Oral PD-L1 inhibitor GS-4224 selectively engages PD-L1 high cells and elicits pharmacodynamic responses in patients with advanced solid tumors.

BACKGROUND: Checkpoint inhibitors targeting the programmed cell death 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) pathway are effective therapies in a range of immunogenic cancer types. Blocking this pathway with an oral therapy could benefit patients through greater convenience, particularly in combination regimens, and allow flexible management of immune-mediated toxicities. METHODS: PD-L1 binding activity was assessed in engineered dimerization and primary cell target occupancy assays. Preclinical antitumor activity was evaluated in ex vivo and in vivo human PD-L1-expressing tumor models. Human safety, tolerability, pharmacokinetics, and biomarker activity were evaluated in an open-label, multicenter, sequential dose-escalation study in patients with advanced solid tumors. Biomarkers evaluated included target occupancy, flow cytometric immunophenotyping, plasma cytokine measurements, and T-cell receptor sequencing. RESULTS: GS-4224 binding caused dimerization of PD-L1, blocking its interaction with PD-1 and leading to reversal of T-cell inhibition and increased tumor killing in vitro and in vivo. The potency of GS-4224 was dependent on the density of cell surface PD-L1, with binding being most potent on PD-L1-high cells. In a phase 1 dose-escalation study in patients with advanced solid tumors, treatment was well tolerated at doses of 400-1,500 mg once daily. Administration of GS-4224 was associated with a dose-dependent increase in plasma GS-4224 exposure and reduction in free PD-L1 on peripheral blood T cells, an increase in Ki67 among the PD-1-positive T-cell subsets, and elevated plasma cytokines and chemokines. CONCLUSIONS: GS-4224 is a novel, orally bioavailable small molecule inhibitor of PD-L1. GS-4224 showed evidence of expected on-target biomarker activity, including engagement of PD-L1 and induction of immune-related pharmacodynamic responses consistent with PD-L1 blockade. TRIAL REGISTRATION NUMBER: NCT04049617.

Phase I Study of GS-3583, a FLT3 Agonist Fc Fusion Protein, in Patients with Advanced Solid Tumors.

PURPOSE: GS-3583, a FMS-like tyrosine kinase 3 (FLT3) agonist Fc fusion protein, expanded conventional dendritic cells (cDCs) in the periphery of healthy volunteers, suggesting potential for GS-3583 to increase cDCs in the tumor microenvironment and promote T cell-mediated antitumor activity in cancer patients. This phase Ib open-label study assessed GS-3583 in adults with advanced solid tumors. PATIENTS AND METHODS: Multiple escalating doses of GS-3583 (standard 3+3 design) were administered intravenously on days 1 and 15 of cycle 1 and day 1 of each subsequent 28-day cycle for up to 52 weeks. Dose-limiting toxicity (DLT) was evaluated during the first 28 days of GS-3583 at each dose level. RESULTS: Thirteen participants enrolled in 4 dose-escalation cohorts, after which the study was terminated following safety review. Median (range) age was 71 (44-79), and 7 (54%) participants were male. There were no DLTs. Seven participants had grade ≥3 AEs; 2 participants had grade 5 AEs, including a second primary malignancy (acute myeloid leukemia) considered treatment-related. Dose-dependent increase in GS-3583 serum exposure was observed in the dose range of 2-20 mg with GS-3583 accumulation at higher dose levels. Expansions of cDCs occurred at all 4 doses with a dose-dependent trend in the durability of the cDC expansion. CONCLUSIONS: GS-3583 was relatively well tolerated and induced dose-dependent expansion of cDCs in the periphery of patients with advanced solid tumors. However, development of a second primary malignancy provides a cautionary tale for the FLT3 agonist mechanism.

Randomized, open-label, phase 2 study of andecaliximab plus nivolumab versus nivolumab alone in advanced gastric cancer identifies biomarkers associated with survival.

BACKGROUND: Matrix metalloproteinase-9 (MMP9) selectively cleaves extracellular matrix proteins contributing to tumor growth and an immunosuppressive microenvironment. This study evaluated andecaliximab (ADX), an inhibitor of MMP9, in combination with nivolumab (NIVO), for the treatment of advanced gastric cancer. METHODS: Phase 2, open-label, randomized multicenter study evaluating the efficacy, safety, and pharmacodynamics of ADX+NIVO versus NIVO in patients with pretreated metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and adverse events (AEs). We explored the correlation of efficacy outcomes with biomarkers. RESULTS: 144 patients were randomized; 141 were treated: 81% white, 69% male, median age was 61 years in the ADX+NIVO group and 62 years in the NIVO-alone group. The ORR was 10% (95% CI 4 to 19) in the ADX+NIVO group and 7% (95% CI 2 to 16) in the NIVO-alone group (OR: 1.5 (95% CI 0.4 to 6.1; p=0.8)). There was no response or survival benefit associated with adding ADX. AE rates were comparable in both treatment groups; the most common AEs were fatigue, decreased appetite, nausea, and vomiting. Programmed cell death ligand 1, interferon-γ (IFN), and intratumoral CD8+ cell density were not associated with treatment response or survival. The gene signature most correlated with shorter survival was the epithelial-to-mesenchymal gene signature; high transforming growth factor (TGF)-ß fibrosis score was negatively associated with OS (p=0.036). Gene expression analysis of baseline tumors comparing long-(1+ years) and short-term (<1 year) survivors showed that GRB7 was associated with survival beyond 1 year. Human epidermal growth factor receptor 2 (HER2)-positive disease was associated with significantly longer survival (p=0.0077). Median tumor mutation burden (TMB) was 2.01; patients with TMB ≥median had longer survival (p=0.0025) and improved PFS (p=0.016). Based on a model accounting for TMB, TGF-ß fibrosis, and HER2, TMB was the main driver of survival in this patient population. CONCLUSION: Combination of ADX+NIVO had a favorable safety profile but did not improve efficacy compared with NIVO alone in patients with pretreated metastatic gastric or GEJ adenocarcinoma. HER2 positivity, higher TMB or GRB7, and lower TGF-ß were associated with improved outcomes. TRIAL REGISTRATION NUMBER: NCT02864381 or GS-US-296--2013.

Chemical Constituents and Anti-Gastric Ulcer Activity of Essential Oils of Alpinia officinarum (Zingiberaceae), Cyperus rotundus (Cyperaceae), and Their Herbal Pair.

The essential oil (EO) of the herbal pair (HP), Alpinia officinarum-Cyperus rotundus (HP G-X) has been conventionally used in traditional Chinese medicine (TCM) for 'warming the stomach' and relieving pain. However, its pharmacologically active compounds, as well as the mechanism of its anti-gastric ulcer properties remain unclear. In this study, the EOs obtained from HP G-X and its corresponding single herbs were analyzed using GC/MS. A total of 74, 56, and 85 compounds were detected in A. officinarum (GLJ), C. rotundus (XF), and HP G-X, accounting for 93.2 %, 89.5 %, and 92.0 % of the total content, respectively. GLJ mainly contains 1,8-cineol (22.0 %) and α-terpineol (11.8 %), whereas cyperenone (22.4 %) and cyperene (12.3 %) were the major constituents in XF. These four compounds were also detected in the HP G-X with relatively high composition as 11.8 %, 5.5 %, 11.8 %, and 10.6 %, respectively. Although no new compounds were detected in HP G-X, the relative concentration of some compounds increased, while others decreased or even disappeared. HP G-X showed the lowest toxicity (TC50 >800 µg/mL) against human gastric mucosal epithelial cells (GES-1) and had the best protective effect against ethanol-induced GES-1 cell damage compared to the individual herbs. In vitro studies demonstrated that HP G-X and the corresponding single herbs significantly reduced IL-6, TNF-α, and COX-2. In addition, in vivo investigations indicated that HP G-X can protect the gastric mucosa of mice from ethanol-induced damage by inhibiting the inflammatory reaction and providing analgesia. It can also inhibit the expression of NF-κBp65, COX-2, and TRPV1 protein, reduce the concentrations of IL-6 and TNF-α, and relieve heat-induced pain. This study further substantiated the traditional application of HP G-X against gastric ulcers through both in vivo and in vitro investigations.

Use of the Taguchi Method to Optimize an Immunodetection System for Quantitative Analysis of a Rapid Test.

In this research, the Taguchi method was used to optimize the detection accuracy and reproducibility of an immunodetection system used for a quantitative analysis of a rapid test. Furthermore, the standard deviation (SD) and coefficient of variation (CV) between the theoretical value and the measured value of the self-made simulated rapid test became smaller, and the linearity became higher. The results thus indicated that the immunodetection system became more reliable. In the present research, a camera was used to capture an image containing the control line (C line) and the test line (T line) in the self-made simulated rapid test. The captured image was then analyzed, and the grayscales of the C line and T line were calculated. The Taguchi method was used to adjust the light intensity of the light-emitting diode (LED) and the camera parameters in the immunodetection system to determine the optimal parameters by which to optimize the performance of the immunodetection system. The goal of the present research was to obtain a measurement with a minimum SD and CV between the detected grayscales and the grayscales of the self-made simulated rapid test, thus indicating successful development of a practical, stable, and accurate immunodetection system. To mimic the color expression in an actual rapid test, the ratio of the red, green, blue (RGB) components of the self-made simulated rapid test had to be adjusted to closely fit the color expression of the actual rapid test. After the RGB ratio was set, the Taguchi method was used to optimize the parameters for the purpose of detection. When the optimal parameters were found, the signal-to-noise ratio (S/N ratio) had been increased from -12.89 dB to -10.91 dB, which means the accuracy of the color detection had been improved. Compared to the original detection system, the quality loss had been reduced to 33.1%.

Embedded Immunodetection System for Fecal Occult Blood.

In this paper, a rapid test system with high sensitivity, linearity, and stability is presented for fecal occult blood (FOB) detection. The coloration results of the immune response are used as the basis for the determination of the detection target in combination with an immunochromatographic strip. The rapid test system can be used to detect and calculate the concentration of the sample, so detection of the immune coloration response is more accurate in a quantitative analysis. The system is composed of both hardware and software. The programs used for the analysis and programmed by Python include the main program, polarization calibration, QR Code decoding, Bluetooth transmission, and image processing. After verification of each part of the system, it was found that the rapid test system successfully detects from 0 ng/mL to 400 ng/mL of FOB with coefficients of variation (CV) below 3.7% and 1000 ng/mL with a CV only at 7.41%.

Impact of Top Electrodes on the Nonvolatile Resistive Switching Properties of Citrus Thin Films.

Natural citrus thin films on an indium tin oxide (ITO)/glass substrate were synthesized using the solution method for resistive random access memory (RRAM) applications. The results indicated that the citrus memory device possessed stable resistive switching behavior. For a clear understanding of the role of the interface reaction between the top metal electrode and the citrus film, we investigated the influences of various top electrode (TE) materials on the resistive switching in TE/citrus/ITO devices. In comparison with Au/citrus/ITO and Ti/citrus/ITO devices, the Al/citrus/ITO device can be reproduced with a DC voltage of more than 100 times while only showing a slight decrease in the ON/OFF ratio. In addition, the Al/citrus/ITO device exhibited a high ON/OFF ratio of over 104 and an outstanding uniformity, which was attributed to the fast formation of a native oxide layer (AlOx), as confirmed by the line scan analysis. This indicated that the interface layer, created by the redox reaction between the Al electrode and citrus film, played an important role in the resistive switching properties of TE/citrus/ITO structures. These findings can serve as design guidelines for future bio-based RRAM devices.

Influence of Characteristics of Thermoplastic Polyurethane on Graphene-Thermoplastic Polyurethane Composite Film.

Graphene-thermoplastic polyurethane (G-TPU) composite films were fabricated by traditional blending method and tape casting process with commercial graphene sheets as functional fillers and TPU masterbatches of four different melting points as matrix, respectively. The effects of matrix on the distribution of graphene, the electrical conductivity, and infrared (IR) light thermal properties of the G-TPU composite films were investigated. The experimental results reveal that the characteristics of TPU has little influence on the electrical conductivity of the G-TPU composite films, although the four TPU solutions have different viscosities. However, under the same graphene mass content, the thermal conductivity of four G-TPU composite films with different melting points is significantly different. The four kinds of G-TPU composite films have obvious infrared (IR) thermal effect. There is little difference in the temperatures between the composite films prepared by TPU with melting a point of 100 °C, 120 °C, and 140 °C, respectively; however, when the content of graphene is less than 5 wt%, the temperature of the composite film prepared by TPU with a melting point of 163 °C is obviously lower than that of the other three composite films. The possible reason for this phenomenon is related to the structure of TPU.