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Annals of the Rheumatic Diseases ; 80(SUPPL 1):198-199, 2021.
Article in English | EMBASE | ID: covidwho-1358911


Background: Granulocyte/macrophage-colony stimulating factor (GM-CSF) is a cytokine both vital to lung homeostasis and important in regulating inflammation and autoimmunity1,2,3 that has been implicated in the pathogenesis of respiratory failure and death in patients with severe COVID-19 pneumonia and systemic hyperinflammation. 4-6 Mavrilimumab is a human anti GM-CSF receptor α monoclonal antibody capable of blocking GM-CSF signaling and downregulating the inflammatory process. Objectives: To evaluate the effect of mavrilimumab on clinical outcomes in patients hospitalized with severe COVID-19 pneumonia and systemic hyperinflammation. Methods: This on-going, global, randomized, double-blind, placebo-controlled seamless transition Phase 2/3 trial was designed to evaluate the efficacy and safety of mavrilimumab in adults hospitalized with severe COVID-19 pneumonia and hyperinflammation. The Phase 2 portion comprised two groups: Cohort 1 patients requiring supplemental oxygen therapy without mechanical ventilation (to maintain SpO2 ≥92%) and Cohort 2 patients requiring mechanical ventilation, initiated ≤48 hours before randomization. Here, we report results for Phase 2, Cohort 1: 116 patients with severe COVID-19 pneumonia and hyperinflammation from USA, Brazil, Chile, Peru, and South Africa;randomized 1:1:1 to receive a single intravenous administration of mavrilimumab (10 or 6 mg/kg) or placebo. The primary efficacy endpoint was proportion of patients alive and free of mechanical ventilation at Day 29. Secondary endpoints included [1] time to 2-point clinical improvement (National Institute of Allergy and Infectious Diseases COVID-19 ordinal scale), [2] time to return to room air, and [3] mortality, all measured through Day 29. The prespecified evidentiary standard was a 2-sided α of 0.2 (not adjusted for multiplicity). Results: Baseline demographics were balanced among the intervention groups;patients were racially diverse (43% non-white), had a mean age of 57 years, and 49% were obese (BMI ≥ 30). All patients received the local standard of care: 96% received corticosteroids (including dexamethasone) and 29% received remdesivir. No differences in outcomes were observed between the 10 mg/kg and 6 mg/ kg mavrilimumab arms. Results for these groups are presented together. Mavrilimumab recipients had a reduced requirement for mechanical ventilation and improved survival: at day 29, the proportion of patients alive and free of mechanical ventilation was 12.3 percentage points higher with mavrilimumab (86.7% of patients) than placebo (74.4% of patients) (Primary endpoint;p=0.1224). Mavrilimumab recipients experienced a 65% reduction in the risk of mechanical ventilation or death through Day 29 (Hazard Ratio (HR) = 0.35;p=0.0175). Day 29 mortality was 12.5 percentage points lower in mavrilimumab recipients (8%) compared to placebo (20.5%) (p=0.0718). Mavrilimumab recipients had a 61% reduction in the risk of death through Day 29 (HR= 0.39;p=0.0726). Adverse events occurred less frequently in mavrilimumab recipients compared to placebo, including secondary infections and thrombotic events (known complications of COVID-19). Thrombotic events occurred only in the placebo arm (5/40 [12.5%]). Conclusion: In a global, diverse population of patients with severe COVID-19 pneumonia and hyperinflammation receiving supplemental oxygen therapy, corticosteroids, and remdesivir, a single infusion of mavrilimumab reduced progression to mechanical ventilation and improved survival. Results indicate mavrilimumab, a potent inhibitor of GM-CSF signaling, may have added clinical benefit on top of the current standard therapy for COVID-19. Of potential importance is that this treatment strategy is mechanistically independent of the specific virus or viral variant.

Clinical Cancer Research ; 26(18 SUPPL), 2020.
Article in English | EMBASE | ID: covidwho-992079


Cancer patients infected with the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have ahigher mortality rate compared to non-cancer patients. Recent anticancer treatment, including immunotherapy, isassociated with severe infection including development of acute respiratory distress syndrome (ARDS) and highlevels of cytokine release resulting in cytokine storm. Immune checkpoint inhibitors (ICIs) are approved for use inmultiple cancer types and function by blocking the interaction between PD-1 and its ligand PD-L1, activatingantitumor cytotoxic immune cells. However, ICIs can also increase inflammatory cytokine secretion, which maypredispose to the development of cytokine storm. In fact, we have shown via single-cell cytokine secretion analysisthat pembrolizumab (anti-PD-1 antibody) increases cytokine secretion by polyfunctional strength index, a measureof the percentage of cells secreting multiple functional cytokines. Therefore, we hypothesize that ICIs may worseninflammatory cytokine secretion and potentiate cytokine storm and downstream complications in COVID-19 patients.Peripheral blood mononuclear cells (PBMCs) were isolated via Ficoll density gradient centrifugation from healthydonors, head and neck cancer (HNC) patients, and COVID-19-infected cancer patients. Flow cytometry wasperformed on patient PBMCs, after staining for viability and immune cell markers including CD3, CD8, CD19, andCD45. PBMCs were also activated overnight with low-dose IL-2, cocultured with Cal27 or HN5 cell lines, andsubjected to various treatment conditions. For non-COVID-19 patients, PBMCs were exposed to 25 nM SARS-CoV-2 recombinant spike (S) protein, a virulent protein associated with cytokine storm, or control prior to drug treatments.Preliminary flow cytometry analysis showed that a COVID-19-positive patient with thyroid cancer had an increasedproportion of CD8+ cells compared with a COVID-negative ovarian cancer patient and healthy donor. RecombinantSARS-CoV-2 S protein caused increased secretion of IL-6, IL-2, perforin, and MIP-1b from PBMCs isolated fromboth healthy donors and HNC patients, which was measured by IsoLight Codeplex bulk cytokine analysis or ELISA.We have previously shown that metformin, a commonly prescribed antidiabetes drug, decreases the proportion ofcells that secrete inflammatory cytokines such as IL-6, which is thought to be an important cytokine for cytokinestorm. Interestingly, we observed that metformin treatment resulted in decreased IL-6 secretion from PBMCsisolated from a COVID-19-positive patient. Results from this project suggest that ICIs may potentiate cytokine storm, and ongoing investigation will be informative to oncologists as to whether ICI treatment should be postponed insevere COVID-19 infections. In addition, metformin may be a novel potential treatment for COVID-19 patients toprevent and treat cytokine storm.