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The Society for Immunotherapy of Cancer Perspective on Regulation of Interleukin-6 Signaling in COVID-19-­ Related Systemic Inflammatory Response

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The Society for Immunotherapy of Cancer Perspective on Regulation of Interleukin-6 Signaling in COVID-19-­ Related Systemic Inflammatory Response Open access Position article and guidelines J Immunother Cancer: first published as 10.1136/jitc-2020-000930 on 7 May 2020. Downloaded from The Society for Immunotherapy of Cancer perspective on regulation of interleukin-6 signaling in COVID-19- related systemic inflammatory response Fernanda I Arnaldez,1 Steven J O'Day,2,3 Charles G Drake,4 Bernard A Fox,5 Bingqing Fu,6 Walter J Urba,5 Vincenzo Montesarchio,7 Jeffrey S Weber,8 6 9 10 Haiming Wei, Jon M Wigginton, Paolo Antonio Ascierto To cite: Arnaldez FI, O'Day SJ, ABSTRACT facilitated its spread across the globe, with Drake CG, et al. The Society The pandemic caused by the novel coronavirus the first detected case in the USA reported on for Immunotherapy of Cancer SARS- CoV-2 has placed an unprecedented burden on 1 perspective on regulation January 19, 2020. On March 11, 2020, WHO healthcare systems around the world. In patients who 2 of interleukin-6 signaling in declared the outbreak a pandemic. experience severe disease, acute respiratory distress is COVID-19- related systemic The ongoing COVID-19 outbreak is chal- often accompanied by a pathological immune reaction, inflammatory response. Journal lenging every aspect of daily life, including sometimes referred to as ‘cytokine storm’. One hallmark for ImmunoTherapy of Cancer the implementation of public health policy, 2020;8:e000930. doi:10.1136/ feature of the profound inflammatory state seen in jitc-2020-000930 patients with COVID-19 who succumb to pneumonia the nature of social interactions, adaptation and hypoxia is marked elevation of serum cytokines, of the workforce to a ‘new normal’ and the ► Additional material is especially interferon gamma, tumor necrosis factor alpha, medical research and clinical care infra- published online only. To view, interleukin 17 (IL-17), interleukin 8 (IL-8) and interleukin 6 structure, including the care for oncology please visit the journal online (IL-6). Initial experience from the outbreaks in Italy, China patients. Economic forecasts are concerning, (http:// dx. doi. org/ 10. 1136/ jitc- and the USA has anecdotally demonstrated improved and a global financial crisis is anticipated. 2020- 000930). outcomes for critically ill patients with COVID-19 with the Mathematical modeling based on available administration of cytokine-modula tory therapies, especially data shows that in the face of rapid geograph- Accepted 15 April 2020 anti-IL-6 agents. Although ongoing trials are investigating anti-IL-6 therapies, access to these therapies is a ical spread and a high case- fatality ratio, even concern, especially as the numbers of cases worldwide the most advanced healthcare systems are http://jitc.bmj.com/ continue to climb. An immunology- informed approach very likely to be overwhelmed in the coming 3 may help identify alternative agents to modulate the weeks and months. It will be critical to iden- pathological inflammation seen in patients with COVID-19. tify therapies with low barriers to rapid clin- Drawing on extensive experience administering these ical deployment. and other immune- modulating therapies, the Society It is becoming apparent that in some for Immunotherapy of Cancer offers this perspective patients, severe COVID-19 disease occurs, and on September 23, 2021 by guest. Protected copyright. on potential alternatives to anti-IL-6 that may also is accompanied by a fulminant and damaging warrant consideration for management of the systemic immune reaction, sometimes called the ‘cyto- inflammatory response and pulmonary compromise that can be seen in patients with severe COVID-19. kine storm’, characterized by pronounced infiltration of macrophages and mono- cytes into the alveolae, a pro- inflammatory INTRODUCTION T- helper 17 (Th17) response, and elevated Coronaviruses are a family of enveloped, levels of inflammatory cytokines, particularly positive sense, single- strand RNA viruses that IL-6, IL-1β, IL-8, interferon gamma (IFNγ) 4–7 © Author(s) (or their infect mammals and birds. In humans, coro- and tumor necrosis factor alpha (TNFα). employer(s)) 2020. Re- use navirus infections typically cause mild respi- This pro- inflammatory cytokine profile has permitted under CC BY-NC. No commercial re- use. See rights ratory disease, including seasonal colds, yet been with poor prognosis and severe lung and permissions. Published by some members of the family can be highly pathology characterized by interstitial mono- BMJ. virulent. In December 2019, a novel coro- nuclear inflammatory infiltrates, diffuse alve- For numbered affiliations see navirus, SARS- CoV-2, structurally related to olar damage, hyaline membrane formation end of article. the virus that causes severe acute respiratory and pulmonary edema.8–10 Correspondence to syndrome (SARS) and Middle East respiratory As the oncology community rallies Dr Paolo Antonio Ascierto; syndrome (MERS), was identified in Wuhan, behind our colleagues in intensive care, paolo. ascierto@ gmail. com China. Its efficient transmission (R0 of 2.2) internal medicine, emergency medicine and Arnaldez FI, et al. J Immunother Cancer 2020;8:e000930. doi:10.1136/jitc-2020-000930 1 Open access J Immunother Cancer: first published as 10.1136/jitc-2020-000930 on 7 May 2020. Downloaded from infectious disease, the immunotherapy field is poised to epidemiological analysis is ongoing worldwide and offer insights into the application of immune- modulatory facing the challenge of testing availability. Death is therapies. Modulation of IL-6, in particular, which has typically due to massive alveolar damage and irrevers- emerged as a potentially promising option for COVID- ible respiratory failure.18 19- related acute respiratory distress syndrome (ARDS), Almost 75% of patients with COVID-19 acute respira- is used for the treatment of some rheumatological disor- tory disease present with abnormal findings on chest ders,11 and has become a mainstay in recent years in the CT scans. Ground-glass opacities are the most common management of cytokine release syndrome (CRS) after finding, reported in as many as 60% of patients. Other chimeric antigen receptor (CAR) T cell therapy for hema- findings include patchy infiltrates, and interstitial lung tological malignancies.12–14 Although the cytokine levels disease, although some patients present with minimal observed in patients with COVID-19 experiencing ARDS imaging abnormalities.5 7 17 19 are much lower than those seen in CRS after delivery Pathological findings resemble those seen in SARS and of CAR Tcell therapies and CD3-based bispecific Tcell MERS: edema, proteinaceous exudates, focal reactive engagers, the cancer immunotherapy community’s expe- pneumocyte type II hyperplasia, patchy cellular inflam- rience in using the IL-6 receptor antagonists to modulate mation and multinucleated giant cells.9 Notably, neutro- severe inflammatory pathology in the setting of CRS may phil infiltration is not significant.20 prove to be useful in identifying therapies that could be Elevated C reactive protein (CRP) and elevated aspar- of use in this setting. tate transaminase are common in patients with COVID-19 Healthcare and research organizations continue to and reports from Hubei province in China indicate that aggressively pursue development of a vaccines and effec- severe cases are associated with elevated levels of inflam- tive therapeutic strategies to attenuate the burden of matory markers including serum d- dimer, ferritin and SAR- CoV-2 (including antimalarial, antimicrobial and lactate dehydrogenase.21 The cytokine profile of severe directed antiviral agents as well as convalescent serum COVID-19 disease is characterized by elevated IL-2, IL-6, from patients who have cleared virus and recovered) IL-7, IL-8, granulocyte-colony stimulating factor, IL-17, and to support patients through the severe inflamma- TNFα and other markers that indicate systemic inflam- tory response and pulmonary complications that can matory response,22 similar to what has been described frequently occur. The aim of this analysis is to describe in macrophage activation syndrome (MAS) or in available strategies that could alleviate the burden on the hemophagocytic lymphohistiocytosis (HLH).23 24 More- healthcare system with a specific emphasis on therapeu- over, a retrospective multicenter study of 150 patients tics that could block or modulate the systemic inflamma- performed from Wuhan, China suggested that among tory response and pulmonary complications caused by other clinical parameters, CRP and IL-6 levels can be COVID-19, in particular, IL-6, IL-1 and TNFα pathways.15 predictors of mortality. Among 68 patients who died, median IL-6 level was 11.4 ng/mL as opposed to 6.8 ng/ mL in those 82 who survived (p<0.001).25 Additionally, an http://jitc.bmj.com/ RATIONALE FOR TARGETING IL-6 elevated neutrophil- to- leukocyte ratio was also predictive SARS- CoV-2 causes the emergent respiratory disease of poor prognosis. called COVID-19. One of the challenging aspects in In the USA, anticipated shortages of key resources management of the infection is that different presenta- including intensive care unit (ICU) beds and mechan- tions have been identified16: ical ventilators has led to the implementation of social ► Asymptomatic carrier state distancing measures to avoid overloading a medical system on September 23, 2021 by guest. Protected copyright. ► Mild respiratory symptoms, not requiring that is not prepared to care for an overwhelming number hospitalization of affected individuals.26 While a concerted effort to ► Recovered and re-
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