1. Nalley, Catlin

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As the coronavirus pandemic continues, researchers worldwide are looking for effective treatment approaches. While many are focused on developing novel therapeutics, including antivirals and vaccines, others are turning to existing therapies with proven safety profiles. One approach being explored includes treatments utilized for cytokine release syndrome (CRS).

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CRS can occur among cancer patients following some types of immunotherapy, such as monoclonal antibodies and CAR-T cells. It is caused, according to the NCI, by a large, rapid release of cytokines into the blood from immune cells affected by the immunotherapy.


"There has been an emerging interest in CRS because of COVID-19. CRS is well-described in patients with certain cancers as a direct complication or as a side effect to certain types of therapies, such as CAR T-cell therapy," noted Ned Sharpless, MD, Director of NCI, on Twitter.


"Signs of CRS can include severe flu-like symptoms, low blood pressure, rapid heartbeat, trouble breathing, and end-organ failure, including sometimes acute respiratory distress syndrome (ARDS)," he noted in the thread posted on March 15. "CRS is managed with anti-IL-6 receptor antibodies (e.g., tocilizumab), which are now being used off-label in critically ill COVID-19 patients."


Exploring the Potential

With an urgent need for effective treatments, investigators are seeking ways to help patients with COVID-19, especially those with severe complications, such as respiratory failure from ARDS-a leading cause of mortality.


A subgroup of patients with severe COVID-19 might have a cytokine storm syndrome, according to a recent paper (Lancet 2020; doi:10.1016/S0140-6736(20)30628). "We recommend identification and treatment of hyperinflammation using existing, approved therapies with proven safety profiles to address the immediate need to reduce the rising mortality," the authors noted.


They suggest that all patients with severe COVID-19 should be screened for hyperinflammation to identify the subgroup of patients for whom immunosuppression could improve mortality. "Therapeutic options include steroids, intravenous immunoglobulin, selective cytokine blockade (e.g., anakinra or tocilizumab), and JAK inhibition."


"Since lymphocytopenia is often seen in severe COVID-19 patients, the CRS caused by SARS-CoV-2 virus has to be mediated by leukocytes other than T cells, as in patients receiving CAR-T therapy; a high WBC-count is common, suggesting it, in association with lymphocytopenia, as a differential diagnostic criterion for COVID-19," according to a recently published editorial in Cell Death & Differentiation (2020; "In any case, blocking IL-6 may be effective. Blocking IL-1 and TNF may also benefit patients."


The authors also noted that while a number of clinical sites in China have announced the use of mesenchymal stromal/stem cells in severe COVID-19 cases, solid results have yet to be seen.


With the hope that it could benefit patients with COVID-19, researchers are taking a closer look at tocilizumab, which is currently FDA-approved for the treatment of severe or life-threatening CAR T cell-induced CRS in adults and in pediatric patients 2 years of age and older. There are a number of studies underway, but the need for definitive evidence remains.


Preliminary findings suggest tocilizumab may help COVID-19 patients with severe lung disease. Chinese authorities have issued guidelines recommending the drug in an effort to combat severe complications associated with the infection. And, researchers in China are currently testing the drug in a clinical trial that is expected to include 188 coronavirus patients.


On Monday, March 23, the FDA approved the initiation of a randomized, double-blind, placebo-controlled, phase III clinical trial that will evaluate the safety and efficacy of intravenous tocilizumab plus standard of care in hospitalized adult patients with severe COVID-19 pneumonia.


The primary and secondary endpoints include clinical status, mortality, mechanical ventilation, and intensive care unit variables. Investigators will follow enrolled patients for 60 days post-randomization. An interim analysis will be conducted to assess early evidence of efficacy.


In an effort to further support COVID-19 response efforts, the sponsors of the study will also provide 10,000 vials of tocilizumab to the U.S. Strategic National Stockpile for potential future use at the direction of the U.S. Department of Health and Human Services.


When asked to comment on the potential of using anti-IL-6 receptor antibodies like tocilizumab," Julian Schink, MD, Chief Medical Officer, Cancer Treatment Centers of America, told Oncology Times: "Certainly, COVID-19 can be a life-threatening illness and treating it will require us to draw on all of our resources.


"Surprisingly, blocking the effects of an overzealous immune response may have the potential to help COVID-19 patients, and I'm anxious to see scientific evidence to support that," he noted. "Hopefully, the supply of these drugs is adequate because CRS is relatively uncommon. But if we run out of these drugs after establishing their benefit it will be an additional tragedy."


Just one of many therapeutic approaches being studied, researchers are working around the clock to uncover and test therapies that could offer hope to not only COVID-19 patients and their loved ones, but the entire world.


Catlin Nalley is a contributing writer.