Littérature scientifique sur le sujet « ICMP Redirect »

Microstimulation of the lateral wall of the intraparietal sulcus compared with the frontal eye field during oculomotor tasks. We compared the effects of intracortical microstimulation (ICMS) of the lateral wall of the intraparietal sulcus (LIP) with those of ICMS of the frontal eye field (FEF) on monkeys performing oculomotor tasks. When ICMS was applied during a task that involved fixation, contraversive saccades evoked in the LIP and FEF appeared similar. When ICMS was applied to the FEF at the onset of voluntary saccades, the evoked saccades collided with the ongoing voluntary saccade so that the trajectory of voluntary saccade was compensated by the stimulus. Thus the resultant saccade was redirected and came close to the endpoint of saccades evoked from the fixation point before the start of voluntary saccade. In contrast, when ICMS was applied to the LIP at the onset of voluntary saccades, the resultant saccade followed a trajectory that was different from that evoked from the FEF. In that case, the colliding saccades were redirected toward an endpoint that was close to the endpoint of saccades evoked when animals were already fixating at the target of the voluntary saccade. This finding suggests that the colliding saccade was directed toward an endpoint calculated with reference to the target of the voluntary saccade. We hypothesize that, shortly before initiation of voluntary saccades, a dynamic process occurs in the LIP so that the reference point for calculating the saccade target shifts from the fixation point to the target of a voluntary saccade. Such predictive updating of reference points seems useful for immediate reprogramming of upcoming saccades that can occur in rapid succession.

Introduction: CD20-TCB (RG6026) is a novel T-cell-engaging bispecific (TCB) antibody with a '2:1' molecular format that comprises two fragment antigen binding regions that bind CD20 (on the surface of B cells) and one that binds CD3 (on the surface of T cells). CD20-TCB offers the potential for increased tumor antigen avidity, rapid T-cell activation, and enhanced tumor cell killing versus other bispecific formats. An ongoing Phase I dose-escalation study (NP30179; NCT03075696) has shown promising antitumor activity and acceptable safety in relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL) patients (pts) (Dickinson et al. ICML 2019). We investigated population pharmacokinetics (popPK) and exposure-response (E-R) relationships for CD20-TCB in NP30179. Methods: Indolent (i) and aggressive (a) R/R NHL pts received CD20-TCB doses of 0.005 to 25mg every 2 or 3 weeks following single 1000mg obinutuzumab (G) pre-treatment (Gpt) on Cycle 1 Day −7 to mitigate for cytokine release syndrome (CRS). Serial and spare PK data collected from pts were used to develop a popPK model in NONMEM v7.4. Physiologically relevant covariates were investigated for their potential influence on CD20-TCB PK variability. Using the previously established G popPK model (Gibiansky et al. CPT Pharmacometrics Syst Pharmacol 2014;3:e144), full G concentration-time profiles were constructed in order to estimate CD20-TCB receptor occupancy (RO%) in the presence of G concentrations competing for CD20 receptors over time. E-R relationships between CD20-TCB time-averaged RO% (AvgRO%) up to Cycle 3 Day 1 and objective response rate (ORR) and complete response rate (CRR) were investigated in aNHL pts who reached Cycle 3 Day 1, and the relationship between CD20-TCB AvgRO% over the first 24 hours (as the majority of events occurred within the first 24 hours) and CRS, the most common safety event, as defined by Lee et al. (Blood 2014;124:188-95), was investigated in iNHL and aNHL pts combined using logistic regression. Results: The popPK analysis included 139 iNHL and aNHL pts with at least one PK sample. The E-R analysis for efficacy included 76 aNHL pts with PK and efficacy data at Cycle 3 Day 1. The E-R analysis for safety included 121 iNHL and aNHL pts with PK and safety data. CD20-TCB PK was best described using a two-compartment PK model with linear clearance. Body weight had a statistically significant influence on PK and was retained using theory-based allometric scaling. There were no obvious differences in PK between iNHL and aNHL pts. In aNHL pts, logistic regression analyses demonstrated a significant positive E-R relationship between AvgRO% up to Cycle 3 Day 1 and efficacy (ORR and CRR, p=0.007; Figure 1 for CRR). In the highest tertile of AvgRO% (≥0.48%), the observed ORR was 76% versus 38.5% (<0.041%) and 52% (0.041%-0.48%) in the lower tertiles; CRR was 48% versus 19.2% and 36%. A significant positive E-R relationship was identified between CD20-TCB AvgRO% over the first 24 hours and Grade (Gr) ≥2 CRS (p<0.001; Figure 2), consistent with the clinical safety profile showing first-dose-dependent CRS, with the majority of events occurring within the first 24 hours (Dickinson et al. ICML 2019). Following administration of a CD20-TCB dosing regimen of 10/16mg q3w (10mg in Cycle 1 followed by 16mg thereafter), the AvgRO% (median [P10-P90]) up to Cycle 3 was 0.466% (0.249%-1.63%), corresponding to an anticipated CRR at Cycle 3 of 43.6% (38.2%-54.7%) based on the exposure-efficacy model (Figure 1), in line with the clinical CRR seen in the 10 and 16mg q3w dose cohorts previously reported (Dickinson et al. ICML 2019). The resulting AvgRO% over the first 24 hours following an initial 10mg dose in Cycle 1 was 0.797% (0.344%-1.78%), corresponding to a Gr ≥2 CRS rate of 36.7% (27.1%-45.4%) based on the exposure-safety model (Figure 2), in line with the CRS incidences observed in the 10mg q3w dose cohort reported previously (Dickinson et al. ICML 2019). These PopPK and ER analyses are being used to simulate CD20-TCB dosing regimens that maximize efficacy and mitigate CRS risk, including fixed and step-up dosing regimens. Conclusions: PopPK and E-R relationships are characterized for the novel CD20/CD3 TCB antibody CD20-TCB and are being used to support optimal biological-dose selection as a single agent in ongoing combination investigations (Morschhauser et al. ASH 2019; Hutchings et al. ASH 2019). Disclosures Djebli: F. Hoffmann-La Roche Ltd: Employment. Jaminion:F. Hoffmann-La Roche Ltd: Employment. Laurent:F. Hoffmann-La Roche Ltd: Employment. Mercier:F. Hoffmann-La Roche Ltd: Employment. Kratochwil:F. Hoffmann-La Roche Ltd: Employment. Bröske:Roche: Employment, Equity Ownership. Dimier:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Ferlini:Roche: Employment, Equity Ownership. Moore:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Weisser:Pharma Research and Early Development Roche Innovation Center Munich: Employment, Equity Ownership, Patents & Royalties. Morcos:Roche: Employment, Equity Ownership. OffLabel Disclosure: CD20-TCB (also known as RG6026, RO7082859) is a full-length, fully humanized, immunoglobulin G1 (IgG1), T-cell-engaging bispecific antibody with two fragment antigen binding ('Fab') regions that bind to CD20 (on the surface of B cells) and one that binds to CD3 (on the surface of T cells) (2:1 format). The 2:1 molecular format of CD20-TCB, which incorporates bivalent binding to CD20 on B cells and monovalent binding to CD3 on T cells, redirects endogenous non-specific T cells to engage and eliminate malignant B cells. CD20-TCB is an investigational agent.

CD20-TCB (RG6026) is a novel T-cell-engaging bispecific (TCB) antibody with a '2:1' molecular format that comprises two fragment antigen binding regions that bind CD20 (on the surface of B cells) and one that binds CD3 (on the surface of T cells). CD20-TCB offers the potential for increased tumor antigen avidity, rapid T-cell activation, and enhanced tumor cell killing versus other bispecific formats. CD20-TCB has demonstrated highly promising single-agent activity in relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL) patients (pts) (Dickinson et al. ICML 2019). Preclinical data demonstrate CD20-TCB-induced programmed cell death protein 1 (PD-1) and programmed cell death-ligand-1 (PD-L1) upregulation on T cells and tumor cells. We hypothesized that the combination of T-cell engagement by CD20-TCB and PD-L1 inhibition by atezolizumab could lead to additive anti-tumor activity in B-NHL. We report preliminary data from NP39488 (NCT03533283), an ongoing Phase Ib study evaluating the safety, tolerability, pharmacokinetics, and preliminary efficacy (objective response rate [ORR] and complete response [CR] rate per modified Lugano 2014 criteria) of CD20-TCB in combination with atezolizumab in R/R B-NHL pts. A single dose of 1000mg obinutuzumab (G) is administered on Day −7 of Cycle 1 as pretreatment (Gpt) to mitigate for potential cytokine release syndrome (CRS). CD20-TCB is initiated on Day 1 of Cycle 1 and given in a q3w schedule. From Cycle 2 onwards, atezolizumab (1200mg) is added and given on the same day as CD20-TCB. CD20-TCB dose-escalation is ongoing and is guided by the modified continual reassessment method-escalation with overdose control (mCRM-EWOC). As of June 25, 2019, 38 pts with aggressive B-NHL (n=33; diffuse large B-cell lymphoma [DLBCL], transformed [tr] follicular lymphoma [FL], primary mediastinal large B-cell lymphoma, mantle cell lymphoma, tr lymphoplasmacytic lymphoma, tr Waldenstrom`s macroglobulinemia) or indolent B-NHL (n=5; FL) had received CD20-TCB doses from 0.07mg to currently 6mg. Pts (52.6% male) had a median age of 67 years (range: 38-82) and a median of three prior treatment lines (range: 1−10); 84% had refractory B-NHL. Two dose-limiting toxicities (Grade [Gr] 3 tumor flare at 6mg during Cycle 1 and Gr 3 myopathy at 1.8mg during Cycle 2) were transient and resolved completely. The most frequent adverse event (AE) was CRS (42%; 16/38 pts), with 24% Gr 1 (n=9), 18% Gr 2 (n=7), and no Gr ≥3 (according to Lee criteria, Lee et al. Blood 2014;124:188-95). The most common AEs (>20%) were pyrexia (37%), anemia (29%), fatigue (24%), neutropenia (21%), diarrhea (21%), and decreased appetite (21%). The most common Gr ≥3 AEs (>10%) were neutropenia (18%) and anemia (13%), with a single Gr 5 unrelated pneumonia. Three pts experienced a transient Gr ≥3 neurotoxicity (Gr 4 polyneuropathy, Gr 3 trigeminal nerve herpes zoster infection, and Gr 3 post-infection encephalopathy), all of which resolved. Thirty-six pts reached their first response assessment or withdrew early and were eligible for efficacy analysis. Across all doses, ORR and CR rates by investigator assessment were 36% (13/36 pts) and 17% (6/36), respectively (indolent NHL: 4/5 and 3/5 pts; aggressive NHL: 9/31 and 3/31 pts). All CRs are ongoing at the time of abstract submission. CD20-TCB exposure and receptor occupancy (RO%) increased dose-dependently across the dose-range evaluated, and are expected to be further optimized (Djebli et al. ASH 2019). At the higher CD20-TCB doses investigated, a trend towards increased clinical activity was observed (ORR of 60% [9/15 pts] in the 4mg and 6mg cohorts combined). The combination of CD20-TCB and atezolizumab has manageable safety in R/R B-NHL pts. No new safety signals or signs of increased immune-related AEs were detected, and the overall safety profile was consistent with that reported with single-agent CD20-TCB (Dickinson et al. ICML 2019). Dose escalation is ongoing and aims to optimize the dose and schedule of CD20-TCB when combined with atezolizumab using the established exposure-response model for CD20-TCB (Djebli et al. ASH 2019). Updated safety, efficacy, and biomarker data will be presented. Disclosures Hutchings: Genmab: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Celgene: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Janssen: Research Funding; Incyte: Research Funding. Gritti:Roche: Other: Not stated; Abbvie: Other: Not stated; Becton Dickinson: Other: Not stated; Autolus Ltd: Honoraria. Sureda:Sanofi: Honoraria; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Gilead: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; BMS: Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support. Terol:Roche: Consultancy; Abbvie: Consultancy; Astra Zeneca: Consultancy; Janssen: Consultancy, Research Funding; Gilead: Research Funding. Dyer:Roche: Research Funding. Iacoboni:Novartis: Consultancy, Honoraria; Roche: Honoraria; Janssen: Honoraria; Abbvie: Honoraria; Celgene: Honoraria. Townsend:Roche: Consultancy, Honoraria. Bacac:Roche: Employment, Equity Ownership, Patents & Royalties: Patents, including the one on CD20-TCB. Bröske:Roche: Employment, Equity Ownership. Dimier:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Ferlini:Roche: Employment, Equity Ownership. Keelara:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Lahr:Roche: Employment, Honoraria. Lechner:Roche: Employment, Other: Roche shareholder. Moore:Roche: Employment, Equity Ownership. Morcos:Roche: Employment, Equity Ownership. Panchal:Roche: Employment. Weisser:Pharma Research and Early Development Roche Innovation Center Munich: Employment, Equity Ownership, Patents & Royalties. OffLabel Disclosure: CD20-TCB (also known as RG6026, RO7082859) is a full-length, fully humanized, immunoglobulin G1 (IgG1), T-cell-engaging bispecific antibody with two fragment antigen binding (Fab) regions that bind to CD20 (on the surface of B cells) and one that binds to CD3 (on the surface of T cells) (2:1 format). The 2:1 molecular format of CD20-TCB, which incorporates bivalent binding to CD20 on B cells and monovalent binding to CD3 on T cells, redirects endogenous non-specific T cells to engage and eliminate malignant B cells. CD20-TCB is an investigational agent.

Introduction: CD20-TCB (RG6026) is a novel T-cell-engaging bispecific (TCB) antibody with a '2:1' molecular format that comprises two fragment antigen binding regions that bind CD20 (on the surface of B cells) and one that binds CD3 (on the surface of T cells). CD20-TCB offers the potential for increased tumor antigen avidity, rapid T-cell activation, and enhanced tumor cell killing versus other bispecific formats. The safety, tolerability, pharmacokinetics, biomarkers, and antitumor activity of CD20-TCB are currently being investigated in a multicenter Phase I dose-escalation trial (NP30179; NCT03075696). We recently presented preliminary clinical data demonstrating promising clinical activity in relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL) patients with indolent or aggressive disease (Dickinson et al. ICML 2019). Here, we present preliminary blood and tissue biomarker analyses to explore modes of action, support optimal biological dose selection, and identify potential outcome predictors. Methods: For biomarker analyses, we performed immune profiling of peripheral blood by flow cytometry, analyzed plasma cytokine levels by ELISA, and characterized baseline and on-treatment tumor biopsies by immunohistochemistry/immunofluorescence assays and RNA sequencing. Biomarker data were obtained from 122 patients dosed with 0.005-25mg CD20-TCB. Results: CD20-TCB infusion led to a rapid and transient reduction in T cells in the peripheral circulation (T-cell margination) in all patients. T-cell margination reached nadir 6 hours after the first CD20-TCB infusion, and showed a strong association with CD20-TCB dose and receptor occupancy (RO%; as determined by Djebli et al. ASH 2019). Interestingly, rebound of T cells 160 hours after the first CD20-TCB infusion was associated with response to treatment. Responding patients showed long-term T-cell activation after the first infusion of CD20-TCB at doses from 0.6mg and above. T-cell activation was demonstrated by 2-4-fold elevation of T-cell activation markers such as Ki67, HLA-DR, PD-1, ICOS, OX40, and 4-1BB, which was sustained up to Cycle 5 (105 days). Analysis of paired pre- and on-treatment tumor biopsies (n=6) obtained before and 2-3 weeks after the first dose of CD20-TCB showed evidence of T-cell-mediated tumor cell killing. Analysis of archival and pre-treatment tumor biopsies (n=80) revealed that clinical responses were achieved irrespective of the amount of tumor T-cell infiltration at baseline. In contrast, preliminary baseline bulk tumor RNA sequencing data (n=46) showed upregulation of gene signatures associated with cell proliferation/Myc and T-cell subsets (effector vs exhausted-like) in non-responding patients. Conclusions: In this study, we demonstrated the mode of action of CD20-TCB, a novel bispecific antibody with promising clinical activity in R/R NHL. We also demonstrated that biomarker data on T-cell activation can support dose finding in conjunction with pharmacokinetics. Additional analysis is ongoing to evaluate response predictors and better characterize the population that will benefit most from T-cell mediated therapies. Disclosures Bröske: Roche: Employment, Equity Ownership. James:A4P Consulting Ltd: Consultancy. Belousov:Roche: Employment. Gomez:F. Hoffmann-La Roche Ltd: Employment. Canamero:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Ooi:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Grabole:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Wilson:F. Hoffmann-La Roche Ltd: Employment. Korfi:F. Hoffmann-La Roche Ltd: Consultancy. Kratochwil:F. Hoffmann-La Roche Ltd: Employment. Morcos:Roche: Employment, Equity Ownership. Ferlini:Roche: Employment, Equity Ownership. Thomas:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Dimier:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Moore:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Bacac:Roche: Employment, Equity Ownership, Patents & Royalties: Patents, including the one on CD20-TCB. Weisser:Pharma Research and Early Development Roche Innovation Center Munich: Employment, Equity Ownership, Patents & Royalties. Dickinson:Merck Sharpe and Dohme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. OffLabel Disclosure: CD20-TCB (also known as RG6026, RO7082859) is a full-length, fully humanized, immunoglobulin G1 (IgG1), T-cell-engaging bispecific antibody with two fragment antigen binding (Fab) regions that bind to CD20 (on the surface of B cells) and one that binds to CD3 (on the surface of T cells) (2:1 format). The 2:1 molecular format of CD20-TCB, which incorporates bivalent binding to CD20 on B cells and monovalent binding to CD3 on T cells, redirects endogenous non-specific T cells to engage and eliminate malignant B cells. CD20-TCB is an investigational agent.

This diploma thesis deals with the design and implementation of a tool for network attack detection from a captured network communication. It utilises the tshark packet analyser, the meaning of which is to convert the input file with the captured communications to the PDML format. The objective of this conversion being, increasing the flexibility of input data processing. When designing the tool, emphasis has been placed on the ability to expand it to detect new network attacks and on integrating these additions with ease. For this reason, the thesis also includes the design of a complex declarative descriptions for network attacks in the YAML serialization format. This allows us to specify the key properties of the network attacks and the conditions for their detection. The resulting tool acts as an interpreter of proposed declarative descriptions allowing it to be expanded with new types of attacks.