SITC Statement on anti-IL-6/IL-6R for COVID-19

The following statement was posted on March 24, 2020 and updated April 2, 2020. It has been accepted for upcoming publication in the Journal for ImmunoTherapy of Cancer (JITC). 


Insights from immuno-oncology: The Society for Immunotherapy of Cancer statement on access to IL-6-targeting therapies for COVID-19

Paolo A. Ascierto, Bernard A. Fox, Walter J. Urba, Ana Carrizosa Anderson, Michael Atkins, Ernest C. Borden, Julie R. Brahmer, Lisa H. Butterfield, Alessandra Cesano, Daniel S. Chen, Tanja D. De Gruijl, Robert O. Dillman, Charles G. Drake, Leisha A. Emens, Thomas F. Gajewski, James L. Gulley, F. Stephen Hodi Jr., Patrick Hwu, David Kaufman, Howard L. Kaufman, Michael T. Lotze, Francesco M. Marincola, Kim A. Margolin, Michael J. Mastrangelo, Marcela V. Maus, Douglas G. McNeel, David R. Parkinson, Pedro J. Romero, Paul M. Sondel, Stefani Spranger, Mario Sznol, George J. Weiner, Jon M. Wigginton and Jeffrey S. Weber

Author affiliations below the text

The hypoxia and profound inflammatory response associated with the pneumonitis observed with the SARS-COV-2 virus responsible for the recent COVID-19 pandemic has overwhelmed intensive care facilities in the epicenters of infection including Wuhan, China, Northern Italy, and in the United States, the Seattle and New York City areas. The Society for Immunotherapy of Cancer (SITC) stands along with and supports our colleagues in emergency departments, intensive care units and inpatient wards in the global effort to overcome this unprecedented pandemic. It is becoming apparent that the “ground glass” infiltrative appearance seen on CT scans from COVID-19 patients with pneumonitis is reminiscent of imaging from patients with immune checkpoint inhibitor (ICI)-induced pneumonitis [1, 2]. Additionally, elevated IL-6 is a hallmark inflammatory signature seen in serum of patients with severe COVID-19 acute respiratory distress ­­[3]. Many of us have experience with the administration of immune-modulatory agents, which is why the cancer immunotherapy community is poised to contribute to the current fight against COVID-19.  

One possibility is to encourage the use of IL-6 or IL-6-receptor (IL-6R) blocking antibodies like tocilizumab (Actemra, Roche-Genentech), sarilumab (Kevzara, Regeneron) and siltuximab (Sylvant, EUSA Pharma) that are FDA-approved for various conditions including rheumatologic disease and the lymphoproliferative disorder Castleman’s syndrome. These agents could be used on easily and immediately available compassionate use protocols that could be approved on an emergency basis by all institutional review boards (IRBs) around the world for critically ill patients with COVID-19-induced hypoxia. Tocilizumab also is already FDA-approved to manage cytokine release syndrome (CRS) in patients receiving chimeric antigen receptor (CAR) T cell therapy [4, 5]. In addition, tocilizumab has been shown to reduce toxicity in patients treated with immune checkpoint inhibitors (ICIs) who were steroid refractory [6], and has been added to the ICI agents ipilimumab and nivolumab in an ongoing US phase II study (NCT03999749) to ameliorate immune-related toxicity. In Castleman’s disease, a lymphoproliferative disorder caused by Kaposi’s Sarcoma Herpesvirus, a pathogen that produces viral IL-6, tocilizumab has been shown to reduce viral loads [7]. Tocilizumab is also being explored as a potential supportive care measure for the management of CRS in cancer patients treated with a number of CD3-based bispecific molecules. Now, data from the frontlines of the pandemic indicates that the agent may offer lifesaving benefit for COVID-19 patients with respiratory distress.

Emerging evidence suggests that high levels of CRP and IL-6 are observed in patients infected with COVID-19 [1, 8]. Anecdotal experience on the use of tocilizumab at doses comparable to those used for the management of CRS from investigators in Italy [9] and from China [10] has reported rapid improvement in both intubated and non-intubated patients. In these reports, expeditious administration of anti-IL-6R therapy for patients in acute respiratory distress has been critical. A recent study protocol to evaluate the efficacy of tocilizumab in COVID-19 induced pneumonitis accrued over 300 patients worldwide in less than 24 hours. Additionally, Genentech will also provide 10,000 vials of tocilizumab to the U.S. Strategic National Stockpile [11]. Tocilizumab was also approved in China in March 2020, for the treatment of patients with COVID-19 with serious lung damage and elevated IL-6. Sponsors, investigators, and regulators have moved with unprecedented speed and collaboration to initiate protocols to formally study the safety and efficacy of antiviral agents and vaccines, as well as various anti-IL-6 antibodies in patients with COVID-19.  In the US, a trial of sarilumab in the COVID-19 setting is ongoing [12].

Although randomized data definitively showing that IL-6R blockade benefits patients with COVID-19 induced pneumonitis are currently lacking, we propose that an effort should be made to maximize the availability of anti-IL-6 agents, including tocilizumab and sarilumab for use on a compassionate basis to critically ill hospitalized COVID-19 infected patients during this extraordinary situation. In addition, consideration should be given to focus efforts on rapidly expanding the ability of clinicians and clinical investigators to access investigational anti-IL-6 agents, in particular for those agents where Phase 1 and/or Phase 2 studies have been completed, and acceptable safety has been demonstrated. Even if the primary impact of a single dose of these drugs is to accelerate recovery and get patients off ventilator support and out of the ICU more rapidly, this could significantly decompress our severely over-burdened healthcare systems. We suggest that straightforward parameters including complete blood counts and differentials, serum LDH, ferritin, CRP and IL-6 be recorded in treated patients, that serum be retained for future analyses, and simple clinical parameters be assessed including time in ICU, days of hospitalization, and pulmonary parameters including FEV1 (for non-intubated patients), Fi02, PaO2/FiO2 ratio and type of oxygen supplementation need be recorded pre- and post-anti-IL-6R therapy. A simple compassionate use protocol could be assembled from existing templates, and all efforts should be made for emergency approval of the use of IL-6R blocking antibodies by local IRBs within 24 hours of the request being made. Additionally, consideration should be given by pharma and biotech to redirect the use of facilities and increase personnel involved in drug manufacturing and those serving as liaisons to the frontlines to facilitate drug availability. Extraordinary times call for extraordinary measures, and SITC calls on all involved, including pharmaceutical sponsors, health authorities and IRBs, to continue to move swiftly and creatively to remove barriers and increase access to agents like anti-IL-6R drugs that may improve our care for COVID-19 pneumonitis.  

Acknowledgements

The authors thank the clinicians working tirelessly on the frontlines of the COVID-19 pandemic.

 

References

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  1. Xu, X et al Effective Treatment of Severe COVID-19 Patients with Tocilizumab chinaXiv:202003.00026v1

 

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  1. http://www.news.sanofi.us/2020-03-16-Sanofi-and-Regeneron-begin-global-Kevzara-R-sarilumab-clinical-trial-program-in-patients-with-severe-COVID-19

 

Author affiliations

PAA – Istituto Nazionale Tumori IRCCS Fondazione 'G. Pascale'

BAF – Earle A. Chiles Research Institute, Providence Cancer Institute

WJU – Earle A. Chiles Research Institute, Providence Cancer Institute

ACA – Harvard Medical School

MA – Georgetown Lombardi Comprehensive Cancer Center

ECB – University of Wisconsin Clinical Cancer Center, Madison

JRB – Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

LHB – Parker Institute for Cancer Immunotherapy

AC – ESSA Pharma, Inc.

DSC – IGM Biosciences, Inc.

TDG – Amsterdam University Medical Centers, Vrije Universiteit-Cancer Center Amsterdam

ROD – AIVITA Biomedical, Inc.

CDG – Columbia University Medical Center

LAE – UPMC Hillman Cancer Center

TFG – University of Chicago

JLG – National Cancer Institute

FSH – Dana Farber Cancer Institute

PH – The University of Texas MD Anderson Cancer Center

DK – Bill & Melinda Gates Medical Research Institute

HLK – Immuneering Corporation

MTL – University of Pittsburgh

FMM – Refuge Biotechnologies, Inc.

KAM – City of Hope National Medical Center

MJM – Thomas Jefferson Medical College

MVM – Massachusetts General Hospital

DGM – Carbone Cancer Center, University of Wisconsin-Madison

PJR – University of Lausanne

DRP – ESSA Pharma, Inc.

PMS – University of Wisconsin, Madison

SS – Koch Institute for Integrative Cancer Research at MIT

MS – Yale School of Medicine

GJW – University of Iowa

JMW – MacroGenics, Inc.

JSW – NYU Langone Health