Cellular and Molecular Immunology Approaches for the Development of Immunotherapies against the New Coronavirus (SARS-CoV-2): Challenges to Near-Future Breakthroughs

Table 1

Clinical trials with results disclosure and ongoing clinical trials focused on immunotherapy to attempt immune regulation during COVID-19.

(a) Clinical trials with result disclosures

Product	Benefits for COVID-19	ClinicalTrials.gov reference number	Reference
Dexamethasone/methyl prednisolone	Corticosteroids: reduce hyperinflammation and mortality rates	NCT04445506; NCT04323592; NCT04244591; NCT04273321; NCT04374071	Gangopadhyay et al./Chroboczek et al./Ledford/Wang et al. [131–134]
Convalescent plasma	Antibodies from plasma: reduce viral load, days of hospitalization, and the number of deaths. Increase of effector T cell responses helping in viral elimination	NCT04407208; NCT04346446; NCT04441424; NCT04442958	Vabret et al./Shang et al. [30, 108]
Chloroquine and hydroxychloroquine	Antiviral compounds with immunomodulatory effect: without proven effectiveness or potential benefit in COVID-19	NCT04307693; NCT04261517; NCT04434144; NCT04345861; NCT04376814; NCT04343768; NCT04423991; NCT04389320; NCT04441424; NCT04308668; NCT04323592; NCT04306497; NCT04362332; NCT04342650; NCT04323527; NCT04358068; NCT04321278; NCT04333654; NCT04475588; NCT04453501; NCT04308668; NCT04304053	Vabret et al./Zhang et al. [30, 111]
Ivermectin	Antiviral compounds with immunomodulatory effect: reduce mortality rates. Possible effect on raising antibody production and leukocytes	NCT04343092; NCT04434144	Rajter et al. [114]
Oseltamivir	Antiviral compounds with immunomodulatory effect: reduce the hospitalization days for COVID-19 patients	NCT04349241	Coenen et al. [119]
Interferon β-1b	Cytokine-directed therapy: combined with other antivirals, reduces the duration of viral shedding, days of hospitalization and mitigation of symptoms	NCT04343768; NCT04276688	Shalhoub [125]
Anti-IL-6 and anti-IL-6R (Tocilizumab/Siltuximab)	Inhibition/blockade of immune response pathways: combined with other antivirals, presented resolution on lung opacities on chest computed tomography and hospital discharge using tocilizumab	NCT04331795; NCT04346355; NCT04322188	Xu et al. [138]
Heparin	Anticoagulants: a preliminary study with D-dimer elevation levels, high platelet count in severe COVID-19	NCT04412304	Zhang et al. [111]
Azithromycin	Antibiotics: used as an adjuvant in therapies with antiviral drugs and immunomodulatory components to avoid secondary infections in hospitalized patients, with good results in mortality reduction and intubation shortening time	NCT04345861; NCT04434144; NCT04343092; NCT04441424; NCT04358068; NCT04321278; NCT04453501	Saghazadeh and Rezaei/Falsenstein et al. [142, 153]
Multipotent mesenchymal stem cells (MSC)	Immune cell-based therapy: results showed a reduction of pulmonary edema and decreased circulating proinflammatory cytokines and mortality rates	ChiCTR2000029990	Zhang et al./ Leng et al. [111, 154]
Vitamin D, zinc, Traditional Chinese Medicine	Biomolecule effect on immune response: contributing to the reduction of hyper inflammation	NCT04407572; NCT04435119; NCT04306497	Zhang et al./Zhang et al./Meltzer et al. [111, 157, 158]

(b) Ongoing clinical trials

Product	Benefits for COVID-19	ClinicalTrials.gov reference number	Reference
Intravenous gamma globulin (IVIG)	Antibodies from plasma: may suppress inflammatory cytokines and modulate T cell responses	NCT04411667; NCT04403269; NCT04400058	Zhang et al. [111]
Anti-CCR5 (Leronlimab)	Inhibition/blockade of immune response pathways: may promote monocyte and T cell recruitment in tissues in COVID-19	NCT04347239; NCT04343651	Merad and Martin [140]
Recombinant IL-1 receptor antagonist (Anakinra)	Inhibition/blockade of immune response pathways: may reduce proinflammatory cytokines in COVID-19, as seen in patients with rheumatologic disorders	NCT04339712; NCT04324021; NCT04330638; NCT04443881; NCT04362943; NCT04412291; NCT04364009; NCT04357366; NCT04408326; NCT02735707; NCT04374539; NCT04278404; NCT04462757	Muskardin [139]
Anti-IFN-γ (Emapalumab)	Inhibition/blockade of immune response pathways: may reduce pro-inflammatory cytokines in COVID-19	NCT04324021	Merad and Martin [140]
Anti-GM-CSF (Lenzilumab)/GM-CSF (Sargramostim)	Inhibition/blockade of immune response pathways: may reduce proinflammatory cytokines, and promotes macrophage differentiation and survival driving to tissue repair in lungs in COVID-19	NCT04351152; NCT04326920; NCT04400929	Merad and Martin [140]
JAK/STAT inhibition (Baricitinib/Ruxolitinib)	Inhibition/blockade of immune response pathways: may induce impairment of the signaling transduction on cell immune response using bioinformatic tools	NCT04390464; NCT04321993NCT04334044; NCT04351503; NCT04377620; NCT04362137; NCT04338958; NCT04348695; NCT04403243; NCT04359290; NCT04477993	Richardson et al. [141]
Anti-C5 (Eculizumab)	Inhibition/blockade of immune response pathways: diminishing C reactive protein and shortening period of hospitalization	NCT04346797; NCT04351503	Diurno et al. [145]
Anti-TNF (Infliximab)	Inhibition/blockade of immune response pathways: cytokine profile improved with normalization of TNF-α, a decrease in IL-6, and IL-8 concentrations	NCT04425538; NCT04344249	Dolinger et al. [146]
Anti-CD147 (humanized Meplazumab)	Inhibition/blockade of immune response pathways: inhibition of SARS-CoV-2 entry and replication using in vitro cell cultures, may reduce T cell activation and T cell infectivity. Reduce viral replication in humans with COVID-19	NCT04275245	Wang et al./Ulrich and Pillat [147, 149]
rhACE2	Inhibition/blockade of immune response pathways: inhibition of SARS-CoV-2 entry and replication as well as may control immune cell response	NCT04335136	Zhang et al./Tu et al. [111, 150]
Natural killer cells (NK)	Immune cell-based therapy: may help in elimination of infected cells	NCT04365101; NCT04280224NCT04324996; NCT04375176	Zhang et al./Tu et al. [111, 150]
Biomolecules: vitamin C, melatonin, nitric oxide (iNO)	Immunomodulatory effects of biomolecules: may contribute to reducing hyperinflammation and prevention of hypoxic respiratory failure	NCT04323514; NCT04357782; NCT04370288; NCT04328961; NCT04354428; NCT04264533; NCT04409522; NCT04353128; NCT04446104; NCT04326725; NCT04360980; NCT04368897; NCT04388683; NCT04338828; NCT04305457; NCT04337918; NCT04306393; NCT04312243; NCT04445246; NCT04334512; NCT03680274; NCT04335084; NCT04468139; NCT04421508; NCT04397692	Zhang et al./Tu et al./Zhang et al./Parikh et al. [111, 150, 157, 159]
Atazanavir	Antiviral compounds with immunomodulatory effect: reduce viral load and proinflammatory cytokines using in vitro cell cultivation with SARS-CoV-2	NCT04452565	Merad and Martin [140]
Humanized monoclonal antibody to P-selectin (Crizanlizumab)	Anticoagulants: anti-P-selectin may help to maintain the hemostatic homeostasis, being an essential cofactor for the extrinsic pathway of blood coagulation	NCT04435184	Neri et al. [103]
CAR-T cell therapy	Immunotherapeutic approaches with similarities to other immunopathological diseases: may help the elimination of infected cells	NCT04474067	Bachanova et al./Ljungman et al. [155, 156]