3. Other therapies and future perspectives
Many other drugs with disparate mechanisms of actions are evaluated in patients with COVID-19. For instance, a PD-1 immune checkpoint inhibitor monoclonal antibody, camrelizumab, which recently received a conditional approval in China for the treatment of relapsed or refractory classical Hodgkin lymphoma, is evaluated in a phase 2 study involving patients with SARS-Cov-2 infection. PD-1 and its ligand (PD-L1) are key mediators in T cell depletion in patients with sepsis. Preclinical studies have demonstrated that the blockade of PD-1 or PD-L1 can prevent T cell death, regulate cytokine production and reduce organ dysfunction [97,98 ]. The study was launched on February 2020 to verify its efficacy in combination with thymosin in 120 patients with severe pneumonia associated with lymphocytopenia [99 ].
A further experimental monoclonal antibody for the treatment of COVID-19 is bevacizumab, approved for the treatment of metastatic colorectal cancer, non-small cell lung cancer, metastatic breast cancer and advanced and/or metastatic renal cell carcinoma. By binding to the growth factor of vascular endothelial cells (VEGF), a key promoter of vasculogenesis and angiogenesis, bevacizumab is able to prevent its biological activity [100,101 ]. A key role of VEGF in acute lung injury and ARDS was confirmed [102 ]. Based on these findings, two clinical trials are currently evaluating the efficacy and safety of bevacizumab in patients with COVID-19 (BEST-RCT and BEST-CP) [103,104 ].
Also for thalidomide, a drug widely used in the treatment of Interstitial Pulmonary Fibrosis, lung damage from paraquat and myeloma, a possible role for the treatment of COVID-19 was hypothesized. Indeed, the drug has been reported to be effective against HIV [105,106 ] by modulating TNF-a-induced replication. Moreover, thalidomide suppresses the production of proinflammatory cytokines such as TNF-alpha and IL-8 through the inhibition of NF-κB [107 ]. Two studies are currently testing its efficacy in patients with COVID19 [108,109 ].
In addition, other drugs are currently evaluated in Chinese clinical trials involving patients with COVID-19, including fingolimod [110 ], high-dose Vitamin C, adalimumab, piperaquine, and leflunomide [111 ]. Lastly, considering the key role of ACE2 for the attachment and cell entry of SARS-Cov-2, researchers recently suggested that the development of specific neutralizing monoclonal antibodies that bind to ACE2 might block the virus entry [112 ].
Lastly, given that the therapy for COVID-19 is dependent on the patients’ immune system, researchers are evaluating two possible engineering therapies: expanded umbilical cord mesenchymal stem cells in critically ill patients [113 ] and intravenous immunoglobulin purified from IgG antibodies of patients who recovered from COVID-19 [114 ]. Finally, the development of a vaccine against SARS-CoV-2 is urgently needed. However, according to Shang W et al., researchers would bring a new SARS-CoV-2-based vaccine in approximately 16–20 weeks [115 ]. On March 2020, there were 2 candidate vaccines in phase 1 development (studies ChiCTR2000030906 and NCT04283461) and 42 candidate vaccines in preclinical phase of evaluation [116 ]. Researchers from the University of Pittsburgh School of Medicine announced a potential vaccine against SARS-CoV-2 that was tested in mice and produced antibodies specific to SARS-CoV-2 able to neutralize the virus [117 ]. Furthermore, an experimental mRNA vaccine against the pandemic coronavirus was already administered to one person in US [118 ].