Phase I trial of ATM inhibitor M3541 in combination with palliative radiotherapy in patients with solid tumors.

BACKGROUND: Ataxia telangiectasia mutated (ATM) kinase orchestrates DNA double strand break (DSB) repair; ATM inhibitors may therefore enhance the therapeutic effect of DSB-inducing treatments such as radiotherapy (RT). M3541 is an orally administered selective inhibitor of ATM. METHODS: This phase I dose-escalation study evaluated the maximum-tolerated dose (MTD), recommended phase II dose(s) (RP2D), safety, pharmacokinetics (PK) and antitumor activity of M3541 in combination with fractionated palliative RT in patients with solid tumors. Fifteen patients received palliative RT (30 Gy in 10 fractions) and escalating doses of M3541 (50-300 mg administered on RT fraction days) guided by a Bayesian 2-parameter logistic regression model with overdose control. RESULTS: Doses of M3541 up to 300 mg/fraction day were well tolerated. One patient (200 mg group) experienced two dose-limiting toxicities (urinary tract infection, febrile neutropenia) that resolved with antibiotics. All patients reported ≥ 1 treatment-emergent adverse event (TEAE) but none led to treatment discontinuation. No grade ≥ 4 TEAEs were reported and there was no indication of a dose effect for any TEAE. Three patients (20.0%; 95% confidence interval 4.3-48.1) had confirmed complete or partial response. M3541 total plasma levels did not increase with dose following single or repeated dosing. No relationship was observed between dose and changes in the ratio of phosphorylated to total ATM or in immune cell counts. CONCLUSIONS: The MTD and RP2D could not be established as the study closed early due to the absence of a dose-response relationship and non-optimal PK profile. No further clinical development of M3541 was pursued. (Trial registration number ClinicalTrials.gov NCT03225105. Registration date July 21, 2017).

Chimeric rat/human HER2 efficiently circumvents HER2 tolerance in cancer patients.

PURPOSE: Despite the great success of HER2 vaccine strategies in animal models, effective clinical results have not yet been obtained. We studied the feasibility of using DNA coding for chimeric rat/human HER2 as a tool to break the unresponsiveness of T cells from patients with HER2-overexpressing tumors (HER2-CP). EXPERIMENTAL DESIGN: Dendritic cells (DCs) generated from patients with HER2-overexpressing breast (n = 28) and pancreatic (n = 16) cancer were transfected with DNA plasmids that express human HER2 or heterologous rat sequences in separate plasmids or as chimeric constructs encoding rat/human HER2 fusion proteins and used to activate autologous T cells. Activation was evaluated by IFN-γ ELISPOT assay, perforin expression, and ability to halt HER2+ tumor growth in vivo. RESULTS: Specific sustained proliferation and IFN-γ production by CD4 and CD8 T cells from HER2-CP was observed after stimulation with autologous DCs transfected with chimeric rat/human HER2 plasmids. Instead, T cells from healthy donors (n = 22) could be easily stimulated with autologous DCs transfected with any human, rat, or chimeric rat/human HER2 plasmid. Chimeric HER2-transfected DCs from HER2-CP were also able to induce a sustained T-cell response that significantly hindered the in vivo growth of HER2(+) tumors. The efficacy of chimeric plasmids in overcoming tumor-induced T-cell dysfunction relies on their ability to circumvent suppressor effects exerted by regulatory T cells (Treg) and/or interleukin (IL)-10 and TGF-ß1. CONCLUSIONS: These results provide the proof of concept that chimeric rat/human HER2 plasmids can be used as effective vaccines for any HER2-CP with the advantage of being not limited to specific MHC. Clin Cancer Res; 20(11); 2910-21. ©2014 AACR.

Observador: un biosensor para monitorear el río

La localidad de Romang está ubicada al noreste de la Provincia de Santa Fe, Argentina, en el albardón costero del Río San Javier. La vida y la cultura de los habitantes de esta localidad están intimamente ligadas al río, que provee formas de subsistencia a gran parte de la población a traves de la pesca, la recreación y el suministro de agua potable. El objetivo de este trabajo, ganador del Segundo Premio del concurso Premio Argentino Junior del Agua AIDIS-WEF, fue seleccionar un biosensor (en este caso, se escogió a la especie Elodea o Egeria densa) y determinar si con este, se puede monitorear la calidad del agua del río San Javier desde el laboratorio escolar, detectando la presencia de pesticidas, que llegan al río por escorrentía de los campos cultivados

Observador: un biosensor para monitorear el río

La localidad de Romang está ubicada al noreste de la Provincia de Santa Fe, Argentina, en el albardón costero del Río San Javier. La vida y la cultura de los habitantes de esta localidad están intimamente ligadas al río, que provee formas de subsistencia a gran parte de la población a traves de la pesca, la recreación y el suministro de agua potable. El objetivo de este trabajo, ganador del Segundo Premio del concurso Premio Argentino Junior del Agua AIDIS-WEF, fue seleccionar un biosensor (en este caso, se escogió a la especie Elodea o Egeria densa) y determinar si con este, se puede monitorear la calidad del agua del río San Javier desde el laboratorio escolar, detectando la presencia de pesticidas, que llegan al río por escorrentía de los campos cultivados