Impact of dose modification of immune-checkpoint inhibitors in lung cancer patients during the COVID-19 pandemic

Background: COVID-19 pandemic has led physicians to change their practice in the treatment of non-small cell lung cancer (NSCLC) to reduce hospital stays of patients. Objective(s): We aimed to assess toxicity and efficacy of extended-interval (EI) dosing of immune checkpoint inhibitors (ICI) compared to standard dose (SD). Method(s): In a retrospective bicentric study, patients with stage III/IV NSCLC treated with ICI +/- pemetrexed in maintenance setting during the month before March 2020 were included. Immune-related adverse events (IRAE) and efficacy were collected until June 2021. Toxicity and survival were assessed using multivariate logistic regression and Cox models. Result(s): Among the 134 identified patients (8 stage III and 126 stage IV, 66 in 1st line and 60 in 2nd or further lines), 70.9% had an EI dosing. In the EI dosing group, 12.6% patients developed grade 3 or more IRAE and 15.4% in the SD group (p=0.8). Treatment was definitively discontinued for toxicity for 9 patients in the EI dosing group and 5 patients in the SD group (p=0.5). Overall survival was not associated with dosage or occurrence of toxicity as timedependent variable (Table). Conclusion(s): Our study suggests that EI dosing of ICI did not affect toxicity, efficacy and survival in NSCLC patients.

Development of an In Vitro Model of SARS-CoV-Induced Acute Lung Injury for Studying New Therapeutic Approaches.

One of the causes of death of patients infected by SARS-CoV-2 is the induced respiratory failure caused by excessive activation of the immune system, the so-called "cytokine storm", leading to damage to lung tissue. In vitro models reproducing various stages of the disease can be used to explore the pathogenetic mechanisms and therapeutic approaches to treating the consequences of a cytokine storm. We have developed an in vitro test system for simulating damage to the pulmonary epithelium as a result of the development of a hyperinflammatory reaction based on the co-cultivation of pulmonary epithelial cells (A549 cells) and human peripheral blood mononuclear cells (PBMC) primed with lipopolysaccharide (LPS). In this model, after 24 h of co-cultivation, a sharp decrease in the rate of proliferation of A549 cells associated with the intrinsic development of oxidative stress and, ultimately, with the induction of PANoptotic death were observed. There was a significant increase in the concentration of 40 cytokines/chemokines in a conditioned medium, including TNF-α, IFN-α, IL-6, and IL-1a, which corresponded to the cytokine profile in patients with severe manifestation of COVID-19. In order to verify the model, the analysis of the anti-inflammatory effects of well-known substances (dexamethasone, LPS from Rhodobacter sphaeroides (LPS-RS), polymyxin B), as well as multipotent mesenchymal stem cells (MSC) and MSC-derived extracellular vesicles (EVs) was carried out. Dexamethasone and polymyxin B restored the proliferative activity of A549 cells and reduced the concentration of proinflammatory cytokines. MSC demonstrated an ambivalent effect through stimulated production of both pro-inflammatory cytokines and growth factors that regenerate lung tissue. LPS-RS and EVs showed no significant effect. The developed test system can be used to study molecular and cellular pathological processes and to evaluate the effectiveness of various therapeutic approaches for the correction of hyperinflammatory response in COVID-19 patients.

Application of meso-CF3-Fluorophore BODIPY with Phenyl and Pyrazolyl Substituents for Lifetime Visualization of Lysosomes.

A bright far-red emitting unsymmetrical meso-CF3-BODIPY fluorescent dye with phenyl and pyrazolyl substituents was synthesized by condensation of trifluoropyrrolylethanol with pyrazolyl-pyrrole, with subsequent oxidation and complexation of the formed dipyrromethane. This BODIPY dye exhibits optical absorption at λab ≈ 610-620 nm and emission at λem ≈ 640-650 nm. The BODIPY was studied on Ehrlich carcinoma cells as a lysosome-specific fluorescent dye that allows intravital staining of cell structures with subsequent real-time monitoring of changes occurring in the cells. It was also shown that the rate of uptake by cells, the rate of intracellular transport into lysosomes, and the rate of saturation of cells with the dye depend on its concentration in the culture medium. A concentration of 5 µM was chosen as the most suitable BODIPY concentration for fluorescent staining of living cell lysosomes, while a concentration of 100 µM was found to be toxic to Ehrlich carcinoma cells.

Filterability of Erythrocytes in Patients with COVID-19.

For the first time, the influence of COVID-19 on blood microrheology was studied. For this, the method of filtering erythrocytes through filters with pores of 3.5 µm was used. Filterability was shown to significantly decrease with the increasing severity of the patient's condition, as well as with a decrease in the ratio of hemoglobin oxygen saturation to the oxygen fraction in the inhaled air (SpO2/FiO2). The filterability of ≤ 0.65, or its fast decrease during treatment, were indicators of a poor prognosis. Filterability increased significantly with an increase in erythrocyte count, hematocrit and blood concentrations of hemoglobin, albumin, and total protein. The effect of these parameters on the erythrocyte filterability is directly opposite to their effect on blood macrorheology, where they all increase blood viscosity, worsening the erythrocyte deformability. The erythrocyte filterability decreased with increasing oxygen supply rate, especially in patients on mechanical ventilation, apparently not due to the oxygen supplied, but to the deterioration of the patients' condition. Filterability significantly correlates with the C-reactive protein, which indicates that inflammation affects the blood microrheology in the capillaries. Thus, the filterability of erythrocytes is a good tool for studying the severity of the patient's condition and his prognosis in COVID-19.

Learning COVID-19 Mitigation Strategies Using Reinforcement Learning

COVID-19 has resulted in the mathematical modelling community producing a wide range of analyses, forecasting and scenario modelling efforts. In our work, we propose a novel approach using Reinforcement Learning to answer the question: “What agent behaviours reduce the spread of COVID-19?”. We address this question by creating an agent-based simulation environment and modelling the environment as a multi-agent Markov Decision Process (MDP). By providing agents the freedom to select their actions and learn from their experiences, RL allows agents to learn behavioural policies that reduce the spread of COVID-19. These behaviours can be analyzed, conditional on demographic attributes with the hopes of providing a more granular analysis to inform public health policymakers. The learned agent behaviours are compared to multiple baselines, as well we introduce two non-compliant scenarios, namely the addition of wildcard agents and compliance attrition. We found that the RL model was able to considerably reduce the number of infections, hospitalizations and deaths in the population, even in the non-compliance model scenarios. From the learned agent behaviours, we suggest enhancing public education on self-isolating at home and highlight the importance of mitigation strategies in schools. We hope this work will influence a new wave of research in Canada using RL for public health crises, including pandemic control. © 2022, Springer Nature Switzerland AG.

The efficacy and safety of levilimab in severely ill COVID-19 patients not requiring mechanical ventilation: results of a multicenter randomized double-blind placebo-controlled phase III CORONA clinical study.

OBJECTIVE AND DESIGN: The aim of this double-blind, placebo-controlled, phase III CORONA clinical trial was to evaluate the efficacy and safety of IL-6 receptor inhibitor levilimab (LVL) in subjects with severe COVID-19. SUBJECTS: The study included 217 patients. The eligible were men and non-pregnant women aged 18 years or older, hospitalized for severe COVID-19 pneumonia. TREATMENT: 206 subjects were randomized (1:1) to receive single subcutaneous administration of LVL 324 mg or placebo, both in combination with standard of care (SOC). 204 patients received allocated therapy. After the LVL/placebo administration in case of deterioration of symptoms, the investigator could perform a single open-label LVL 324 mg administration as the rescue therapy. METHODS: The primary efficacy endpoint was the proportion of patients with sustained clinical improvement on the 7-category ordinal scale on Day 14. All efficacy data obtained after rescue therapy administration were considered missing. For primary efficacy analysis, all subjects with missing data were considered non-responders. RESULTS: 63.1% and 42.7% of patients in the LVL and in the placebo groups, respectively, achieved sustained clinical improvement on Day 14 (P = .0017). The frequency of adverse drug reactions was comparable between the groups. CONCLUSION: In patients with radiologically confirmed SARS-CoV-2 pneumonia, requiring or not oxygen therapy (but not ventilation) with no signs of other active infection administration of LVL + SOC results in an increase of sustained clinical improvement rate. TRAIL REGISTRATION: The trial is registered at the US National Institutes of Health (ClinicalTrials.gov; NCT04397562).

A Case of Moderately Severe COVID-19 in a Healthcare Worker in Russia: Virus Isolation and Full Genome Sequencing.

The coronavirus disease 2019 (COVID-19) pandemic is probably the most studied one in history from both clinical and molecular-epidemiological perspectives. Nonetheless, data on the correlation between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral genotypes and COVID-19 symptoms caused by them are still scarce. In this report, we present a moderately severe COVID-19 case in a healthcare worker in Moscow, Russia, supplemented with the data on its causative agent's phenotype regarding in vitro and full-genome characterization. The 44-year-old male healthcare worker who had frequent professional contacts with COVID-19 patients was hospitalized with a viral pneumonia diagnosis and soon started to exhibit fever, dry paroxysmal cough, loss of smell, and typical ground-glass opacities found in both lungs on chest CT scans. The COVID-19 diagnosis was verified by real-time quantitative polymerase chain reaction (qRT-PCR), immunochromatography, and immunochemiluminescent assays. The patient was treated with hydroxychloroquine, azithromycin, paracetamol, and enoxaparin, leading to his recovery after two weeks from the disease onset. The virus was successfully isolated from the nasopharyngeal swab sample taken on the fifth day of the disease onset using the Vero E6 cell line and exhibited a pronounced cytopathic effect (CPE) with a viral titer reaching 106 TCID50/ml in the cell culture medium. The full genome sequence of the viral isolate was obtained and 8 nucleotide and 5 amino acid mutations compared to the Wuhan-Hu-1 reference genome were identified. Viral isolate belonged to GR / 20B / B.1.1 genetic lineage (GISAID, Nextstrain, Pangolin nomenclatures, respectively) - the most prevalent genotype found in Russia to date.