Repurposing Immunomodulatory Therapies against Coronavirus Disease 2019 (COVID-19) in the Era of Cardiac Vigilance: A Systematic Review
Abstract
:1. Introduction
2. COVID-19 Clinical Observations
2.1. Viral Phase
2.2. Immune Response Phase
2.3. Thromboembolism
2.4. Cardiovascular Complications
3. Systematic Review Methodology
3.1. Search Strategy
3.2. Inclusion/Exclusion Critieria
3.3. Screening Based on Inclusion/Exclusion Criteria
3.4. World Heat Map
4. Results of Repurposed Therapeutic Clinical Trials for COVID-19 Inflammation
4.1. Anti-Inflammatory Agents
4.1.1. Overview
4.1.2. Clinical Uses
- JAK inhibitor: A pilot study of ruxolitinib demonstrated improvement in HLH [46]. In addition, an artificial intelligence algorithm predicted baricitinib to be a numb-associated kinase (NAK) inhibitor at the doses used for rheumatoid arthritis treatment [47]. In vitro NAK inhibition can reduce viral infection through clathrin-mediated endocytosis blockade [48]. These data suggest baricitinib may have both anti-inflammatory and anti-viral effects. Tofacitinib has not directly been trialed CRS but is a significant cytokine inhibitor [49]. TD-0903 is an investigational JAK inhibitor that is nebulized and lung-selective, per press releases [50].
- IL-6 inhibitor: IL-6 levels correlate with severe disease in SARS [54]. Tocilizumab has been used to treat HLH, GvHD, and CRS induced by CAR T-cell therapy [55,56]. Preclinical studies are supportive of siltuximab for CRS induced by CAR T-cell therapy [57]. Sarilumab has not been directly tested in CRS.
- IL-8 inhibitor: IL-8 is elevated in CRS induced by CAR-T cell therapy [58]. No IL-8 inhibitors are currently FDA approved. IL-8 inhibitors are under investigation for the treatment of malignant solid tumors. High IL-8 levels are associated with tumor progression and epithelial-mesenchymal transition [59].
- IFN-beta-1: Interferon-beta-1 is a cytokine that has anti-viral, anti-proliferative, and immunomodulatory effects. It is FDA-approved to treat multiple sclerosis. IFN-beta increases the production of anti-inflammatory cytokines, such as IL-10, and limits leukocyte migration across the blood-brain-barrier [62,63]. IFN-beta was protective in septic shock and ARDS murine models [64,65]. In an open-label study, treatment with IFN-beta in ARDS was associated with decreased 28-day mortality [66]. However, IFN-beta did not improve outcomes in a recent randomized control trial for the treatment of moderate to severe ARDS [67].
- GM-CSF: No GM-CSF inhibitors under investigation for COVID-19 are currently FDA-approved for other indications. Lenzilumab and TJ003234 are under investigation to treat CRS induced by CAR T cell therapy. GM-CSF inhibitors are also under investigation to treat acute graft versus host disease, ankylosing spondylitis, and rheumatoid arthritis [68,69].
- TNF-alpha: Although TNF-alpha inhibitors are commonly used to treat rheumatoid arthritis, only one investigational TNF-alpha inhibitor, XPro1595, is being evaluated in a clinical trial for COVID-19. Murine models of severe influenza treated with TNF-alpha inhibitors had reduced cytokine production without changes in survival rates [70,71].
4.1.3. Cardiotoxicity
4.1.4. Early COVID-19 Experience
4.2. Anti-Rejection Agents
4.2.1. Overview
4.2.2. Clinical Uses
4.2.3. Cardiotoxicity
4.2.4. Early COVID-19 Experience
4.3. Anti-Complement Agents
4.3.1. Overview
4.3.2. Clinical Uses
4.3.3. Cardiotoxicity
4.3.4. Early COVID-19 Experience
4.4. Anti-Cancer Agents
4.4.1. Overview
4.4.2. Clinical Uses
- Targeted therapies:
- Breakpoint cluster region (BCR)-Abelson’s (ABL) tyrosine kinase inhibitor: Imatinib may have both anti-viral and anti-inflammatory effects. In vitro studies demonstrate that the imatinib target, Abelson tyrosine-protein kinase 2, is required for efficient SARS-CoV1 and MERS-CoV replication [111]. In murine models, imatinib inhibited endothelial permeability, attenuating pulmonary edema in sepsis models [112,113].
- PI3 kinase inhibitors: Some isoforms of PI3 kinase are preferentially expressed in leukocytes, and inhibition resulted in blocking B and T cell proliferation and neutrophil migration in rodents [116]. Blockade of PI3 kinase also improved rodent models of arthritis, asthma, and systemic lupus erythematosus. Inhibition of PI3 decreased bronchoalveolar lavage eosinophils in a murine pulmonary inflammation model [117].
- VEGF inhibitors: Elevated VEGF levels have been observed in COVID-19 patients, and VEGF activation is associated with ARDS. Anti-VEGF therapies may suppress pulmonary edema, improving ARDS [118].
- Cytotoxic therapies: Etoposide, a topoisomerase II inhibitor, is used as part of the standard of care of HLH [119,120], likely effective through activated T cells ablation [121]. Melphalan, a DNA alkylator, used in non-cytotoxic doses, has been associated with anti-inflammatory effects through disruption of IL-2-beta and TNF-alpha receptor signaling [122]. Selinexor is an inhibitor of exportin-1, a nuclear export protein. Exportin-1 is thought to be important in both viral replication and mediating the inflammatory response through nuclear factor kappa-B signaling [123].
- Immunomodulatory: Thalidomide and lenalidomide have been shown to reduce the inflammatory response in patients with idiopathic pulmonary fibrosis and in rat models of paraquat lung toxicity [124,125]. In mouse studies of H1N1 influenza, thalidomide was shown to reduced inflammation and improved survival rate [126].
- Immune checkpoint inhibitors (ICIs): The use of ICIs in COVID-19 is controversial as the rare complication of inflammatory pneumonitis may overlap with COVID-19 interstitial pneumonia [127]. Clinical trials are aimed at ICI use in early viral clearance and the safety of continued ICI use in patients with cancer that become infected with COVID-19.
4.4.3. Cardiotoxicity
4.4.4. Early COVID-19 Experience
4.5. Limitations
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
Abbreviations
A3AR | A3 adenosine receptor |
Abl2 | Abelson tyrosine kinase 2 |
AKT/PKB | serine/threonine-specific protein kinase/protein kinase B; |
BCR-ABL TK | breakpoint cluster region protein-Abelson tyrosine kinase; |
BTK | Bruton’s tyrosine kinase |
C5aR or C3aR | complement component receptor |
CD | cluster of differentiation |
CXCR2 | C-X-C motif chemokine receptor 2 |
DAG | diacylglycerol |
DNA | deoxyribonucleic acid. |
EF1A2 | elongation factor 1-alpha 2 |
ERK1/2 | extracellular signal-related protein kinase 1/2 |
FGFR | fibroblast growth factor receptor; |
GM-CSF | granulocyte-macrophage colony-stimulating factor |
GM-CSFR | granulocyte-macrophage colony-stimulating factor receptor |
IFN | interferon |
IFN-g | interferon gamma |
IFN-gR | interferon gamma receptor |
IL | interleukin |
IL-1B | interleukin 1-beta |
IL-1BR | interleukin-1-beta receptor |
IL-6 | interleukin 6 |
IL-6R | interleukin 6 receptor |
IL-8 | interleukin 8 |
IP3 | inositol trisphosphate |
JAK | Janus tyrosine kinase |
MAPK | mitogen-activated protein kinase |
miR | micro-ribonucleic acid |
mTOR | mammalian target of rapamycin |
MYD88 | myeloid differentiation primary response 88 |
PDGFR | platelet-derived growth factor receptor |
PI3K | phosphoinositide 3-kinase |
PIP2 | phosphatidylinositol (4,5)-bisphosphate |
PIP3 | phosphatidylinositol (3,4,5)-triphosphate |
Ras | rat sarcoma |
SRC | cytoplasmic tyrosine kinase |
ST2 | serum stimulation 2 |
STAT | signal transducer and activator of transcription |
TLR | Toll-like receptor |
TNF | tumor necrosis factor |
VEGF | vascular endothelial growth factor |
VEGFR | vascular endothelial growth factor receptor |
XPO1 | exportin-1 |
‘C’ | denotes complement component |
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Therapy | Mechanism of Action | FDA Approval Status | Primary Indications or Disease Targets | Cardiotoxicity (Reported) | Ongoing Clinical Trials |
---|---|---|---|---|---|
Anti-inflammatory agents | |||||
Emapalumab | IFN-gamma inhibitor | Approved | Hemophagocytic lymphohistiocytosis | N/A | 1 trial |
Interferon-beta-1a | Interferon-beta-1a | Approved | Multiple sclerosis | N/A | 9 trials |
Ruxolitinib | JAK-1 and JAK-2 inhibitor | Approved | Myelofibrosis and polycythemia vera | N/A | 13 trials |
Baricitinib | JAK-1 and JAK-2 inhibitor | Approved | Rheumatoid arthritis | N/A | 13 trials |
Tofacitinib | JAK inhibitor | Approved | Rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis | N/A | 2 trials |
TD-0903 | JAK inhibitor | Investigational | Lung transplant graft rejection | N/A | 1 trial |
Tocilizumab | IL-6 receptor inhibitor | Approved | Rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, juvenile idiopathic arthritis | N/A | 31 trials |
Sarilumab | IL-6 receptor inhibitor | Approved | Rheumatoid arthritis | N/A | 10 trials |
Siltuximab | IL-6 inhibitor | Approved | Idiopathic multicentric Castleman’s disease | N/A | 3 trials |
Sirukumab | IL-6 inhibitor | Investigational | Rheumatoid arthritis | N/A | 1 trial |
Clazakizumab | IL-6 inhibitor | Investigational | Psoriatic arthritis | Unknown | 5 trials |
Olokizumab | IL-6 inhibitor | Investigational | Rheumatoid arthritis | Unknown | 1 trial |
Canakinumab | IL-1-beta inhibitor | Approved | Cryopyrin-associated periodic syndromes and systemic juvenile idiopathic arthritis | N/A; decreases cardiovascular events in trials | 2 trials |
Anakinra | IL-1 receptor inhibitor | Approved | Rheumatoid arthritis, neonatal-onset multisystem inflammatory disease | N/A; decreases cardiovascular events in trials | 9 trials |
BMS-986253 | IL-8 inhibitor | Investigational | Hematological malignancy, solid tumor | Unknown | 1 trial |
Lenzilumab | GM-CSF inhibitor | Investigational | Cytokine release syndrome induced by CAR T cell therapy; graft versus host disease | Unknown | 1 trial |
Gimsilumab | GM-CSF inhibitor | Investigational | Ankylosing Spondylitis | Unknown | 1 trial |
Otilimab | GM-CSF inhibitor | Investigational | Rheumatoid arthritis | Unknown | 1 trial |
TJ003234 | GM-CSF inhibitor | Investigational | CAR T cell cytokine storm | Unknown | 1 trial |
XPro1595 | TNF-alpha soluble inhibitor | Investigational | Alzheimer’s disease | Unknown | 1 trial |
ABX464 | miR-124 overexpression | Investigational | Ulcerative colitis, rheumatoid arthritis, Crohn’s disease, hepatocellular cancer, HIV | Unknown | 1 trial |
Ulinastatin | Serine protesase inhibitor | Investigational | Acute pancreatitis, severe sepsis | Unknown | 1 trial |
Piclidenoson | A3AR inhibitor | Investigational | Inflammatory bowel disease, rheumatoid arthritis | Unknown | 1 trial |
Anti-ST2 | ST2 receptor inhibitor | Investigational | Asthma | Unknown | 1 trial |
IC14 | CD14 inhibitor | Investigational | Amyotrophic lateral sclerosis | Unknown | 2 trials |
IMU-838 | Dihydroorotate dehydrogenase inhibitor | Investigational | Ulcerative colitis | Unknown | 1 trial |
Lefunomide | Dihydroorotate dehydrogenase inhibitor | Approved | Rheumatoid arthritis | Hypertension | 1 trial |
Methotrexate | Multiple including IL-1-beta inhibitor and dihydrofolate reductase inhibitor | Approved | Rheumatoid arthritis, juvenile dermatomyositis, psoriasis, lupus, sarcoidosis, Crohn’s disease, eczema, vasculitis, multiple cancers | N/A | 1 trial |
CM4620 | Calcium release-activated calcium channel inhibitor | Investigational | Pancreatitis | Unknown | 1 trial |
CD24Fc | Danger-Associated Molecular Patterns (DAMPs) | Investigational | Graft-versus-host disease | Unknown | 1 trial |
Finglimod | Sphingosine-1-phosphate receptor modulator | Approved | Multiple sclerosis | Bradycardia, atrioventricular block | 1 trial |
Anti-rejection agents | |||||
Sirolimus | mTOR pathway inhibitor | Approved | Organ transplant rejection | Hyperlipidemia | 3 trials |
Tacrolimus | Calcineurin phosphatase inhibitor | Approved | Organ transplant rejection | Cardiomyopathy (rare) | 1 trial |
Cyclosporine | Calcineurin inhibitor | Approved | Organ transplant rejection | Hypertension | 1 trial |
Anti-complement agents | |||||
AMY-101 | C3 inhibitor | Investigational | Complement 3 glomerulopathy, paroxysmal nocturnal hemoglobinuria, periodontitis | Unknown | 1 trial |
Ravulizumab | C5 inhibitor | Approved | Paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome | N/A | 2 trials |
Eculizumab | C5 inhibitor | Approved | Atypical hemolytic uremic syndrome | N/A | 3 trials |
Zilucoplan | C5 inhibitor | Investigational | Myasthenia gravis | Unknown | 1 trial |
IFX-1 | C5a inhibitor | Investigational | Hidradenitis suppurativa, ANCA-associated vasculitis, pyoderma gangrenosum | Unknown | 1 trial |
Avdoralimab | C5a receptor inhibitor | Investigational | Hepatocellular carcinoma, non-small cell lung cancer | Unknown | 1 trial |
Anti-Cancer agents | |||||
Ibrutinib | BTK inhibitor | Approved | Mantel cell lymphoma, chronic lymphocytic leukemia, Waldenstrom’s macroglobulinemia | Atrial fibrillation, hypertension, bleeding, ventricular fibrillation | 1 trial |
Acalabrutinib | BTK inhibitor | Approved | Mantle cell lymphoma, chronic lymphocytic leukemia | Atrial fibrillation, hypertension, bleeding | 2 trials |
Zanubrutinib | BTK inhibitor | Approved | Mantle cell lymphoma | Atrial fibrillation, hypertension, bleeding | 1 trial |
Imatinib | BCR-ABL TK inhibitor | Approved | Chronic myelogenous leukemia | Cardiomyopathy | 2 trials |
Bevacizumab | VEGF inhibitor | Approved | Colorectal, lung, glioblastoma, kidney, cervical, and ovarian cancer | Hypertension, cardiac ischemia, congestive heart failure, venous thromboembolic events | 3 trials |
Nintedanib | VEGF inhibitor, FGFR inhibitor, PDGFR inhibitor | Approved | Idiopathic pulmonary fibrosis, chronic fibrosing interstitial lung disease | Hypertension, thromboembolic events | 1 trial |
Duvelisib | PI3 Kinase inhibitor | Approved | Chronic lymphocyte leukemia, small lymphocytic lymphoma | N/A | 1 trial |
Thalidomide | Uncertain—angiogenesis inhibitor, anti-inflammatory, anti-proliferative | Approved | Multiple myeloma, graft-versus-host disease, leprosy | Cardiac ischemia, arrhythmias, venous thromboembolic events | 2 trials |
Lenalidomide | Uncertain—angiogenesis inhibitor, anti-inflammatory, anti-proliferative | Approved | Myelodysplastic syndrome, multiple myeloma, mantle cell lymphoma | Venous thromboembolism (black box warning), cardiac ischemia | 1 trial |
Plitidepsin | EF1A2 inhibitor (translation) | Investigational | Multiple myeloma | Unknown | 1 trial |
Etoposide | Topoisomerase inhibitor | Approved | Testicular cancer, lung cancer, lymphoma, leukemia, neuroblastoma, ovarian cancer | Atrial fibrillation (rare) | 1 trial |
Melphalan | DNA alkylation | Approved | Multiple myeloma, ovarian cancer, melanoma, amyloidosis | Case report of sustained ventricular tachycardia | 1 trial |
Selinexor | Exportin 1 inhibitor | Approved | Multiple myeloma | N/A | 2 trials |
Veru-111 | Tubulin inhibitor | Investigational | Prostate cancer | Unknown | 1 trial |
Pembrolizumab | Immune checkpoint inhibitor | Approved | Melanoma, lung cancer, head and neck cancer, Hodgkin lymphoma, stomach cancer | Myocarditis, pericarditis, arrhythmia | 1 trial |
Nivolumab | Immune checkpoint inhibitor | Approved | Melanoma, lung cancer, renal cell carcinoma, colon cancer, liver cancer, head and neck cancer, Hodgkin lymphoma | Myocarditis, pericarditis, arrhythmia | 3 trials |
AVM0703 | Uncertain—lymphodepletion | Investigational | Non-Hodgkins lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia | Unknown | 1 trial |
TAK-981 | Small ubiquitin-like modifier | Investigational | Non-Hodgkin’s lymphoma | Unknown | 1 trial |
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Campbell, C.M.; Guha, A.; Haque, T.; Neilan, T.G.; Addison, D. Repurposing Immunomodulatory Therapies against Coronavirus Disease 2019 (COVID-19) in the Era of Cardiac Vigilance: A Systematic Review. J. Clin. Med. 2020, 9, 2935. https://doi.org/10.3390/jcm9092935
Campbell CM, Guha A, Haque T, Neilan TG, Addison D. Repurposing Immunomodulatory Therapies against Coronavirus Disease 2019 (COVID-19) in the Era of Cardiac Vigilance: A Systematic Review. Journal of Clinical Medicine. 2020; 9(9):2935. https://doi.org/10.3390/jcm9092935
Chicago/Turabian StyleCampbell, Courtney M., Avirup Guha, Tamanna Haque, Tomas G. Neilan, and Daniel Addison. 2020. "Repurposing Immunomodulatory Therapies against Coronavirus Disease 2019 (COVID-19) in the Era of Cardiac Vigilance: A Systematic Review" Journal of Clinical Medicine 9, no. 9: 2935. https://doi.org/10.3390/jcm9092935