Search

Abstract: Dry plasma etching of sub-micron structures in a SiO2/Si/SiO2 layer system using Cr as a mask was performed in a fluorocarbon plasma. It was determined that the best anisotropy could be achieved in the most electropositive plasma. A gas composition yielding the desired SOI planar photonic crystal structures was optimized from the available process gases, Ar, He, O2, SF6, CF4, c-C4F8, CHF3, using DC bias data sets. Application of the c-C4F8/(noble gas) chemistry allowed fabrication of the desired SOI planar photonic crystal. The average etching rates for the pores and ridge waveguide regions were about 71 and 97nm/min, respectively, while the average SiO2/Si/SiO2 to Cr etching selectivity for the ridge waveguide region was about 33:1 in case of the c-C4F8/90%Ar plasma with optimized parameters. [Copyright &y& Elsevier]

Abstract: RIE-plasma etching of sub-micron structures in 150–200-nm thick Cr layers deposited on 4-inch SiO2/Si/SiO2 wafers was investigated as a function of the gas composition, RF power, and resist type. An optimal recipe is obtained yielding a Cr etching rate of about 7 nm/min and a ratio of the resist to the Cr etching rates of about 2 in case of etching the sub-micron structures in Cr with a ZEP 520 resist mask. SEM investigations show nearly vertical sidewalls of features etched in Cr layers with a lateral size ranging from 0.3 to 0.5 μm. [Copyright &y& Elsevier]

Existing survival prediction models rely only on baseline or tumor kinetics data and lack machine learning integration. We introduce a novel kinetics-machine learning (kML) model that integrates baseline markers, tumor kinetics, and four on-treatment simple blood markers (albumin, C-reactive protein, lactate dehydrogenase, and neutrophils). Developed for immune-checkpoint inhibition (ICI) in non-small cell lung cancer on three phase II trials (533 patients), kML was validated on the two arms of a phase III trial (ICI and chemotherapy, 377 and 354 patients). It outperformed the current state-of-the-art for individual predictions with a test set C-index of 0.790, 12-months survival accuracy of 78.7% and hazard ratio of 25.2 (95% CI: 10.4-61.3, P < 0.0001) to identify long-term survivors. Critically, kML predicted the success of the phase III trial using only 25 weeks of on-study data (predicted HR = 0.814 (0.64-0.994) vs. final study HR = 0.778 (0.65-0.931)). Modeling on-treatment blood markers combined with predictive machine learning constitutes a valuable approach to support personalized medicine and drug development. The code is publicly available at https://gitlab.inria.fr/benzekry/nlml&#95;onco., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Abstract: Effective T-cell responses not only require the engagement of T-cell receptors (TCRs; "signal 1"), but also the availability of costimulatory signals ("signal 2"). T-cell bispecific antibodies (TCBs) deliver a robust signal 1 by engaging the TCR signaling component CD3ε, while simultaneously binding to tumor antigens. The CD20-TCB glofitamab redirects T cells to CD20-expressing malignant B cells. Although glofitamab exhibits strong single-agent efficacy, adding costimulatory signaling may enhance the depth and durability of T-cell-mediated tumor cell killing. We developed a bispecific CD19-targeted CD28 agonist (CD19-CD28), RG6333, to enhance the efficacy of glofitamab and similar TCBs by delivering signal 2 to tumor-infiltrating T cells. CD19-CD28 distinguishes itself from the superagonistic antibody TGN1412, because its activity requires the simultaneous presence of a TCR signal and CD19 target binding. This is achieved through its engineered format incorporating a mutated Fc region with abolished FcγR and C1q binding, CD28 monovalency, and a moderate CD28 binding affinity. In combination with glofitamab, CD19-CD28 strongly increased T-cell effector functions in ex vivo assays using peripheral blood mononuclear cells and spleen samples derived from patients with lymphoma and enhanced glofitamab-mediated regression of aggressive lymphomas in humanized mice. Notably, the triple combination of glofitamab with CD19-CD28 with the costimulatory 4-1BB agonist, CD19-4-1BBL, offered substantially improved long-term tumor control over glofitamab monotherapy and respective duplet combinations. Our findings highlight CD19-CD28 as a safe and highly efficacious off-the-shelf combination partner for glofitamab, similar TCBs, and other costimulatory agonists. CD19-CD28 is currently in a phase 1 clinical trial in combination with glofitamab. This trial was registered at www.clinicaltrials.gov as #NCT05219513., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Cibisatamab is a bispecific antibody-based construct targeting carcinoembryonic antigen (CEA) on tumour cells and CD3 epsilon chain as a T-cell engager. Here we evaluated cibisatamab for advanced CEA-positive solid tumours in two open-label Phase 1 dose-escalation and -expansion studies: as a single agent with or without obinutuzumab in S1 (NCT02324257) and with atezolizumab in S2 (NCT02650713). Primary endpoints were safety, dose finding, and pharmacokinetics in S1; safety and dose finding in S2. Secondary endpoints were anti-tumour activity (including overall response rate, ORR) and pharmacodynamics in S1; anti-tumour activity, pharmacodynamics and pharmacokinetics in S2. S1 and S2 enrolled a total of 149 and 228 patients, respectively. Grade ≥3 cibisatamab-related adverse events occurred in 36% of S1 and 49% of S2 patients. The ORR was 4% in S1 and 7% in S2. In S2, patients with microsatellite stable colorectal carcinoma (MSS-CRC) given flat doses of cibisatamab and atezolizumab demonstrated an ORR of 14%. In S1 and S2, 40% and 52% of patients, respectively, developed persistent anti-drug antibodies (ADAs). ADA appearance could be mitigated by obinutuzumab-pretreatment, with 8% of patients having persistent ADAs. Overall, cibisatamab warrants further exploration in immunotherapy combination strategies for MSS-CRC., (© 2024. The Author(s).)