Structure-guided engineering of immunotherapies targeting TRBC1 and TRBC2 in T cell malignancies

Peripheral T cell lymphomas are typically aggressive with a poor prognosis. Unlike other hematologic malignancies, the lack of target antigens to discriminate healthy from malignant cells limits the efficacy of immunotherapeutic approaches. The T cell receptor expresses one of two highly homologous chains [T cell receptor β-chain constant (TRBC) domains 1 and 2] in a mutually exclusive manner, making it a promising target. Here we demonstrate specificity redirection by rational design using structure-guided computational biology to generate a TRBC2-specific antibody (KFN), complementing the antibody previously described by our laboratory with unique TRBC1 specificity (Jovi-1) in targeting broader spectrum of T cell malignancies clonally expressing either of the two chains. This permits generation of paired reagents (chimeric antigen receptor-T cells) specific for TRBC1 and TRBC2, with preclinical evidence to support their efficacy in T cell malignancies

JUVIL: A new innovative software framework for data analysis of JET imaging systems intended for the study of plasma physics and machine operational safety

A new powerful software framework JUVIL (JET Users Video Imaging Library) has been developed and successfully installed at JET for fast data visualization and advanced analysis of all types of imaging data. The JUVIL framework is based on modular object-oriented components implemented in Python to simplify work with JET scientific data. It provides standard interfaces to access video data and post-processing, which are highly configurable and can be easily extended and adapted for new data formats and imaging cameras. One of the GUI components is the video player, widely used during the last JET campaign. It displays the video data for NIR/IR/VIS cameras and automatically carries out the post-processing (image rotation, data format conversion, scaling of non-interlaced fields to full frames)

The software and hardware architecture of the real-time protection of in-vessel components in JET-ILW

For the first time, the JET operation in deuterium–tritium (D–T) plasma, which is scheduled to take place on JET in 2020, will be performed in the ITER mix of plasma-facing component materials. In view of the preparation of the DT campaign (DTE2), several aspects of the plasma operation require significant improvements, such as a real-time protection of the first wall. The risk of damaging the metallic PFCs caused by beryllium melting or cracking of tungsten owing to thermal fatigue required a new reliable D–T compatible active protection system. Therefore, the future development of the JET real time first wall protection is focused on the D–T campaign and the ITER relevant conditions which may cause failure of camera electronics within the Torus hall. In addition to the technological aspect, the intensive preparation of the diverse software tools and real time algorithms for hot spot detection as well as alarm handling strategy required for the wall protection is in progress.This contribution describes the improved design, implementation, and operation of the near infrared (NIR) imaging diagnostic system of the JET-ILW plasma experiment and its integration into the existing JET protection architecture. To provide the reliable wall protection during the DTE2, two more sensitive logarithmic NIR camera systems equipped with new optical relays to take images and cameras outside of the biological shield have been installed on JET-ILW and calibrated with an in-vessel calibration light source (ICLS). Additionally, post-pulse data visualization and advanced analysis of all types of imaging data is provided by the new software framework JUVIL (JET users video imaging library). The formation of hot spots is recognized as a significant threat due to rapid surface temperature rise. Because it could trigger the protection system to stop a pulse, it is important to identify the mechanisms and conditions responsible for the formation of such hot spots. To address this issue the new software tool 'Hotspot Editor' has been developed

Response of the imaging cameras to hard radiation during JET operation

The analysis of the radiation damage of imaging systems is based on all different types-of aiialoiue/digital cameras with uncooled as well as actively cooled image sensors in the VIS/NIR/MWIR spectral ranges. The Monte Carlo N-Particle (MCNP) code has been used to determine the neutron fluence at different camera locations in JET. An explicit link between the sensor damage and the neutron fluence has been observed. Sensors show an increased dark-current and increased numbers of hot-pixels. Uncooled cameras must be replaced once per year after exposure to a neutron fluence of similar to 1.9-3.2 x 10(12)neutrons/cm(2). Such levels of fluence will be reached after approximate to 14-22 ELMy H-mode pulses during the future D-T campaign. Furthermore, dynamical noise seen as a random pattern of bright pixels was observed in the presence of hard radiation (neutrons and gammas). Failure of the digital electronics inside the cameras as well as of industrial controllers is observed beyond a neutron fluence of about similar to 4 x 10(9) neutrons/cm(2). The impact of hard radiation on the different types of electronics and possible application of cameras during future D-T campaign is discussed

Designer Small-Molecule Control System Based on Minocycline-Induced Disruption of Protein–Protein Interaction

A versatile, safe, and effective small-molecule control system is highly desirable for clinical cell therapy applications. Therefore, we developed a two-component small-molecule control system based on the disruption of protein–protein interactions using minocycline, an FDA-approved antibiotic with wide availability, excellent biodistribution, and low toxicity. The system comprises an anti-minocycline single-domain antibody (sdAb) and a minocycline-displaceable cyclic peptide. Here, we show how this versatile system can be applied to OFF-switch split CAR systems (MinoCAR) and universal CAR adaptors (MinoUniCAR) with reversible, transient, and dose-dependent suppression; to a tunable T cell activation module based on MyD88/CD40 signaling; to a controllable cellular payload secretion system based on IL12 KDEL retention; and as a cell/cell inducible junction. This work represents an important step forward in the development of a remote-controlled system to precisely control the timing, intensity, and safety of therapeutic interventions

Designer Small-Molecule Control System Based on Minocycline-Induced Disruption of Protein–Protein Interaction

A versatile, safe, and effective small-molecule control system is highly desirable for clinical cell therapy applications. Therefore, we developed a two-component small-molecule control system based on the disruption of protein–protein interactions using minocycline, an FDA-approved antibiotic with wide availability, excellent biodistribution, and low toxicity. The system comprises an anti-minocycline single-domain antibody (sdAb) and a minocycline-displaceable cyclic peptide. Here, we show how this versatile system can be applied to OFF-switch split CAR systems (MinoCAR) and universal CAR adaptors (MinoUniCAR) with reversible, transient, and dose-dependent suppression; to a tunable T cell activation module based on MyD88/CD40 signaling; to a controllable cellular payload secretion system based on IL12 KDEL retention; and as a cell/cell inducible junction. This work represents an important step forward in the development of a remote-controlled system to precisely control the timing, intensity, and safety of therapeutic interventions