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{"project":"LitCovid-PD-GO-BP","denotations":[{"id":"T12","span":{"begin":2609,"end":2621},"obj":"http://purl.obolibrary.org/obo/GO_0006954"},{"id":"T13","span":{"begin":2810,"end":2822},"obj":"http://purl.obolibrary.org/obo/GO_0006954"},{"id":"T14","span":{"begin":3669,"end":3684},"obj":"http://purl.obolibrary.org/obo/GO_0006955"},{"id":"T15","span":{"begin":5439,"end":5451},"obj":"http://purl.obolibrary.org/obo/GO_0009405"},{"id":"T16","span":{"begin":6002,"end":6014},"obj":"http://purl.obolibrary.org/obo/GO_0009405"},{"id":"T17","span":{"begin":6065,"end":6082},"obj":"http://purl.obolibrary.org/obo/GO_0033673"},{"id":"T18","span":{"begin":6280,"end":6289},"obj":"http://purl.obolibrary.org/obo/GO_0023052"},{"id":"T19","span":{"begin":7494,"end":7500},"obj":"http://purl.obolibrary.org/obo/GO_0040007"},{"id":"T20","span":{"begin":7631,"end":7637},"obj":"http://purl.obolibrary.org/obo/GO_0040007"},{"id":"T21","span":{"begin":7655,"end":7659},"obj":"http://purl.obolibrary.org/obo/GO_0005006"},{"id":"T22","span":{"begin":7718,"end":7722},"obj":"http://purl.obolibrary.org/obo/GO_0005006"}],"text":"Potential Overlapping Mechanisms in COVID-19 and Cardiovascular Disease and Anti-cancer Treatments\nMultiple treatments are being assessed in various trials including antivirals, anti-inflammatories, immunotherapies, and cardiovascular medications for the treatment of COVID-19. Although some these therapies have potential to provide benefit, there are numerous potential cardiac toxicities and drug-drug interactions that may be harmful to cardio-oncology patients, which is critically relevant since a high percentage of COVID-19 patients have cardiovascular comorbidities [65–68]. An appraisal of these agents and their potential cardiotoxicities—of which there is no current proven efficacy at this time—is beyond the scope of this review. However, some agents are actively used in the treatment of cardiovascular disease and/or cancer-related conditions, and the unique disease states of the cardio-oncology population may yield insights into the mechanisms of COVID-19 pathophysiology.\nFor instance, the idea of using medications that have already been well-studied and target host responses by boosting host immunity was in discussion during prior significant outbreaks and epidemics including Ebola and influenza [69, 70]. ACE inhibitors (ACEI), angiotensin-receptor blockers (ARB), and statins are of particular importance during this current pandemic.\nThere has been a theoretical uncertainty in regard to the safety of ACEI/ARB use in patients with COVID-19 based on the ACE2 viral entry mechanism [71, 72]. The virus gains cellular entry by attaching to the ACE2 receptor [72]. ACE2 expression and activity have shown to be increased in by ACEI/ARB use [73]. Although there is theoretical risk that ACE2 upregulation may increase the susceptibility of infection, other conflicting evidence indicates that upregulation of ACE2 in fact has a more protective effect. Studies in mouse models have shown that ACE2 is protective against acute lung injury and blocking the renin-angiotensin-aldosterone system pathway decreases lung failure [74, 75]. Based on the review of the literature to date, the Heart Failure Society of America recommends continuation of ACEI/ARB use for patients that are prescribed them for heart failure, hypertension, and ischemic disease [76••]. Abrupt discontinuation of medications is not recommended and can worsen clinical stability especially in patients with existing cardiovascular conditions [71].\nAdditionally, statins have long been shown to have anti-inflammatory properties through multiple studies. For instance, simvastatin has been shown to decrease pulmonary inflammation in human subjects [77]. Although the benefits for cardiovascular patients have been numerous from a lipid lower standpoint, it is important to note that the ability of statins to decrease inflammation also improves mortality [78]. A retrospective analysis of patients from the Veterans Administration showed that statin use, ACEI use, or ARB use each independently improved 30 day mortality of patients \u003e 65 years old who were hospitalized for pneumonia [79]. However, in the era of the COVID-19 pandemic, studies are needed to evaluate its role in COVID-19–related illness.\nAlthough cancer patients have been considered immunosuppressed as a result of their underlying malignancy and cytoreduction therapies, patients that undergo immunotherapy including immune checkpoint inhibitors (ICIs) or CAR-T cell therapy may have different immuno-physiology that responds to COVID-19 differently [80]. Anti-PD-1/PD-L1 and anti-CTLA-4 ICIs have been approved by the FDA for use in a variety of cancers. These drugs primarily work by enhancing a patient’s immune response to tumors through inhibiting negative regulators of T cell function [81]. CAR-T cell therapy involves reprogramming a patient’s own T cells to directly target their specific tumor [82].\nAn adverse effect that can occur with either anti-PD-1 therapy or CAR-T cell therapy involves cytokine release syndrome (CRS) which is similar to the cytokine storm phenomenon that occurs in patients with severe COVID-19 [80, 82, 83]. CRS occurs as a result of hyperimmune activation in response to tumor death, whereas cytokine storm in COVID-19 patients occurs as a result of T cell hyperactivation from immune dysregulation [80, 84]. Similar markers are elevated in both phenomena, including IL-6, TNF-alpha, and IFN-λ, of which IL-6 has also been shown to be a mortality predictor in COVID-19 patients [27, 64, 80, 84]. COVID-19 patients that develop cytokine storm syndrome are at risk of developing ARDS and multi-organ failure [84, 85]. Immunosuppression with tocilizumab, an IL-6 inhibitor, is used to treat CRS associated with CAR-T cell therapy [80, 86]. Additionally, tocilizumab immunosuppression is used to treat immune-related adverse events (irAEs) from PD-1 inhibitors that are refractory to steroids; irAEs also occur as a result of hyperimmune activation [80, 87]. Moreover, the cytokine storm observed with COVID-19 has also been noted to be similar to that of secondary hemophagocytic lymphohistiocytosis (HLH) which is also treated with immunosuppression [64].\nCurrent trials are underway with using tocilizumab and sarilumab (another IL-6 inhibitor) to treat COVID-19 patients [88–90]. Although immunotherapy may be thought to reinstate a cancer patient’s immunocompetence, there is potential for synergy from CRS and the COVID-19 cytokine storm pathogenesis which can further worsen a patient’s mortality risk. Further unfavorable synergy between ICI immune-related adverse events (irAEs) can also be seen potentially between the pneumonitis that ICIs can cause and the lung involvement with COVID-19 [80]. Pneumonitis occurs in \u003c 10% of patients being treated with anti-CTLA-4 and anti-PD-1 ICIs and is potentially life-threatening [81]. Therefore, if combined with lung injury from COVID-19, there is a theoretical potential for poor outcomes.\nThere are potential cancer treatments that may counteract the pathogenesis of COVID-19, such as CCR5 treatments and tyrosine kinase inhibitors (TKIs) [91–93]. The CCR5 receptor is a G protein–coupled receptor selectively expressed on macrophages, T cells, eosinophils, dendritic cells, and microglia and is implicated in chemokine-mediated signaling [94]. This receptor has historically been targeted for HIV antiviral therapy, in the setting of disrupting viral entry, specifically through small molecule inhibition with maraviroc and vicriviroc, and monoclonal antibody treatment with leronlimab [95]. Moreover, multiple cancers have been shown to overexpress CCR5 which has been linked to a cancer’s metastatic potential. CCR5 therapies are currently being studied in metastatic colorectal and breast cancers [91, 94]. Due to its immune system restorative properties, leronlimab is being investigated for compassionate use in the treatment of COVID-19 patients [96, 97]. Studies examining receptor blockade in leronlimab preliminarily have shown decreases in IL-6, restoration of CD4/CD8 ratios, and reduction in overall COVID-19 viremia [98]. These collective findings suggest possible therapeutic role in establishing immune reconstitution in patients that are critically ill and may provide dual benefit in patients with shared cancer diagnoses.\nTKIs like sunitinib and erlotinib that specifically inhibit AAK1, a protein regulator that allows passage of the virus into cells, have theorized utility [92]. Sunitinib is an anti-vascular endothelial growth factor (VEGF) TKI which is used in first-line for treatment of advanced renal cell carcinoma [99]. Erlotinib is an anti-epidermal growth factor receptor (EGFR) TKI which is used in first-line treatment for metastatic EGFR-mutant non-small cell lung cancer [100]. Both these TKIs have shown to reduce the infectivity of Dengue and Ebola through in vivo studies with murine models which showed decreased viremia and mortality with treatments. Moreover, in vitro studies in cultured cells and hepatitis C in this same study showed that use of these TKIs reduced intracellular trafficking and inhibited viral entry [101]. However, the high doses required to achieve this effect may potentially exhibit harm to patients [92, 93]. Regardless, there is potential for cancer patients receiving these therapies to achieve dual benefit as referenced before, but warrant further investigation. Further studies are warranted in tracking the outcomes of cancer patients with COVID-19 and the type of treatments they received."}

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