Early combination therapy of COVID-19 in high-risk patients.

PURPOSE: Prolonged shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been observed in immunocompromised hosts. Early monotherapy with direct-acting antivirals or monoclonal antibodies, as recommended by the international guidelines, does not prevent this with certainty. Dual therapies may therefore have a synergistic effect. METHODS: This retrospective, multicentre study compared treatment strategies for corona virus disease-19 (COVID-19) with combinations of nirmatrelvir/ritonavir, remdesivir, molnupiravir, and/ or mABs during the Omicron surge. Co-primary endpoints were prolonged viral shedding (≥ 106 copies/ml at day 21 after treatment initiation) and days with SARS-CoV-2 viral load ≥ 106 copies/ml. Therapeutic strategies and risk groups were compared using odds ratios and Fisher's tests or Kaplan-Meier analysis and long-rank tests. Multivariable regression analysis was performed. RESULTS: 144 patients were included with a median duration of SARS-CoV-2 viral load ≥ 106 copies/ml of 8.0 days (IQR 6.0-15.3). Underlying haematological malignancies (HM) (p = 0.03) and treatment initiation later than five days after diagnosis (p < 0.01) were significantly associated with longer viral shedding. Prolonged viral shedding was observed in 14.6% (n = 21/144), particularly in patients with underlying HM (OR 3.5; 95% CI 1.2-9.9; p = 0.02). Clinical courses of COVID-19 were mild to moderate with only few adverse effects potentially related to combination treatment. CONCLUSION: Early combination treatment of COVID-19 effectively prevented prolonged viral shedding in 85.6% of cases. Considering the rapid viral clearance rates and low toxicity, individualized dual therapy approaches may be beneficial in high-risk patients.

Efficacy of cytokine-induced killer cells targeting CD40 and GITR.

Since the publication of a novel protocol in 1991, cytokine-induced killer (CIK) cells have shown promising results in the treatment against neoplastic diseases. Despite ongoing preclinical and clinical studies, CIK cell treatment in the context of human monoclonal antibodies targeting tumor-necrosis factor receptors remains overlooked. The present study investigated whether a combination of CIK cells with human monoclonal antibody anti-CD40 and anti-Glucocorticoid-induced TNF-related protein (GITR) would lead to further cytotoxicity against tumor cells expressing CD40 and GITR ligand (L). Therefore, in vitro experiments with human lymphoma cell lines SU-DHL-4 and Daudi (both CD40 positive) and human breast adenocarcinoma MCF-7 (GITRL positive) were performed and the secretion of interferon (IFN)-γ was measured. Three interesting results emerged: i) a combination of CIK cells and anti-CD40 mAb is more effective than CIK cell treatment alone; ii) the use of anti-GITR mAb and CIK cells significantly enhanced the cytotoxicity of CIK cells against MCF-7 compared with single CIK cell treatment and iii) the combination of both antibodies and CIK cells abrogates the anti tumoral effect of CIK cells on all three cell lines. By performing an ELISA for IFN-γ measurement, a lower secretion was observed when anti-CD40 or anti-GITR mAb was added. This outcome indicates that further studies in vitro and in vivo may aid in understanding the synergistic molecular mechanisms of CIK cells, and anti-CD40 and anti-GITR mAb.