STING Agonist 8803 Reprograms the Immune Microenvironment and Increases Survival in Preclinical Models of Glioblastoma

STING agonists can reprogram the tumor microenvironment to induce immunological clearance within the central nervous system. Using multiplexed sequential immunofluorescence (SeqIF) and the Ivy Glioblastoma Atlas, STING expression was found in myeloid populations and in the perivascular space. The STING agonist 8803 increased median survival in multiple preclinical models of glioblastoma, including QPP8, an immune checkpoint blockade-resistant model, where 100% of mice were cured. Ex vivo flow cytometry profiling during the therapeutic window demonstrated increases in myeloid tumor trafficking and activation, alongside enhancement of CD8+ T cell and NK effector responses. Treatment with 8803 reprogrammed microglia to express costimulatory CD80/CD86 and iNOS, while decreasing immunosuppressive CD206 and arginase. In humanized mice, where tumor cell STING is epigenetically silenced, 8803 therapeutic activity was maintained, further attesting to myeloid dependency and reprogramming. Although the combination with a STAT3 inhibitor did not further enhance STING agonist activity, the addition of anti-PD-1 antibodies to 8803 treatment enhanced survival in an immune checkpoint blockade-responsive glioma model. In summary, 8803 as a monotherapy demonstrates marked in vivo therapeutic activity, meriting consideration for clinical translation

Age, anticoagulants, hypertension and cardiovascular genetic traits predict cranial ischaemic complications in patients with giant cell arteritis

\ua9 Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.Objectives: This project aimed to determine whether cranial ischaemic complications at the presentation of giant cell arteritis (GCA) were associated with pre-existing cardiovascular (CV) risk factors, CV disease or genetic risk of CV-related traits. Methods: 1946 GCA patients with clinicodemographic data at GCA presentation were included. Associations between pre-existing CV-related traits (including Polygenic Risk Scores (PRS) for CV traits) and cranial ischaemic complications were tested. A model for cranial ischaemic complications was optimised using an elastic net approach. Positional gene mapping of associated PRS was performed to improve biological understanding. Results: In a sample of 1946 GCA patients (median age=71, 68.7% female), 17% had cranial ischaemic complications at presentation. In univariable analyses, 10 variables were associated with complications (likelihood-ratio test p≤0.05). In multivariable analysis, the two variables with the strongest effects, with or without PRS in the model, were anticoagulant therapy (adjusted OR (95% CI)=0.21 (0.05 to 0.62), p=4.95 710-3) and age (adjusted OR (95% CI)=1.60 (0.73 to 3.66), p=2.52 710-3, for ≥80 years versus <60 years). In sensitivity analyses omitting anticoagulant therapy from multivariable analysis, age and hypertension were associated with cranial ischaemic complications at presentation (hypertension: adjusted OR (95% CI)=1.35 (1.03 to 1.75), p=0.03). Positional gene mapping of an associated transient ischaemic attack PRS identified TEK, CD96 and MROH9 loci. Conclusion: Age and hypertension were risk factors for cranial ischaemic complications at GCA presentation, but in this dataset, anticoagulation appeared protective. Positional gene mapping suggested a role for immune and coagulation-related pathways in the pathogenesis of complications. Further studies are needed before implementation in clinical practice

A multifunctional covalently linked graphene-MOF hybrid as an effective chemiresistive gas sensor

A hybrid of GA@UiO-66-NH2 was synthesized based on the covalent assembly of graphene acid (GA) and the amine functionalized UiO-66 metal-organic framework through amide bonds. This strategy endows the material with unique properties, such as hierarchical pores, a porous conductive network decorated with functional groups, a high specific surface area, and a good chemical and thermal stability. The resultant hybrid has an electrical resistance of similar to 10(4) omega, whereas the pristine GA and UiO-66-NH2 possess an electrical resistance of similar to 10(2) omega and similar to 10(9) omega, respectively. The hybrid GA@UiO-66-NH2 was demonstrated for CO2 chemiresistive sensing and displayed a very fast response and quick recovery time of similar to 18 s for 100% CO2, at 200 degrees C. While the pristine GA exhibits negligible response under the same conditions, GA@UiO-66-NH2 exhibited a response of 10 +/- 0.6%. Further, in situ temperature dependent Raman studies during CO2 exposure confirm the presence of strong hydrogen bonding interaction between CO2 and the amide functionality present on GA@UiO-66-NH2. The resulting gas sensing characteristics of GA@UiO-66-NH2 are majorly attributed to the better interaction of CO2 at the amide/amine functional groups and the readily accessible hierarchical pores. This design strategy opens new horizons in the development of covalently linked hybrids with hierarchical porous conductive networks which can help to improve the gas sensing properties of MOF-based materials.Web of Science932174411743

Supplementary Figure S1 from Paclitaxel and Carboplatin in Combination with Low-intensity Pulsed Ultrasound for Glioblastoma

Supplementary Figure 1. Paclitaxel delivered with low-intensity pulsed ultrasound and microbubbles leads to variable local tumor control.  Coronal T1 with contrast MRI images of patients from our phase I clinical trial (NCT04528680) who received the highest dose of Abraxane (260 mg/m2). We illustrate in green the area covered by the sonication, and observe a variable local tumor control within this region. The five patients presented in the upper (blue) panel exhibited tumor control, while the remaining patients (in red) had tumor growth while on therapy.</p

Supplementary Table S2 from Paclitaxel and Carboplatin in Combination with Low-intensity Pulsed Ultrasound for Glioblastoma

Supplementary table 2: Table illustrating the representativeness of our study participants.</p

Supplementary Figure S3 from Paclitaxel and Carboplatin in Combination with Low-intensity Pulsed Ultrasound for Glioblastoma

Supplementary Figure 3. Paclitaxel and carboplatin exhibit synergy in vitro. (A) Dose-response matrices illustrating the Loewe synergy score calculated for 11 glioma cell lines at clinically relevant PTX and CBDCA concentrations. (B) Bar charts showing the viability of cell lines treated with PTX, CBDCA, or a combination of both drugs at concentration that showed the highest synergy.</p

Supplementary Table S1 from Paclitaxel and Carboplatin in Combination with Low-intensity Pulsed Ultrasound for Glioblastoma

Supplementary table 1. Genotype of glioma cell lines used.</p