PD-1 and Tim-3 Regulate the Expansion of Tumor Antigen-Specific CD8+ T Cells Induced by Melanoma Vaccines

Although melanoma vaccines stimulate tumor antigen (TA)-specific CD8+ T cells, objective clinical responses are rarely observed. To investigate this discrepancy, we evaluated the character of vaccine-induced CD8+ T cells with regard to the inhibitory T cell co-receptors PD-1 and Tim-3 in metastatic melanoma patients who were administered tumor vaccines. The vaccines included incomplete Freund's adjuvant (IFA), CpG oligodeoxynucleotide (CpG) and the HLA-A2-restricted analog peptide NY-ESO-1 157-165V, either by itself or in combination with the pan-DR epitope NY-ESO-1 119-143. Both vaccines stimulated rapid TA-specific CD8+ T-cell responses detected ex vivo, however, TA-specific CD8+ T cells produced more IFN-γ and exhibited higher lytic function upon immunization with MHC class I and class II epitopes. Notably, the vast majority of vaccine-induced CD8+ T cells upregulated PD-1 and a minority also upregulated Tim-3. Levels of PD-1 and Tim-3 expression by vaccine-induced CD8+ T cells at the time of vaccine administration correlated inversely with their expansion in vivo. Dual blockade of PD-1 and Tim-3 enhanced the expansion and cytokine production of vaccine-induced CD8+ T cells in vitro. Collectively, our findings support the use of PD-1 and Tim-3 blockades with cancer vaccines to stimulate potent antitumor T cell responses and increase the likelihood of clinical responses in advanced melanoma patients

COVID-19: a confirmed case of reinfection in a nurse

We describe the case of a 63-year-old man who is reported to have the first confirmed case of COVID-19 reinfection in Campania Region, Italy. We found that the two episodes were caused by virus strains with clearly different genome sequences. The patient, a retired nurse, had a very low level of antibodies IgG directed against the spike protein 14 days after his first Pfizer/BioNTek vaccine shot

KL-6 in ARDS and COVID-19 Patients

: The Acute Respiratory Distress Syndrome (ARDS) is a common, devastating clinical pattern characterized by life-threatening respiratory failure. In ARDS there is an uncontrolled inflammatory response that results in alveolar damage, with the exudation of protein-rich pulmonary-edema fluid in the alveolar space. Although severe COVID-19 lung failure (CARDS) often meets diagnostic criteria of traditional ARDS, additional features have been reported, such as delayed onset, binary pulmonary compliant states, and hypercoagulable profile. Increased levels of Krebs von den Lungen 6 (KL-6, also known as MUC1) have been reported in both ARDS and CARDS. KL-6 is a transmembrane protein expressed on the apical membrane of most mucosal epithelial cells and it plays a critical role in lining the airway lumen. Abnormalities in mucus production contribute to severe pulmonary complications and death from respiratory failure in patients with diseases such as cystic fibrosis, chronic obstructive pulmonary disease, and acute lung injury due to viral pathogens. Nevertheless, it is not clear what role KL-6 plays in ARDS/CARDS pathophysiology. KL-6 may exert anti-inflammatory effects through the intracellular segment, as proven in animal models of ARDS, while its extracellular segment will enter the blood circulation through the alveolar space when the alveolar epithelial cells are damaged. Therefore, changes in plasma KL-6 levels may be useful in ARDS and CARDS phenotyping, and KL-6 might guide future clinical trials in 'personalized medicine' settings

An overview of the preclinical discovery and development of remdesivir for the treatment of coronavirus disease 2019 (COVID-19)

Remdesivir (RDV) is an inhibitor of the viral RNA-dependent RNA polymerases that are active in some RNA viruses, including the Ebola virus and zoonotic coronaviruses. When severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) was identified as the etiologic agent of the coronavirus disease 2019 (COVID-19), several investigations have assessed the potential activity of RDV in inhibiting viral replication, giving rise to hope for an effective treatment

The preclinical discovery and development of molnupiravir for the treatment of SARS-CoV-2 (COVID-19)

IntroductionMolnupiravir (MOV) is a broad-spectrum oral antiviral agent approved for the treatment of COVID-19. The results from in vitro and in vivo studies suggested MOV activity against many RNA viruses such as influenza virus and some alphaviruses agents of epidemic encephalitis. MOV is a prodrug metabolized into the ribonucleoside analog beta-D-N-4-hydroxycytidine. It is incorporated into the viral RNA chain causing mutations impairing coding activity of the virus, thereby inhibiting viral replication.Areas coveredThis review analyzes the in vitro and in vivo studies that have highlighted the efficacy of MOV and the main pre-authorization randomized controlled trials evaluating its safety, tolerability, and pharmacokinetics, as well as its antiviral efficacy against SARS-COV-2 infection.Expert opinionMOV is an antiviral agent with an excellent tolerability profile with few drug-drug interactions. Treatment of mild-to-moderate COVID-19 can benefit from MOV administration in the precocious phases of the disease, prior to the trigger of an aberrant immune response responsible for the parenchymal damage to pulmonary and extrapulmonary tissues. However, its suspected mutagenic effect can be a factor limiting its use at least in selected populations and studies on its teratogen effects should be planned before it is authorized for use in the pediatric population or in pregnant women

Preclinical discovery and development of nirmatrelvir/ritonavir combinational therapy for the treatment of COVID-19 and the lessons learned from SARS-COV-2 variants

Introduction: Nirmatrelvir/ritonavir (Paxlovid®) represent an oral antiviral therapy approved for the treatment of COVID-19. Extensive in vitro and in vivo studies have reported the promising activity of nirmatrelvir/ritonavir against numerous emerging viruses. This combination consists of nirmatrelvir, a protease reversible inhibitor of coronavirus 3CLpro mainly metabolized by cytochrome P450 (CYP)3A4, and ritonavir, an inhibitor of the CYP3A isoforms that enhances the efficacy of nirmatrelvir by fixing its suboptimal pharmacokinetic properties. Areas covered: This review comprehensively examines the efficacy of nirmatrelvir/ritonavir through rigorous analysis of in vitro and in vivo studies. Moreover, it thoroughly assesses its safety, tolerability, pharmacokinetics, and antiviral efficacy against SARS-COV-2 infection, based on the main pre-authorization randomized controlled trials. Expert opinion: Nirmatrelvir/ritonavir has a good tolerability profile. Its administration during the early stages of mild-to-moderate COVID-19 holds potential benefits, as it can help prevent the onset of an aberrant immune response that could lead to pulmonary and extra-pulmonary complications. However, its drug - drug interactions can be a factor limiting its use, at least in populations on some chronic therapies, along with the risk of infection relapse after treatment

Effect of remdesivir on mortality rate and clinical status of COVID-19 patients: a systematic review with meta-analysis

Remdesivir (RDV) is a broad-spectrum antiviral drug, now approved by Regulatory Agencies for COVID-19 treatment. RDV is associated with improvements in clinical outcomes, but no conclusive studies have shown an effect in reducing mortality. This study aimed to carry out a systematic review with meta-analysis to investigate whether RDV can significantly modify the outcome of COVID-19 patients evaluating its effects on mortality, length of stay, time to clinical improvement and need for oxygen supplementation. No significant improvement in terms of survival in patients treated with standard therapy (ST)+RDV as compared to ST alone (P = 0.24) was found. The duration of oxygen support was significantly lower in patients treated with ST + RDV compared with ST alone (P = 0.03). Further investigations should be planned to assess the real impact of RDV in the management of COVID-19 patients