/COVID-19: Cancer drug may quench inflammation in severely ill patients

COVID-19: Cancer drug may quench inflammation in severely ill patients

An international clinical trial has been launched after a cancer drug that targets the root cause of extreme inflammation showed promise in a preliminary study.

close up of monitor with vital signs, patient in intensive care in the backgroundShare on Pinterest
A cancer drug could be repurposed to help treat patients with severe COVID-19.

In some people with mild or moderate COVID-19, the illness caused by the SARS-CoV-2 virus, their condition briefly improves, only to suddenly worsen.

These people may then develop severe breathing difficulties, known as acute respiratory distress syndrome.

Scientists speculate that even when the infection is being brought under control, the virus can trigger an excessive immune response, causing hyper-inflammation of the lungs and other organs.

This type of inflammatory response is thought to begin when receptors in immune cells called macrophages recognize the genetic material of viruses such as SARS-CoV-2. They respond by initiating a massive release of immune-signalling molecules called cytokines.

This “cytokine storm” appears to cause the hyper-inflammation that damages the lungs and other organs of critically ill patients. Currently, no proven treatment can prevent or reverse the damage.

In macrophages, an enzyme called Bruton tyrosine kinase (BTK) is responsible for initiating the cytokine storm.

A drug that inhibits the activity of BTK — called acalabrutinib — is already in use as a treatment for certain blood cancers.

Researchers at the National Cancer Institute, in the United States, realized that because acalabrutinib inhibits BTK, it could potentially reduce inflammation in people with severe COVID-19.

To test the safety and efficacy of the drug in this context, they collaborated with scientists at the National Institute of Allergy and Infectious Diseases, the Walter Reed National Military Medical Center, and four other hospitals in the country.

The researchers have published the results of their trial in the journal Science Immunology.

For between 10 and 14 days, the team administered the drug to 19 people hospitalized for COVID-19. At the start of the study, 11 participants were breathing with the help of oxygen masks, and eight were on ventilators.

By the end of the follow-up period, eight of the 11 patients who had been receiving supplemental oxygen no longer needed help breathing and had been discharged from the hospital.

Of the eight patients on ventilators at the start of the treatment, four had been taken off the machines, or “extubated,” and two had been discharged. Two of the patients had died. Figure 3 in the study provides more information about the outcomes of these patients.

The drug, however, appeared to cause no toxic side effects.

The researchers also monitored two markers of inflammation in the blood — levels of a cytokine called interleukin 6 (IL-6) and C-reactive protein (CRP).

Of the 11 patients on supplemental oxygen at the start of the study, CRP levels returned to normal in 10 and were decreasing in one. Of the five patients who also had their IL-6 levels measured, the levels of three had returned to normal, and the levels of two had fallen sharply.

The picture was more mixed among the patients on ventilators. Reductions were smaller overall, and in some of these patients, the levels fluctuated.

“The oxygenation and clinical status of most patients on supplemental oxygen improved relatively rapidly following acalabrutinib initiation, which was temporally associated with a normalization of inflammatory markers,” the researchers write.

“Although the patients on mechanical ventilation had a more variable clinical response to acalabrutinib, improved oxygenation in half of these patients allowed them to be extubated.”

In addition, the number of lymphocytes — a type of white blood cell — increased in the blood of most patients. In people with severe COVID-19, a low lymphocyte count has been associated with worse outcomes.

“Though we expected that the optimal time to initiate anti-inflammatory treatment would be prior to deterioration requiring intubation, these results suggest that BTK inhibition may provide significant benefit to a subset of patients with COVID-19 on ventilators.”

– Mark Roschewski et al.

In support of their hypothesis, the researchers also established that the activity of the BTK enzyme was higher in blood cells from the COVID-19 patients at the start of the study, compared with those from healthy volunteers. The IL-6 levels were likewise higher in the patient group.

The team notes that several well-established risk factors for developing severe COVID-19, including obesity, hypertension, atherosclerosis, and type 2 diabetes, are also associated with excessive inflammation.

Preexisting inflammation may be what makes these groups particularly vulnerable to severe SARS-CoV-2 infections.

Other ways of damping down patients’ immune response have been proposed as potential treatments, such as monoclonal antibodies that target IL-6.

However, the authors of the present study argue that their strategy may be more effective because it tackles the problem of inflammation at its source, in macrophages.

Levels of several cytokines are elevated in patients with severe COVID-19, so targeting just one may only partially reduce the inflammatory process.

The current study was small and there was no control group. However, in April, before the study had been published, its promising results led to the launch of a much larger, randomized controlled clinical trial called CALAVI, which will have international involvement.

CALAVI is evaluating the efficacy and safety of acalabrutinib (Calquence) — a highly selective BTK inhibitor currently used to treat certain types of blood cancers — in patients hospitalized with respiratory complications of COVID-19.

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