0000000000485208
AUTHOR
Jean-charles Soria
showing 8 related works from this author
Abstract LB-220: Translational research with RG7160 (GA201) leads to a phase II clinical study in combination with FOLFIRI in 2nd line metastatic col…
2012
Abstract GA201 is a novel dual-acting humanized, engineered IgG1 anti-EGFR mAb designed to enhance ADCC in combination with signaling inhibition. Superior efficacy was demonstrated versus cetuximab in orthotopic CRC xenograft models. Preclinical data indicated an increase in macrophages (4-5 fold) and NK cells (2-3 fold) infiltration in tumors treated with GA201 compared to cetuximab. In a phase I clinical study objective responses and long lasting disease stabilizations were observed. A marked reduction in circulating NK cells and an increased infiltration of immune cells into skin rash was seen. Preliminary evidence of the enhanced ADCC capacity of GA201 was investigated in 25 third line …
Enterococcus hirae and Barnesiella intestinihominis Facilitate Cyclophosphamide-Induced Therapeutic Immunomodulatory Effects.
2016
International audience; The efficacy of the anti-cancer immunomodulatory agent cyclophosphamide (CTX) relies on intestinal bacteria. How and which relevant bacterial species are involved in tumor immunosurveillance, and their mechanism of action are unclear. Here, we identified two bacterial species, Enterococcus hirae and Barnesiella intestinihominis that are involved during CTX therapy. Whereas E. hirae translocated from the small intestine to secondary lymphoid organs and increased the intratumoral CD8/ Treg ratio, B. intestinihominis accumulated in the colon and promoted the infiltration of IFN-gamma-producing gamma delta Tau cells in cancer lesions. The immune sensor, NOD2, limited CTX…
PARP inhibition enhances tumor cell-intrinsic immunity in ERCC1-deficient non-small cell lung cancer.
2018
The cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway detects cytosolic DNA to activate innate immune responses. Poly(ADP-ribose) polymerase inhibitors (PARPi) selectively target cancer cells with DNA repair deficiencies such as those caused by BRCA1 mutations or ERCC1 defects. Using isogenic cell lines and patient-derived samples, we showed that ERCC1-defective non-small cell lung cancer (NSCLC) cells exhibit an enhanced type I IFN transcriptomic signature and that low ERCC1 expression correlates with increased lymphocytic infiltration. We demonstrated that clinical PARPi, including olaparib and rucaparib, have cell-autonomous immunomodulatory properties in ERCC1-defecti…
A phase Ib study of the Akt inhibitor GDC-0068 with docetaxel (D) or mFOLFOX-6 (F) in patients (pts) with advanced solid tumors.
2012
3021 Background: Activation of the Akt pathway is observed in multiple tumors and may contribute to chemoresistance. GDC-0068 is an ATP-competitive small molecule inhibitor of all three isoforms of Akt; in a phase Ia study, it was well tolerated with maximum tolerated dose (MTD) of 600 mg daily (21 days on/7days off) and pharmacodynamic down-regulation of Akt signaling in tumors at doses ≥100 mg. In vitro, GDC-0068 shows synergism with cytotoxic agents. This phase Ib study defines the dose limiting toxicities (DLT), MTD, safety and pharmacokinetics (PK) of GDC0068 in combination with D and F. Methods: Using a 3+3 designeligible patients (pt) with advanced/metastatic solid tumors were treat…
Abstract P6-12-02: Phase Ib dose-escalation study of an Akt inhibitor ipatasertib (Ipat) in combination with docetaxel (Doc) or paclitaxel (Pac) in p…
2015
Abstract Background: The Akt pathway is frequently aberrantly activated in MBC (e.g. via PTEN loss, and/or alterations of PIK3CA, AKT1, or AKT3); additionally, Akt activation may occur in response to chemotherapy, leading to cell survival and chemoresistance. Ipat (GDC-0068) is a potent oral, ATP-competitive inhibitor of all Akt isoforms. In preclinical models, Ipat synergistically combined with taxanes. In the Phase I dose-escalation single agent study, Ipat was given to pts including MBC, and downregulated Akt signaling at doses ≥ 100 mg. Methods: Eligible pts with MBC, treated with up to 3 prior systemic chemotherapy regimens, received Doc 75 mg/m2 intravenously (IV) on Day 1 with escala…
Dynamic contrast-enhanced MRI parameters as biomarkers for the effect of vatalanib in patients with non-small-cell lung cancer.
2014
ABSTRACT: Aims: To assess the utility of dynamic contrast-enhanced MRI parameters in the demonstration of early antiangiogenic effects and as prognostic biomarkers in second-line treatment of advanced-stage non-small-cell lung cancer with vatalanib. Patients & methods: The transfer constant (Ktrans) and the initial area under the contrast concentration–time curve at 60 s (AUC60) were assessed in 46 patients. Changes were compared with response evaluation from computed tomography imaging and Response Evaluation Criteria In Solid Tumors guidelines. Results: Statistically significant mean reductions in Ktrans (38.4%; p < 0.0001) and AUC60 (24.9%; p < 0.0001) were found at day 2. Af…
Phase I Pharmacokinetic and Pharmacodynamic Dose-Escalation Study of RG7160 (GA201), the First Glycoengineered Monoclonal Antibody Against the Epider…
2011
Purpose We conducted a phase I dose-escalation study to characterize the safety, efficacy, pharmacokinetic (PK), and pharmacodynamic properties of RG7160 (GA201), a humanized and glycoengineered immunoglobulin G1 anti–epidermal growth factor receptor (EGFR) monoclonal antibody with enhanced antibody-dependent cell-mediated cytotoxicity. Patients and Methods Seventy-five patients with advanced EGFR-positive solid tumors received RG7160 (50 to 1,400 mg) administered every week, every 2 weeks, or every 3 weeks. Dose escalation followed a three-plus-three trial design. Results No maximum-tolerated dose was reached for any dosing schedule. Common adverse events (AEs) included rash (80% of patien…
Open-label, multicentre expansion cohort to evaluate imgatuzumab in pre-treated patients with KRAS-mutant advanced colorectal carcinoma.
2014
Abstract Aim Imgatuzumab (GA201) is a novel anti-epidermal growth factor receptor (anti-EGFR) antibody glycoengineered for enhanced antibody-dependent cell-mediated cytotoxicity (ADCC). We investigated the efficacy of imgatuzumab in patients with EGFR-positive, KRAS -mutant advanced colorectal cancer. Methods Patients received single-agent imgatuzumab (1400 mg on day 1 and 8 followed by q2W) as third line therapy in an open-label, multicentre, non-randomised, expansion study. The primary end-point was tumour response. Pre- and on-treatment biopsies and blood samples were investigated for biomarkers related to imgatuzumab’s believed mechanism of action (MoA). Results 25 patients were treated…