Repurposing Anti-Cancer Drugs for COVID-19 Treatment.

Introduction

In December of 2019, a novel coronavirus structurally related to the virus that causes severe acute respiratory syndrome (SARS) was identified as the cause of respiratory disease in Wuhan, a city in the Hubei Province of China and reported to the World Health Organization (WHO). 1 On January 30, 2020, the WHO declared this outbreak from novel coronavirus as a public health emergency of international concern and, in March 2020, began to characterize it as a pandemic. The virus that causes COVID-19 is designated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); previously, it was referred to as 2019-nCoV. In February 2020, the World Health Organization designated the disease COVID-19.

At present, there is a paucity of therapies or vaccines with demonstrated efficacy for the treatment or prevention of COVID-19. Clinical management is currently focused on supportive care and prevention and management of complications like ARDS. Several available agents are being tested, and few have been provided for expanded access use. Remdesivir, a broad-based antiviral drug, an inhibitor of RNA-dependent RNA polymerase, was developed by Gilead Sciences originally to target Ebola and is being repurposed for COVID-19 in clinical trials and for compassionate use. Remdesivir showed promise in a compassionate-use program case series for patients with severe COVID-19, and clinical improvement was noted in 68% of patients treated, but there was no control group. 2 Final data on from Adaptive COVID-19 Treatment Trials (ACTT) sponsored by NIAID found that patients who received remdesivir had faster time to recovery when compared to placebo. 3 Remdesivir has subsequently been approved by the Food and Drug Administration (FDA) for emergency authorization based on several trials that showed benefits outweighing risks. 4 , 5 Enthusiasm for a possible treatment modality for COVID-19 is also tempered by two cohorts of remdesivir-treated patients which found no associated clinical benefit for remdesivir. 6 , 7 One of these cohorts, consisting of 237 randomized COVID-19 patients, was discontinued early due to adverse events at 12% compared to 5% of the placebo-treated arm. 6 Other drugs being used and tested include HIV protease inhibitors like darunavir 8 and lopinavir-ritonavir, which showed no efficacy in clinical improvements in a recent randomized control trial. 9 Anti-inflammatory agents used for rheumatoid arthritis and glucocorticoids are also being tested, with the latter the first agent to show a reduction in mortality for COVID-19. 10 There has been both excitement and controversy around antimalarial drugs being tested for COVID-19. Some of the early results from these drugs have been inconclusive. The FDA issued an emergency use authorization to allow the use of chloroquine and hydroxychloroquine, which has since been revoked based on trial results published that showed no effect on clinical course and elevated side effects. 11–14 The antiparasitic drug ivermectin has shown in vitro activity against SARS-CoV-2. 15 Convalescent plasma from recovered patients has also been a focus in the treatment of severe COVID-19 infection and is being studied in clinical trials and also being used outside of clinical trials. 16 , 17

In order to address the clinical gap, the medical community is turning to repurposing of available antiviral, anti-inflammatory, and certain anti-cancer drugs in the context of individual patients, as well as initiating clinical trials exploring some of these available drugs. Given our expertise in anti-cancer treatments, we here focus on repurposing of anti-cancer drugs that have already been approved by regulatory agencies or are being fast-tracked and are supported by published data and being used in management of cancer patients. Drug repurposing is a valuable strategy in times of crisis like COVID-19 as it provides quick access to agents that not only have available safety data but also established production lines and supply chains. 18 In addition, these therapies have early- and late-phase data on toxicity and managing complications, particularly advantageous in the pandemic setting versus novel therapies. Underscoring the potential of repurposing, estimates using the Covid19_db found 64.4% of trials for COVID-19 include repurposed drugs as of August 3, 2020. 19 Several antineoplastic agents have the potential to improve outcomes of COVID-19 through some of the similar mechanisms utilized in management of cancer mostly pertaining to controlling inflammation, inhibiting cell division, and modulating the host–tumor microenvironment ( Figure 1 ). In this review, we are discussing various anti-cancer agents currently being evaluated as a potential treatment option for COVID-19 ( Table 1 ). As previously mentioned, a major antineoplastic therapy class, steroids, has recently shown efficacy in reducing the risk of death in ventilated patients (relative ratio 0.65) and patients receiving oxygen (relative ratio 0.8) 10 compared to standard of care. As the first treatment to show reduction in mortality in COVID-19, steroids have been summarized previously 20 and will not be the focus of this review. Table 1 NCT Trials Using Anti-Cancer Agents Currently Underway in COVID-19 as of 07/06/2020 Target Interventions NCT Number Status Additional Agent Phases Enrollment IL-6 Tocilizumab NCT04335305 Recruiting Pembrolizumab Phase 2 24 Tocilizumab NCT04315480 Active, not recruiting None Phase 2 38 Tocilizumab NCT04377659 Recruiting None Phase 2 40 Tocilizumab NCT04377503 Not yet recruiting Methylprednisolone Phase 2 40 Tocilizumab NCT04339712 Recruiting None Phase 2 40 Tocilizumab NCT04331795 Completed None Phase 2 50 Tocilizumab NCT04435717 Recruiting None Phase 2 78 Tocilizumab NCT04335071 Not yet recruiting None Phase 2 100 Tocilizumab NCT04412291 Recruiting None Phase 2 120 Tocilizumab NCT04363853 Recruiting None Phase 2 200 Tocilizumab NCT04370834 Recruiting None Phase 2 217 Tocilizumab NCT04331808 Active, not recruiting None Phase 2 240 Tocilizumab NCT04332094 Recruiting Hydroxychloroquine, azithromycin Phase 2 276 Tocilizumab NCT04317092 Recruiting None Phase 2 400 Tocilizumab NCT04317092 Recruiting None Phase 2 400 Tocilizumab NCT04445272 Recruiting None Phase 2 500 Tocilizumab NCT04349410 Enrolling by invitation None Phase 2/3 500 Tocilizumab NCT04381936 Recruiting None Phase 2/3 12,000 Tocilizumab NCT04423042 Not yet recruiting None Phase 3 30 Tocilizumab NCT04403685 Recruiting None Phase 3 150 Tocilizumab NCT04424056 Not yet recruiting Ruxolitinib Phase 3 216 Tocilizumab NCT04361032 Not yet recruiting None Phase 3 260 Tocilizumab NCT04356937 Recruiting None Phase 3 300 Tocilizumab NCT04412772 Recruiting None Phase 3 300 Tocilizumab NCT04345445 Not yet recruiting Methylprednisolone Phase 3 310 Tocilizumab NCT04320615 Recruiting None Phase 3 330 Tocilizumab NCT04372186 Recruiting None Phase 3 379 Tocilizumab NCT04409262 Recruiting Remdesivir Phase 3 450 Tocilizumab NCT04377750 Recruiting None Phase 3 500 Tocilizumab NCT02735707 Recruiting Multifactorial Phase 3 7100 Tocilizumab or siltuximab NCT04330638 Recruiting Anakinra Phase 3 342 Siltuximab NCT04329650 Recruiting None Phase 2 200 JAK Ruxolitinib NCT04334044 Recruiting None Phase 1/2 20 Ruxolitinib NCT04359290 Not yet recruiting None Phase 2 15 Ruxolitinib NCT04374149 Not yet recruiting Plasma exchange Phase 2 20 Ruxolitinib NCT04366232 Not yet recruiting Anakinra Phase 2 54 Ruxolitinib NCT04403243 Recruiting None Phase 2 86 Ruxolitinib NCT04348695 Recruiting Simvastatin Phase 2 94 Ruxolitinib NCT04414098 Not yet recruiting None Phase 2 100 Ruxolitinib NCT04338958 Not yet recruiting None Phase 2 200 Ruxolitinib NCT04338958 Recruiting None Phase 2 200 Ruxolitinib NCT04348071 Not yet recruiting None Phase 2/3 80 Ruxolitinib NCT04362137 Not yet recruiting None Phase 3 402 Ruxolitinib NCT04377620 Recruiting None Phase 3 500 Baricitinib NCT04358614 Completed None Phase 2/3 12 Baricitinib NCT04399798 Not yet recruiting None Phase 2 13 Baricitinib NCT04393051 Not yet recruiting None Phase 2 126 Baricitinib NCT04346147 Recruiting Hydroxychloroquine Phase 2 165 Baricitinib NCT04321993 Recruiting None Phase 2 1000 Baricitinib NCT04340232 Not yet recruiting None Phase 2/3 80 Baricitinib NCT04320277 Not yet recruiting None Phase 2/3 200 Baricitinib NCT04421027 Recruiting None Phase 3 400 Baricitinib NCT04401579 Recruiting Remdesivir Phase 3 1032 Baricitinib NCT04390464 Recruiting None Phase 3 1167 Baricitinib NCT04345289 Recruiting None Phase 3 1500 Tofacitinib NCT04332042 Not yet recruiting None Phase 2 50 Tofacitinib NCT04415151 Not yet recruiting None Phase 2 60 Tofacitinib NCT04390061 Not yet recruiting Hydroxychloroquine Phase 2 54 Tofacitinib NCT04412252 Not yet recruiting None Phase 2 240 Interferon IFN-A1B NCT04293887 Not yet recruiting None Phase 1 328 IFN-A2B NCT04349410 Enrolling by invitation None Phase 2/3 500 Nasal IFN-A1B NCT04320238 Recruiting Anti-thymosin Phase 3 2944 IFN-B1A NCT04449380 Not yet recruiting None Phase 2 126 IFN-B1A NCT04385095 Recruiting None Phase 2 400 IFN-B1A NCT04315948 Recruiting Lopinavir, ritonavir Phase 3 3100 IFN-B1A NCT04315948 Recruiting Lopinavir/ritonavir Phase 3 3100 IFN-B1A NCT04350671 Enrolling by invitation Hydroxychloroquine, lopinavir, ritonavir Phase 4 40 IFN-B1A NCT04350684 Enrolling by invitation Hydroxychloroquine, lopinavir, ritonavir, umifenovir Phase 4 40 IFN-B1A NCT02735707 Recruiting Multifactorial Phase 4 7100 IFN-B1B NCT04350281 Recruiting Hydroxychloroquine, lopinavir, ritonavir Phase 2 80 IFN-B1B NCT04276688 Completed Ribavirin, lopinavir, ritonavir Phase 2 127 IFN-B2 NCT04379518 Not yet recruiting Rintatolimod Phase 1/2 80 IFN-B NCT04324463 Recruiting None Phase 3 4000 IFN-B1A/B NCT04343768 Completed Hydroxychloroquine, lopinavir, ritonavir Phase 4 60 Peg-IFN-L1A NCT04388709 Not yet recruiting None Phase 2 66 Peg-IFN-L1A NCT04344600 Not yet recruiting None Phase 2 164 Peg-IFN-L1A NCT04354259 Not yet recruiting None Phase 2 140 Peg-IFN-L1A NCT04331899 Not yet recruiting None Phase 2 120 Peg-IFN-L1 NCT04343976 Not yet recruiting None Phase 2 40 Interferon NCT04291729 Completed Danoprevir, ritonavir Phase 4 11 Emapalumab NCT04324021 Recruiting None Phase 2/3 54 VEGF Bevacizumab NCT04344782 Not yet recruiting None Phase 2 130 Bevacizumab NCT04275414 Recruiting None Phase 2/3 20 PD-1 Nivolumab NCT04356508 Not yet recruiting None Phase 2 15 Nivolumab NCT04343144 Not yet recruiting None Phase 2 92 Nivolumab NCT04413838 Not yet recruiting None Phase 2 120 Nivolumab NCT04333914 Suspended None Phase 2 384 Pembrolizumab NCT04335305 Recruiting Tocilizumab Phase 2 24 PD-1 blocking antibody NCT04268537 Not yet recruiting None Phase 2 120 CCR5 Leronlimab NCT04343651 Recruiting None Phase 2 75 Leronlimab NCT04347239 Recruiting None Phase 2/3 390 Multi-kinase/BCR-ABL Imatinib NCT04346147 Recruiting Hydroxychloroquine Phase 2 165 Imatinib NCT04422678 Not yet recruiting None Phase 3 30 Imatinib NCT04394416 Recruiting None Phase 3 204 Imatinib NCT04356495 Recruiting Vitamins Phase 3 1057 Thalidomide and Analogs Thalidomide NCT04273581 Not yet recruiting None Phase 2 40 Thalidomide NCT04273529 Not yet recruiting None Phase 2 100 Lenalidomide NCT04361643 Not yet recruiting None Phase 4 120 BTK Acalabrutinib NCT04380688 Not yet recruiting None Phase 2 60 Acalabrutinib NCT04346199 Not yet recruiting None Phase 2 428 Ibrutinib NCT04375397 Recruiting None Phase 2 46 Ibrutinib NCT04439006 Not yet recruiting None Phase 2 72 BCG BCG Vaccine NCT04379336 Recruiting None Phase 3 500 BCG Vaccine NCT04350931 Not yet recruiting None Phase 3 900 BCG Vaccine NCT04362124 Not yet recruiting None Phase 3 1000 BCG Vaccine NCT04384549 Not yet recruiting None Phase 3 1120 BCG Vaccine NCT04328441 Recruiting None Phase 3 1500 BCG Vaccine NCT04373291 Not yet recruiting None Phase 3 1500 BCG Vaccine NCT04327206 Recruiting None Phase 3 10,078 BCG Vaccine NCT04414267 Recruiting None Phase 4 900 BCG Vaccine NCT04369794 Not yet recruiting None Phase 4 1000 BCG Vaccine NCT04348370 Recruiting None Phase 4 1800 BCG Vaccine NCT04417335 Active, not recruiting None Phase 4 2014 Nuclear Transport Selinexor NCT04355676 Not yet recruiting None Phase 2 80 Selinexor NCT04349098 Recruiting None Phase 2 230 DNA Methotrexate NCT04352465 Recruiting None Phase 1/2 42 Etoposide NCT04356690 Not yet recruiting None Phase 2 134 Figure 1 Diverse possible mechanisms of anti-tumor therapies currently being studied in clinical trials for COVID-19. These methods include: 1) altering ability of SARS-CoV-2 to infect, either through vaccination or inhibition; 2) altering the ability of host cells to be infected through activation by interferons; 3) blocking recruitment of immune cells to the lung; 4) altering vascular permeability; 5) inhibiting cytokine signaling; 6) inhibiting immune cell proliferation; and 7) directing the immune response and controlling inflammation.

Materials and Methods

All registered interventional clinical trials ( n =1358) were obtained from clinicaltrials.gov on July 6, 2020. No search terms were used, but rather the tab-delimited summary of the curated COVID-19 section of clinicaltrials.gov was recovered. Trials without phase designations were removed. R (v3.6.3) was used to parse through the listed interventions for anti-neoplastic therapies as identified by Y.J. and P.V. Trials suspended or terminated were removed. Further review of trials by hand eliminated trials with the majority of non-FDA-approved therapies, with the exception of drugs relevant to the review, and the use of steroids for the management of COVID-19. The code used to filter and summarize the data is available at https:www.github.com/ncborcherding/COVID19review .

Pathophysiology and Clinical Course of COVID-19

The pathophysiology of the SARS-CoV-2 infection is an emerging field, but broadly it can be separated into three major categories: 1) lung pathology, 2) inflammation, and 3) thromboembolic events. Although separated conceptually, the interaction of these three categories form a backbone of COVID-19. Based on the WHO–China Joint Report, signs and symptoms of infection occur 5–6 days after transmission (range 1–14 days). 21 Symptoms vary, but over the course of COVID-19 include fever (87.9%), dry cough (67.7%), fatigue (38.1%), sputum production (33.4%), and shortness of breath (18.6%). 21 Although roughly 85% of patients had mild to moderate disease, 14% developed severe (6% critical) disease defined by dyspnea, hypoxemia, and radiographic evidence of lung pathology. Lung pathology in COVID-19 patients has revealed increased alveolar exudate caused by aberrant host immune response and inflammatory cytokine storm that leads to acute respiratory distress syndrome (ARDS), with alveolar gas exchange abnormality leading to mortality of severe COVID-19 patients. In the pathogenesis of SARS-CoV-2 pneumonia, a study found that a cytokine release syndrome (CRS) involving a considerable release of proinflammatory cytokines occurred, including IL-6, IL-12, and tumor necrosis factor α (TNF-α). 22 The serum levels of IL-2R and IL-6 in patients with COVID-19 are positively correlated with the severity of the disease. 23 In addition to interleukins, patients in the ICU displayed increased serum levels of G-CSF, CXCL3, MCP-1, CCL-3, and TNF-α relative to non-ICU COVID patients. 23 Modulation of the infection–immune response axis is a key strategy in limiting the morbidity and mortality from COVID-19. Thromboembolic complications have been noted in the treatment of COVID-19. Observational studies have found rates ranging from 20.6% to 42.7%. 24–26 Increases in circulating D-dimer, Von Willebrand factor, and Factor VIII were also observed in up to 87% of patients, 25 and elevation in these parameters upon admission are predictive of poor survival. 27 The mechanistic basis of the high incidence of thromboembolic events in COVID-19 is currently unknown, with some proposing a link to overall inflammation. 28 Supporting this are studies finding correlating cytokines, like IL-6, with pro-coagulant profiles. 29 This pro-coagulation phenotype might also be connected to the underlying lung injury, with histological analysis showing obliterative lung patterning with extensive intra-alveolar lung fibrin deposition and intraluminal connective tissue deposition. 30

Anti-Cancer Drugs for COVID-19 Treatment

Interleukin Inhibitors: Targeting IL-6 and Other Cytokines

IL-6 or IL-6 receptor blocking antibodies like tocilizumab (Actemra), sarilumab (Kevzara), and siltuximab (Sylvant) are FDA-approved for various conditions including lymphoproliferative disorders, Castleman’s syndrome, and smoldering multiple myeloma. The IL-6 signaling pathway is being explored for targeted therapy for various malignancies. 31 IL-6 signaling plays a role in the pathogenesis of multiple myeloma (MM), and disruption of IL-6 signaling is known to inhibit MM cell growth. 32 IL-6 is among the key components of the inflammatory cascade responsible for host defense against several infections, but excessive IL-6 can lead to an acute severe systemic inflammatory response of CRS. IL-6 blockade has also been used in management of CRS, 33 and tocilizumab is FDA-approved to manage CRS associated with the use of chimeric antigen receptor T cell therapy. 34 The National Health Commission in China in March of 2020 included tocilizumab in their COVID-19 treatment guidelines for patients with severe lung damage and correspondingly high IL-6 levels (> 20 pg/mL). 35 Monoclonal antibodies that target the IL-6 pathways can control the inflammatory storm ( Figure 1 ), possibly by targeting highly inflammatory CD14 + CD16 + monocytes that have high expression of IL-6 in patients infected with COVID-19. 36 Interestingly, increased levels of IL-6 have been associated with increased viral RNA load in the bloodstream, 37 suggesting that the increased levels of IL-6 in COVID-19 patients may be preventing a proper immune response. Tocilizumab has shown promise in early results and can be an effective treatment in severelyill COVID-19 patients to mitigate the inflammatory storm; however, timing of anti-IL-6 induction may be important with reports of less effective results in criticallyill patients. 38 The paper published by Fu et al reports preliminary data collected from 21 patients with COVID-19-induced ARDS treated with tocilizumab with persistence of fever associated with detectable levels of IL-6 after therapy. 35 A secondary case report of a COVID-19 patient with multiple myeloma successfully treated with tocilizumab was recently reported. 39 Interestingly, following administration of anti-IL-6 therapy, there was a transient decrease in CD8 + T cells and increase in CD4 + T cells, with decreased serum concentrations of IL-6. 39 Another study found an overall increase in serum lymphocytes and decrease in C-reactive protein, a surrogate marker for overall inflammation, following tocilizumab induction. 40 The reduction in C-reactive protein was also seen in a prospective cohort study from Italy, specifically in responders. 41 This study also found the administration of tocilizumab led to stabilization or improvement in acute respiratory failure in 77% of patients administered but is limited by lack of control. 41 Other direct inhibitors of cytokines are being evaluated in clinical trials for COVID-19, such as anakinra ( NCT04341584 , NCT04339712 , NCT04357366 , and NCT04324021 ), a peptide inhibitor of IL-1, and monoclonal antibodies targeting receptors or cytokines, such as IL-8 ( NCT04347226 ). Anti-interleukin-based therapies for COVID-19 are one of the most common classes of drugs for interventional trials. However, these therapies likely have a narrow therapeutic window for effectiveness (ie, during the cytokine storm), should not be administered in patients with tuberculosis or other infections, and may lead to further complications in select patients. A retrospective cohort study found tocilizumab therapy to be associated with increased requirement for invasive ventilation, but shortened duration of vasopressor support, 42 while a second study found no such link. 43 Other limitations of monoclonal antibody therapy targeting interleukins for COVID-19 are the overall cost and availability of these agents and significant toxicity.

Janus-Associated Kinase (JAK) Inhibitors

JAK inhibitors like ruxolitinib are approved for primary myelofibrosis and polycythemia vera and are now showing promise in the treatment of COVID-19. JAK functions as a relay in cytokine signaling, promoting immune cell activation and survival genetic programs ( Figure 1 ) with implications in the hyperreactivity of immune response to infection. 44 Inhibition of JAK-STAT pathway can limit systemic inflammatory response and cytokine production. A series of phase 1/2/3 trials are underway investigating the use of JAK2 inhibitor ruxolitinib, for patients with hyperinflammation, CRS, or severe lung pathology subsequent to COVID-19. Preliminary data for patients with severe lung inflammation treated with ruxolitinib showed sustained reduction in inflammation in 11 of 14 patients treated, leading to the initiation of the NCT04338958 trial. 45 Recently, Incyte has made ruxolitinib available through an expanded access program for patients with COVID-19 ( NCT04355793 ). The JAK1/2 kinase inhibitor baricitinib is also being extensively trialed for COVID-19 infections and may be working through inhibition of endocytosis. 46 Further research into antiviral properties of JAK inhibition has found them to work by inhibiting human immunodeficiency virus (HIV) replication in primary peripheral blood mononuclear cells, 47 although this may be offset by inhibition of type I interferons downstream of JAK activation. 48 Results of the completed phase 2/3 trial of baricitinib with the antivirals lopinavir-ritonavir are still forthcoming ( NCT04358614 ); however, preliminary results showed a 2-week mortality rate of 0% in the treatment arm compared to 6.4% in the control arm of the study. 49 In addition, the JAK1/3 inhibitor, thought to be upstream of IL-6 signaling, 50 tofacitinib is being trialed for interstitial pneumonia related to SARS-CoV-2 infection ( NCT04332042 ). The modulation of cytokine signaling may also alter the immune response, with the JAK2 inhibitor, fedratinib, potentially useful to move inflammation away from a Th-17-type of response. 51 Currently no trials are registered evaluating the efficacy of fedratinib for COVID-19. Like the anti-interleukin therapies, JAK inhibitors should not be used in patients with concomitant secondary infections, like tuberculosis, and can increase the risk of upper respiratory infections ( Figure 2 ). More critically, JAK inhibitors, such as tofacitinib and baricitinib, have black box warnings for associations with increased risk of blood clots, pulmonary emboli, and death. Due to the high incidence of thrombotic issues in COVID-19, particular caution should be taken for these particular therapies. Figure 2 Common side effect profiles of anti-neoplastic agents relevant to COVID-19. Reviewed agents in addition to the reported mechanisms of action have documented adverse effect profiles that may alter the usefulness. These side effects include activation of latent infections, promotion of autoimmunity, liver toxicity, hypertension, immune suppression, increased risk of clotting, and toxicity to developing fetus or placenta.

Interferons

Interferons can be classified by the major downstream signaling pathways elicited, with type I interferons (IFN-ɑ/β) vital in antiviral responses, type II interferons (IFN-γ) important in adaptive immune responses, and type III playing a role in fungal and viral response. 52 Both type I and type III interferons can reduce the ability of viruses to infect host cells, but importantly there is a temporal relationship, with early interferons associated with improved viral clearance and late interferon signaling possibly potentiating infections. 53 As a cytokine mediator, type II interferons are indicated in treatment of chronic myelogenous leukemia, hairy cell leukemia, melanoma, renal cell cancer, and Kaposi sarcoma. The use of types I and III interferons is being extensively studied for use in COVID-19 ( Figure 1 ). The majority of type I interferons are being studied accompanying anti-microbial or antiviral agents, such as hydroxychloroquine, lopinavir, and ritonavir. Preliminary results show that the addition of IFN-β1b to ritonavir and ribavirin increased viral clearance as measured by nasopharyngeal swab. 54 However, several studies are also examining the efficacy of IFN-ɑ1 ( NCT04293887 and NCT04349410 ) and IFN-β ( NCT04449380 and NCT04385095 ) as single agents. Pegylated interferon-λ (type III interferon) infusions are also being studied in a number of phase 2 trials as single agents in the context of COVID-19. Another strategy for modulating the immune response to COVID-19 may be targeting type II interferons. The monoclonal antibody against IFN-γ, emapalumab, is approved for the treatment of hemophagocytic lymphohistiocytosis, a systemic form of immune activation. Emapalumab is currently being evaluated for possible use in limiting ventilator requirements for patients with COVID-19 ( NCT04324021 ). Although potent antiviral agents, interferons are potent molecules with systemic effects, with most patients reporting flu-like symptoms, but can also include hematologic suppression, elevated liver enzymes, and psychiatric complications. 55 , 56 In addition, unlike targeting interleukins to limit the inflammatory cascade of COVID-19, interferons should be targeted at limiting the extent of infection, requiring timely testing and diagnosis, which may limit the efficacy of these therapies. These agents have life-threatening side effect,s and so careful selection of patients would be necessary ( Figure 2 ).

Vascular Endothelial Growth Factor (VEGF) Inhibitor: Bevacizumab

Bevacizumab is indicated in treatment of a variety of solid tumor cancers that include colorectal, lung, and renal cancer and is now being explored in treatment of COVID-19. Unlike the potential of other monoclonal antibodies to modulate the immune response in COVID-19, bevacizumab targets vascular endothelial growth factor (VEGF). Bevacizumab is used as antineoplastic through the inhibition of aberrant angiogenesis. 57 In the context of COVID-19 and other respiratory infections, hypoxia and inflammation are thought to cause an upregulation of VEGF, acting in a positive feedback loop to promote vascular permeability, edema, and ultimately ARDS ( Figure 1 ). A major side effect for bevacizumab is hypertension along with thromboembolic risk, which is particularly important as hypertension has been linked to increased complications and mortality in COVID-19 ( Figure 2 ). 58

Immune Checkpoint Inhibitors

Immune checkpoint blockers have revolutionized treatment of several solid tumors and hematological malignancies and are indicated in a wide variety of cancers; they are now being explored in treatment of COVID-19. The methods of altering immune response using effector molecules on the immune cell surface are a growing mainstay in a diverse range of tumors. The most prominent agents, anti-PD-1/PD-L1 and anti-CTLA-4, promote immune activity through the inhibition of negative feedback pathways. 59 Unlike the use of anti-IL-6 therapies, immune checkpoint blockade promotes immune activity, running the risk of overstimulation, such as the autoimmune complications seen in the use of immune checkpoint blockade in oncology. 59 , 60 Despite this risk, anti-PD-1 therapies have been used successfully in the setting of human polyomavirus type 2 central nervous system infections, leading to reduction in viral load and increased antiviral-specific activity in both CD4 + and CD8 + T cells. 61 As of now, anti-PD-1 therapies are being evaluated for efficacy in overall clinical improvement ( NCT04343144 , NCT04413838 , NCT04333914 ), viral clearance ( NCT04356508 ), and modulation of lung injury ( NCT04268537 ). A clinical trial with the combination of pembrolizumab (anti-PD-1) and tocilizumab is underway with a focus on improvement of ARDS ( NCT04335305 ). This approach might stimulate and direct immune activation, providing improvement in viral clearance and limiting inflammation. Immune checkpoint inhibitors can cause several immune-mediated toxicities like pneumonitis, and careful selection of patients and close monitoring for toxicities would be essential ( Figure 2 ).

CCR5 Inhibitor: Leronlimab

Leronlimab, or PRO 140, is a monoclonal antibody against the chemokine receptor, CCR5, currently being investigated as an anti-HIV therapy and inhibitor of metastasis in triple-negative breast cancer. Leronlimab received fast-track designation from the FDA for the use with carboplatin in treatments of metastatic triple-negative breast cancer. Leronlimab also has antiviral properties and has been granted fast-track designation as a combination therapy with HAART for HIV-infected patients. CCR5 represents a major method of viral entry for the HIV virus. In contrast to the antiviral effects, the monoclonal antibody CCR5 is expressed on a large number of nonimmune and immune cells, playing a role in the migration of immune cells into sites of inflammation 62 and M1 polarization in myeloid cells, 63 both of which may alter the natural immune response to COVID-19 ( Figure 1 ). The two trials evaluating leronlimab in COVID-19 are examining symptom improvement in mild-to-moderate patients ( NCT04343651 ) and reduction in mortality for severe patients ( NCT04347239 ). The CCR5 receptor antagonist, maraviroc, used in HIV therapies, is also being tested ( NCT04441385 and NCT04435522 ). Similar to VEGF inhibitors, phase 2a studies of leronlimab were associated with an increase in blood pressure, 64 but overall have shown minor side effects in HIV trials ( Figure 2 ).

Multiple Kinase Inhibitors

The small molecule multiple tyrosine kinase inhibitor imatinib which is approved for chronic myelogenous leukemia, gastrointestinal stromal tumor, acute lymphoblastic leukemia, myelodysplastic syndrome, systemic mastocytosis, and dermatofibrosarcoma protuberans is also being tested for COVID-19 treatment. Designed for the oncogenic product of the BCR-ABL gene fusion seen in chronic myelogenous leukemia, imatinib also inhibits other receptor kinases, like c-Kit and PDGFR. 65 In vitro reports have demonstrated the ability of imatinib and other Abelson kinases to inhibit the viral replication cycle for SARS-CoV and MERS-CoV, two related coronaviruses. 66 Thus, the use of imatinib in clinical trials for COVID-19, unlike other kinase inhibitors listed, may function more proximally on limiting the scale or scope of infection ( Figure 1 ). In terms of safety, imatinib, as an anti-cancer drug, is relatively safe; however, it can increase susceptibility to infection, cause neutropenia, and is contraindicated in patients with congestive heart failure, liver impairment, and in pregnant women ( Figure 2 ). Another nonspecific tyrosine kinase inhibitor, nintedanib, has approval for idiopathic pulmonary fibrosis and as a second-line treatment with docetaxel for non-small cell lung cancer. 67 Like the primary indication, nintedanib is being tested to prevent pulmonary complications of COVID-19, namely pulmonary fibrosis as a consequence of infections ( NCT04338802 ).

Thalidomide and Analogs

Thalidomide and the analog lenalidomide display immunomodulatory and anti-angiogenic properties and are being evaluated in the control of inflammatory complications related to COVID-19. Thalidomide and lenalidomide are both indicated in treatment of multiple myeloma, and lenalidomide is also indicated in myelodysplastic syndrome with 5q deletion. Although the mechanism is not fully elucidated, investigations have pointed to the inhibition of proliferation and angiogenesis through actions on ubiquitin-ligase complexes 68 and the degradation of messenger RNA in blood cells reducing effector molecules, such as tumor necrosis factor-ɑ (TNF-ɑ). 69 Thalidomide also appears to modulate the type of immune response, with reports in multiple myeloma of thalidomide-induced increases in NK cells, effectors in innate antiviral immune response, IL-2 induction, and secretion of interferon-γ. 70 , 71 This may be due to a nonspecific costimulation of CD8 + T cells that has been reported using in vitro studies and tested as an adjuvant for chronic viral infections. 72 , 73 Interestingly, an early case report in a patient with COVID-19 complicated by severe pneumonia observed that thalidomide led to an overall reduction in inflammatory cytokines, but an increase in T, B, and NK cells. 74 This trend may be a reflection of feedback of the disease process itself or therapeutic effect. To differentiate this dichotomy, the authors of the case report have also begun a thalidomide clinical trial ( NCT04273529 ) focusing on early PCR-confirmed COVID-19 with radiographic evidence of lung damage. The related immunomodulatory compound, lenalidomide, which is used in co-injection with steroids to treat multiple myeloma, is also being investigated using low doses in elderly patients with mild-to-moderate COVID-19 ( NCT04361643 ). Both thalidomide and lenalidomide, in addition to increasing the risk for infections via myelosuppression, are teratogenic and should be avoided in pregnant women ( Figure 2 ).

Bruton Tyrosine Kinase (BTK) Inhibitors

In addition to monoclonal therapies, there is interest in the ability of small molecule inhibitors to modulate the immune response to COVID-19. The inhibition of Bruton’s tyrosine kinase (BTK), which is FDA-approved for the treatment of chronic lymphocytic lymphoma and Waldenstrom’s macroglobulinemia, has shown anecdotal efficacy in controlling severe infection in COVID-19 patients. Recent clinical observations of the incidental use of ibrutinib in patients with Waldenstrom’s macroglobulinemia and COVID-19 showed marked improvement in symptoms for 5 of 6 patients taking 420 mg/day and required no hospitalization. 75 The sixth patient was prescribed 140 mg/day of ibrutinib, had a more complicated course, with worsened hypoxia, and required intubation. The course improved with the increase of ibrutinib to 420 mg/day. Acalabrutinib is another BTK inhibitor indicated for CLL and mantle cell lymphoma with potential to treat COVID-19. Intriguingly, the inhibition of BTK or the off-target effects may prove to have multifactorial benefits as acalabrutinib treatment has shown reduction in platelet aggregation compared to healthy controls, a serious and common complication of COVID-19 infections. 76 Currently, trials of ibrutinib and acalabrutinib, to assess the effect on the exaggerated immune response of patients who are severely ill with the COVID-19 infection, are underway. BTK inhibitors have side effect profiles that include increased bleeding and increased risk of infections ( Figure 2 ).

BCG Vaccination

An early report found an epidemiological link between reduced morbidity and mortality of COVID-19 with countries that maintain a Bacillus Calmette–Guerin (BCG) vaccination program for tuberculosis. 77 BCG is likely not an effective vaccine for COVID-19, but should be thought of as an adjuvant for an individual’s immune systems, priming the adaptive immune system ( Figure 1 ). Vaccination with BCG works through the development of antigen-specific T cell responses and has been a mainstay of bladder cancer immunotherapy. 78 A number of BCG-based preventative phase 3 and phase 4 trials have been registered to prevent SARS-CoV-2 infection. Several of these trials, such as the BRACE ( NCT04327206 ), BCG-CORONA ( NCT04328441 ), and BADAS ( NCT04348370 ), focus on inoculating healthcare workers, with outcome measures of reduced infection rates or unplanned absenteeism. Other trials seek to immunize at-risk populations, for example ACTIVATE II ( NCT04414267 ), and even the general population ( NCT04369794 ). As of now, the WHO does not recommend BCG vaccinations as a preventative for COVID-19. BCG vaccinations can cause skin reactions and, in serious cases, abscess and bone inflammation.

XPO-1 Inhibitor (Selective Inhibitor of Nuclear Export) Selinexor

Selinexor, a selective nuclear export inhibitor, has been approved for relapsed/refractory multiple myeloma in combination with steroids. 79 However, there is a growing literature on the direct antiviral effects of XPO-1 inhibitors in a variety of viruses, including HIV, influenza, respiratory syncytial virus, rabies, dengue, and cytomegalovirus by limiting nuclear transport. 80 The side effect profile for selinexor includes moderate rates of bone marrow suppression ( Figure 2 ). The two trials to evaluate selinexor will evaluate the improvement in clinical parameters for moderate to severe COVID-19 infections.

DNA-Damaging Agents: Etoposide and Methotrexate

A commonly used antineoplastic drug in therapeutic regimens for lung cancer, testicular cancer, and hematological malignancies, etoposide inhibits DNA replication and leads to preferential apoptosis in cancer cells. Etoposide has a narrow therapeutic window, and the immunosuppressive effect is being explored to treat cytokine storms in COVID-19 patients ( Figure 1 ). A trial ( NCT04356690 ) will evaluate whether pulse dose of etoposide, given on days one and four, will abate the pulmonary and inflammatory complications due to COVID-19. Likewise, the antifolate metabolite methotrexate, complexed with nanoparticles, is being evaluated for reduction of COVID-19-related lung injury ( NCT04356690 ). Both of these agents target DNA replication, and as such are highly suppressive to bone marrow leading to increased risk of infection ( Figure 2 ).

Conclusion and Future Perspective

The COVID-19 pandemic has resulted in insurmountable loss of life and challenged the medical and scientific community to develop effective treatment. Repurposing of available drugs has the potential to serve the unmet need but requires careful consideration, and clinical trials are underway. Despite the drive to improve clinical outcomes for patients with symptomatic COVID-19, caution should be exercised when using these potential agents and emphasis should be placed on enrollment into carefully constructed clinical trials. This is underscored by the hype surrounding and the subsequent negative randomized-controlled trial results of the use of hydroxychloroquine for COVID-19. 7 , 13 , 14 Along with antiviral and anti-inflammatory drugs, several anti-cancer drugs can be potentially repurposed in the management of COVID-19. Challenges exist in repurposing anti-cancer drugs herein reviewed; like their initial development, these therapies are principally designed to alter proliferation. These agents are now being evaluated for a similar effect in blunting the hyperinflammatory response subsequent to COVID-19. Cytotoxic agents, like etoposide and methotrexate, or immune modulators, like BTK inhibitors or imatinib, run the risk of impairing humoral and cellular immune responses and subsequently leading to secondary infections and complications. This is underscored by the recent analysis comparing differential susceptibilities of patients with cancer, with 30.6% mortality across all cancer types and increased susceptibility of infection in patients with hematological malignancies compared to patients with solid malignancies. 81 This susceptibility for COVID-19 infection in hematologic cancers was increased in patients who recently received chemotherapy, with drugs presumably directed against immune cells. 81 As these anti-cancer drugs have general mechanisms of directing or impairing the immune system, particular attention should be placed on titrating the therapies to prevent over-suppression and further complications for patients hospitalized with COVID-19 ( Figure 2 ). Future clinical trials, either single arm studies or randomized controlled trials, will be useful in determining the usefulness of anti-cancer drugs in COVID-19 patients.

Acknowledgments

The authors are supported by the National Cancer Institute of the National Institutes of Health under award number CA206255 (N.B.).

Disclosure

The authors report no conflicts of interest in this work.

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