IMscin001 Part 2: a randomised phase III, open-label, multicentre study examining the pharmacokinetics, efficacy, immunogenicity, and safety of atezolizumab subcutaneous versus intravenous administration in previously treated locally advanced or metastatic non-small-cell lung cancer and pharmacokinetics comparison with other approved indications.

BACKGROUND: Atezolizumab intravenous (IV) is approved for the treatment of various solid tumours. To improve treatment convenience and health care efficiencies, a coformulation of atezolizumab and recombinant human hyaluronidase PH20 was developed for subcutaneous (SC) use. Part 2 of IMscin001 (NCT03735121) was a randomised phase III, open-label, multicentre, noninferiority study comparing the drug exposure of atezolizumab SC with atezolizumab IV. PATIENTS AND METHODS: Eligible patients with locally advanced/metastatic non-small-cell lung cancer were randomised 2 : 1 to receive atezolizumab SC (1875 mg; n = 247) or IV (1200 mg; n = 124) every 3 weeks. The co-primary endpoints were cycle 1 observed trough serum concentration (Ctrough) and model-predicted area under the curve from days 0 to 21 (AUC0-21 d). The secondary endpoints were steady-state exposure, efficacy, safety, and immunogenicity. Exposure following atezolizumab SC was then compared with historical atezolizumab IV values across approved indications. RESULTS: The study met both of its co-primary endpoints: cycle 1 observed Ctrough {SC: 89 µg/ml [coefficient of variation (CV): 43%] versus IV: 85 µg/ml (CV: 33%); geometric mean ratio (GMR), 1.05 [90% confidence interval (CI) 0.88-1.24]} and model-predicted AUC0-21 d [SC: 2907 µg d/ml (CV: 32%) versus IV: 3328 µg d/ml (CV: 20%); GMR, 0.87 (90% CI 0.83-0.92)]. Progression-free survival [hazard ratio 1.08 (95% CI 0.82-1.41)], objective response rate (SC: 12% versus IV: 10%), and incidence of anti-atezolizumab antibodies (SC: 19.5% versus IV: 13.9%) were similar between arms. No new safety concerns were identified. Ctrough and AUC0-21 d for atezolizumab SC were consistent with the other approved atezolizumab IV indications. CONCLUSIONS: Compared with IV, atezolizumab SC demonstrated noninferior drug exposure at cycle 1. Efficacy, safety, and immunogenicity were similar between arms and consistent with the known profile for atezolizumab IV. Similar drug exposure and clinical outcomes following SC and IV administration support the use of atezolizumab SC as an alternative to atezolizumab IV.

Enhancement of a constitutively active promoter for gene therapy by a positive feed-back transcriptional activator mechanism.

Success of gene replacement therapy depends on long-term, high level expression of the transgene. Gene therapy vectors incorporating a promoter of a constitutively active eukaryotic gene may allow long-term expression in vivo, but the expression level may be insufficient for therapeutic effects. To enhance transcription from eukaryotic promoters, a strategy with dicistronic vectors encoding the therapeutic gene of interest together with a transcription factor that binds and activates the promoter was tested. Expression vectors for the chimeric tet repressor/VP16 transcription factor (tTA) driven by the human beta-actin promoter were constructed, and tandem tet operators were inserted within the promoter. This arrangement significantly enhanced expression of G-CSF in fibroblasts to higher levels than the immediate/early CMV promoter. Stably transfected fibroblast clones produced up to 2.4 microg G-CSF per 10(6) cells x 24 h. After injection of genetically engineered cells into SCID mice, the enhanced beta-actin promoter construct resulted in marked leukocytosis, whereas the unmodified promoter had only a marginal therapeutic effect. Transcription factor-enhanced, feed-back-activated human promoters may thus achieve higher expression levels than viral control elements, and may be advantageous for gene therapy due to high constitutive activity in vivo.

Influencia del G-CSF en el crecimiento celular en el adenocarcinoma ovarico / Influence of G-CSP on the proliferation an ovarian adenocarcinoma cell line

El factor de crecimiento hematopoyético G-CSF (factor estimulante de las colonias de granulocitos) es clínicamente usado para superar períodos de neutropenia y para aumentar los niveles endógenos de neutrófilos durante la quimioterapia. Sin embargo poco es lo conocido acerca de los aspectos sobre células tumorales. Por el otro lado, los cánceres de ovario son frecuentemente infiltrados con glóbulos blancos que producen localmente G-CSF, por lo tanto esta cytoquina puede en forma sistémica o parácrina jugar un importante rol en el desarrollo tumoral en tumores que presentan receptores de G-CSF. Las cytoquinas pueden presentar ambos efectos, positivo o negativo, en las células que presentan cancerogénesis, signos incipientes de proliferación, diferenciación o apoptosis. Ellas juegan un rol mayor en la determinación del microambiente tumoral por las interacciones entre el huésped y las células tumorales en los estadios precoces del desarrollo tumoral y el crecimiento celular

Influencia del G-CSF en el crecimiento celular en el adenocarcinoma ovarico / Influence of G-CSP on the proliferation an ovarian adenocarcinoma cell line

El factor de crecimiento hematopoyético G-CSF (factor estimulante de las colonias de granulocitos) es clínicamente usado para superar períodos de neutropenia y para aumentar los niveles endógenos de neutrófilos durante la quimioterapia. Sin embargo poco es lo conocido acerca de los aspectos sobre células tumorales. Por el otro lado, los cánceres de ovario son frecuentemente infiltrados con glóbulos blancos que producen localmente G-CSF, por lo tanto esta cytoquina puede en forma sistémica o parácrina jugar un importante rol en el desarrollo tumoral en tumores que presentan receptores de G-CSF. Las cytoquinas pueden presentar ambos efectos, positivo o negativo, en las células que presentan cancerogénesis, signos incipientes de proliferación, diferenciación o apoptosis. Ellas juegan un rol mayor en la determinación del microambiente tumoral por las interacciones entre el huésped y las células tumorales en los estadios precoces del desarrollo tumoral y el crecimiento celular (AU)