinase 3 (FLT3)-directed UniCAR T-cell therapy, which is highly effective for in vitro killing of both AML cell lines and primary AML samples. Furthermore, we show in vivo functionality in a murine xenograft model. PET analyses further demonstrate a short serum half-life of FLT3 TMs, which will enable a rapid on/off switch of UniCAR T cells. Overall, the presented preclinical data encourage the further development and clinical translation of FLT3-specific UniCAR T cells for the therapy of AML.

Pesticide residues in essential oils: evaluation of a database.

In the context of a revision of the European Pharmacopoeia (Ph. Eur.) general monograph Essential oils (2098), the need to include a test for pesticides is being discussed. According to published literature, some oils, mainly those produced by cold pressing (e.g. citrus oils), can contain relevant amounts of pesticide residues, whereas distilled oils showed positive findings in only a few cases. Recent evaluation of a database containing 127 517 sets of data compiled over 8 years, showed positive results in 1 150 cases (0.90 per cent), and the limits of Ph. Eur. general chapter 2.8.13 Pesticide residues or Regulation (EC) 396/2005, both applicable to herbal drugs, were exceeded in 392 cases (0.31 per cent, equivalent to 34.1 per cent of the positive results), particularly in cases of oils produced by cold pressing. From these results, it can be concluded that a general test on pesticides in the Ph. Eur. general monograph on essential oils is not required for most oils used in medicinal products. Therefore, it is proposed to limit the testing of essential oils for pesticide residues to those cases where potential residues are more of a concern, either due to the type of production process or to those processes where pesticides are actively used during cultivation of the plant (e.g. as documented according to Good Agricultural and Collection Practice (GACP)). Furthermore, in order to assess any potential risk, an approach using the Acceptable Daily Intake (ADI) can be made.

Two-dimensional electron transfer from cytochrome C to photosynthetic reaction centers.

The arrangement and the electron transfer are studied for photosynthetic reaction centers (RC) of Rhodopseudomonas sphaeroides reconstituted into phospholipid vesicles. Freeze-etch electron micrographs of phase separated mixed vesicles reveal an RC enrichment in the phase containing the acidic lipid serine. It is demonstrated that the electron transfer from cytochrome c to RC involves a two-dimensional diffusion of the membrane bound electron donor with diffusion coefficients (D approximately 10(-9) cm2/sec) characteristic for membrane proteins.