Cytokine Storm Drugs Move from CAR T to COVID-19 Free

A drug used to manage toxicities associated with chimeric antigen receptor (CAR) T-cell therapy seems to help control cytokine storms in people infected with SARS-CoV-2.

According to reports from Europe and China, critically ill patients hospitalized with COVID-19 needed less supplemental oxygen and had less lung inflammation after receiving tocilizumab (Actemra; Roche), an IL6 receptor–targeted antibody approved to treat rheumatologic diseases and to alleviate CAR T cell–induced cytokine-release syndrome (CRS) in people with cancer.

“These are preliminary but encouraging initial signals of potential benefit,” says Eric Coomes, MD, of the University of Toronto in Canada, who conducted a meta-analysis of studies from China showing that patients with severe COVID-19 had three-fold higher serum levels of IL6, on average, than patients who did not experience major complications.

However, “the accumulated data to date do not provide definitive evidence [of efficacy] for tocilizumab or IL6 inhibition” to treat COVID-19, Coomes notes. Only randomized controlled studies can generate that evidence—and the first results to emerge from those kinds of trials paint a mixed picture of who stands to benefit.

On April 27, researchers in France announced that, among 129 patients hospitalized for COVID-19 but not requiring intensive care upon admission, those randomized to receive tocilizumab in addition to standard treatment were significantly less likely to need ventilation or die within 2 weeks compared with those who received standard treatment alone.

That same day, however, Sanofi and Regeneron announced less-promising preliminary data from a placebo-controlled trial in the United States of the companies' IL6-receptor blocker sarilumab (Kevzara), which like tocilizumab is approved for treating rheumatoid arthritis. Although sarilumab lowered levels of C-reactive protein, a marker of inflammation, significantly more than placebo, that did not translate into clinical benefits overall.

Patients who were hospitalized but not on ventilators recovered at the same rate whether they received sarilumab or not. The only hints of benefit were seen in critically ill patients, those who required mechanical ventilation or treatment in an intensive care unit. Researchers are continuing the trial but enrolling only these critically ill patients.

Meanwhile, Roche continues to enroll patients with more moderate disease in its own large randomized trial of tocilizumab versus placebo. And EUSA Pharma—the company behind siltuximab (Sylvant), an antibody directed against IL6 itself, not the receptor—hopes to launch a randomized trial based on encouraging data from a single-arm study, according to Darrel Cohen, MD, PhD, the company's head of clinical development.

None of those trials focus specifically on patients with cancer, but early reports point to favorable responses in some people fighting malignancies and SARS-CoV-2. For example, in China, a 60-year-old man in remission for multiple myeloma received tocilizumab for COVID-19 and recovered—with no signs of cancer recurrence. In France, at Institut Gustave Roussy in Villejuif, a 42-year-old man with just-diagnosed metastatic kidney cancer who contracted COVID-19 received two doses of tocilizumab and his coronavirus symptoms subsided.

However, the next patient with cancer and COVID-19 treated with tocilizumab at Institut Gustave Roussy had no improvement, highlighting that “we don't know yet to what extent the tumor itself, the treatment previously received, or the clinical presentation are of importance to whether the patient will derive benefit from IL6 inhibitors,” says Gustave Roussy's Laurence Albiges, MD.

In most COVID-19 trials of tocilizumab, doctors administer the dose approved to manage CRS in CAR T-cell recipients: 8 mg/kg, up to a maximum dose of 800 mg. Some give a flat dose of 400 mg. However, those doses might be overkill, says Pankti Reid, MD, MPH, of the University of Chicago Medical Center in Illinois. “Potentially lower doses may be sufficient,” she says.

To test that idea, Reid initiated a 50-person trial in April involving patients hospitalized with COVID-19, but not yet in need of mechanical ventilation, to receive 80 mg or 200 mg of tocilizumab, depending on their risk of complications. Data are too preliminary to draw concrete conclusions, she says.

Reid's lower-dose strategy, if proven effective, could help address any shortages of tocilizumab that arise as the COVID-19 pandemic continues. Hydroxychloroquine and chloroquine, two other drugs with anti-coronavirus potential, are already in short supply. Yet, unlike those inexpensive agents, a 400 mg vial of tocilizumab typically costs upward of $2,000.

That's why Erin Fox, PharmD, of the University of Utah in Salt Lake City, does not foresee shortages of IL6- or IL6 receptor–blocking antibodies. Hospitals probably can't afford the medicines for everyone with COVID-19, she says, so there's not likely to be a rush on them. –Elie Dolgin