ABSTRACT
BACKGROUND: Neuroligin 4 X-linked (NLGN4X) harbors a human leukocyte antigen (HLA)-A*02-restricted tumor-associated antigen, overexpressed in human gliomas, that was found to induce specific cytotoxic T cell responses following multi-peptide vaccination in patients with newly diagnosed glioblastoma. METHODS: T cell receptor (TCR) discovery was performed using droplet-based single-cell TCR sequencing of NLGN4X-tetramer-sorted T cells postvaccination. The identified TCR was delivered to Jurkat T cells and primary human T cells (NLGN4X-TCR-T). Functional profiling of NLGN4X-TCR-T was performed by flow cytometry and cytotoxicity assays. Therapeutic efficacy of intracerebroventricular NLGN4X-TCR-T was assessed in NOD scid gamma (NSG) major histocompatibility complex (MHC) I/II knockout (KO) (NSG MHC I/II KO) mice bearing NLGN4X-expressing experimental gliomas. RESULTS: An HLA-A*02-restricted vaccine-induced T cell receptor specifically binding NLGN4X131-139 was applied for preclinical therapeutic use. Reactivity, cytotoxicity, and polyfunctionality of this NLGN4X-specific TCR are demonstrated in various cellular models. Intracerebroventricular administration of NLGN4X-TCR-T prolongs survival and leads to an objective response rate of 44.4% in experimental glioma-bearing NSG MHC I/II KO mice compared to 0.0% in control groups. CONCLUSION: NLGN4X-TCR-T demonstrate efficacy in a preclinical glioblastoma model. On a global scale, we provide the first evidence for the therapeutic retrieval of vaccine-induced human TCRs for the off-the-shelf treatment of glioblastoma patients.Keywords cell therapy | glioblastoma | T cell receptor | tumor antigen.
Subject(s)
Cancer Vaccines , Glioblastoma , Mice , Animals , Humans , Glioblastoma/genetics , Glioblastoma/therapy , Cancer Vaccines/therapeutic use , Vaccines, Subunit , Receptors, Antigen, T-Cell , T-Lymphocytes , Antigens, Neoplasm/genetics , Cell Adhesion Molecules, NeuronalABSTRACT
We report on a Q-switched Ho:Lu2O3 laser resonantly pumped by a GaSb-based laser diode stack at 1.9 µm. The maximum output energy extracted from the compact plano-plano acousto-optically Q-switched resonator was 8 mJ at a 100 Hz pulse repetition rate, while the peak power was 40 kW. The laser wavelength was 2.124 µm.
Subject(s)
Holmium , Lasers, Solid-State , Lutetium , Oxides , Absorption , Spectrum AnalysisABSTRACT
Efficient room-temperature laser operation was obtained in the wavelength range from 2117 nm to 2134 nm with Ho:Lu(2)O(3) and Ho:Y(2)O(3) as the active materials. With an FBG-stabilized Tm-doped fiber laser as the pump source, the maximum slope efficiency and output power of the Ho:Y(2)O(3) laser were 63% and 18.8 W, respectively. With Ho:Lu(2)O(3) the respective values were 76% and 25.2 W. With Ho:Sc(2)O(3) as the active material the accessible wavelength range could be expanded to 2158 nm in a diode-pumped setup.
Subject(s)
Lasers, Semiconductor , Metals/chemistry , Oxides/chemistry , Equipment Design , Equipment Failure AnalysisABSTRACT
Single-walled carbon nanotube saturable absorbers were designed and fabricated for passive mode-locking of bulk lasers operating in the 2 µm spectral range. Mode-locked lasers based on Tm:Lu2O3 single crystals containing different Tm3+-doping concentrations were studied. Nearly transform-limited pulses as short as 175 fs at 2070 nm were generated at 88 MHz repetition rate.
Subject(s)
Lasers , Nanotechnology/instrumentation , Nanotubes, Carbon/chemistry , Nanotubes, Carbon/ultrastructure , Absorption , Equipment Design , Equipment Failure Analysis , LightABSTRACT
We report on the high-energy laser operation of an Ho:YAG oscillator resonantly pumped by a GaSb-based laser diode stack at 1.9 µm. The output energy was extracted from a compact plano-concave acousto-optically Q-switched resonator optimized for low repetition rates. Operating at 100 Hz, pulse energies exceeding 30 mJ at a wavelength of 2.09 µm were obtained. The corresponding pulse duration at the highest pump power was 100 ns, leading to a maximum peak power above 300 kW. Different pulse repetition rates and output coupling transmissions of the Ho:YAG resonator were studied. In addition, intracavity laser-induced damage threshold measurements are discussed.
Subject(s)
Holmium/chemistry , Lasers, Semiconductor , Oscillometry/instrumentation , Equipment Design , Lasers, Solid-StateABSTRACT
We report on a new method for determining dopant ion concentrations in laser materials. This method is based on optical absorption spectroscopy. In contrast to other methods used to measure the dopant concentration that are based on absorption measurements, this method does not require the knowledge of the absorption cross sections. An advantage of this method compared to the micro probe analysis is that only concentrations of dopant ions of a certain valency, which are luminescent, are detected. The method is sensitive especially for small doping concentrations of ions with high absorption cross sections. Another application of this method is the determination of the ratio between luminescent dopant ions to the total number of dopant ions in the case that not all dopant ions are on crystal sites that allow for optical transitions.
ABSTRACT
We report on the first diode-pumped laser operation of thulium-doped Lu2O3. With a very compact setup an output power of 75 W and slope efficiencies of around 40% with respect to the incident pump power were achieved at room temperature. Free running laser operation was observed at wavelengths of 2065 nm and 1965 nm. With a birefringent filter the wavelength could continuously be tuned from 1922 nm to 2134 nm. The thermal conductivity of Tm:Lu2O3 was measured for different dopant concentrations and is compared to the one of thulium-doped YAG.
