Masking and vaccinations can keep COVID-19 infections at bay, but therapies are still sorely needed for those who do get sick, particularly the 15-20% of people whose acute infections progress to a cytokine storm.
These storms can occur with COVID-19 and sepsis and have also been seen in cancer patients after certain cell-based immunotherapies. They’re caused by the rapid release of inflammatory molecules by the body in response to what it perceives as a threat. In COVID-19, these storms bring on respiratory failure and are often deadly. There are few therapies.
Now, researchers at Fred Hutchinson Cancer Research Center have used machine learning, deep neural networks and other artificial intelligence tools to screen, identify and validate a handful of Food and Drug Administration-approved compounds that inhibit this inflammatory response — at least in mice and cells.
All they need now is a clinical trial — with people — to prove it’s possible to calm COVID-19’s cytokine storms and save patient lives with drugs that are already on the market.
“Our goal was to determine if FDA-approved drugs available for clinical use might forestall drug development and deliver a timely solution for the COVID-19 pandemic,” said Hutch systems biologist Dr. Taran Gujral, co-senior author of a new proof-of-concept paper recently published in Molecular Systems Biology. “We were able to identify and validate FDA-approved, or clinical-grade, compounds, inhibiting inflammatory cytokine production in the context of SARS-CoV-2,” the virus that causes COVID-19.
One compound in particular, the multi-enzyme inhibitor ponatinib which has been FDA-approved for use in certain leukemia patients, was identified “as a potent inhibitor of cytokine production in response to … SARS-CoV-2 and its emerging variants,” Gujral said.
Gujral co-authored the new paper with Drs. Julie McElrath and Eric Holland, respective directors of the Hutch’s Vaccine and Infectious Disease and Human Biology divisions, along with Hutch scientists Drs. Marina Chan, Siddharth Vijay and John McNevin.
And it is packed with findings.
First, the team discovered a previously unknown function of one end of the SARS-CoV-2 spike protein that promotes cytokine release in immune cells. This discovery was backed up by an international team of scientists who published data on this relationship in the journal Immunity while Gujral’s paper was being peer-reviewed.
“Their study showed that the SARS-CoV-2 virus induces cytokine production in human myeloid cells,” he said. (These immune cells snap into action when the body is injured or invaded by a pathogen.)
“We aren’t allowed to use the actual virus, we used the spike protein, just part of it,” he said. “But we showed that the spike protein does this and showed the cytokine release.”
Once the source of the storms had been identified, Gujral and his collaborators turned to the sophisticated drug screening platform Gujral and his team developed over the last few years. The platform’s machine learning-based modeling methods allowed them to identify the pathways that the spike protein used to send out the storm signals as well as the drugs that could target those pathways.
Designed with rare diseases in mind — the Gujral Lab’s customary research focus — the scientists believe the platform will become an effective way to speed the identification and use of drugs that can help mediate and even cure overlooked, or “orphan,” diseases.
“My motivation has been to focus on areas that are underrepresented in cancers and other diseases,” Gujral said. “The idea is to find existing drugs approved for other indications that could be applied. But this was a perfect test scenario for COVID-19.”
The team decided to focus on kinases, a type of enzyme that helps orchestrate molecular pathways within cells that regulate everything from cytokine release to cell growth. Quickly narrowing down which kinases are involved in a specific cellular process can be tricky — there are hundreds of kinases, and genetic methods can take time.
That’s why Gujral developed the method he dubbed polypharmacology that combines math with kinase inhibitors.
Kinase inhibitors put the brakes on kinase-controlled molecular pathways, enabling researchers to use them to test which pathways choreograph a particular cellular process. But most kinase inhibitors have more than one target, making it difficult to interpret the results from individual inhibitors.
Gujral has turned this to his advantage: He uses large screens of inhibitors that each hit a different set of kinases, and untangles the results using complex computational methods. With this approach, he was able to narrow down the kinases that contribute most to spike-protein mediated cytokine release. He also discovered some unexpected kinases involved in the cytokine storm pathway that may hold potential for further areas of research.
“Our polypharmacology approach is useful because, in an unbiased way, we can identify all possible downstream kinases important for cytokine release,” he said. Read more about their drug discovery platform.
Many FDA-approved drugs also target kinases. Gujral and his team turned to these tested drugs to screen for potential COVID-19 treatments.
Using what they knew about the cytokine-regulating kinases, Vijay in the Gujral Lab developed algorithms to model how cells might respond to 428 individual kinase inhibitors. The team also predicted responses to 91,000 two-drug combinations that could influence the spike protein-mediated cytokine release.
Their computer models nominated several FDA-approved inhibitors as most likely to block the cytokine-agitating kinases and calm the storm.
“We found five or six FDA-approved compounds, all cancer drugs, out of dozens that we looked at,” he said. “We wanted to find drugs that are immediately useful in the clinic.”
The researchers tested their model’s most promising candidates with cells in petri dishes and in mice.
Ponatinib, a third-generation tyrosine kinase inhibitor approved for certain chronic myeloid leukemia patients, emerged as the best candidate as it was able to block all seven cytokines.
“More-specific inhibitors weren’t that useful, but the nonspecific inhibitors were more effective in inhibiting the cytokine release,” Gujral said. This is likely because the cytokine storm is caused by several molecules working together, he noted.
And several of the drugs identified in the team’s screen are generic.
“What's exciting is that is there are inexpensive, FDA-approved drugs that might be able to reduce the deadly impact of this virus in people who are already infected,” Holland said.
The team also tested and validated the effectiveness of some of the drugs with delta and other emerging COVID variants.
If the drugs the researchers found are effective, they wouldn’t block infection, he said, but could address the dire need for drugs to help keep infected people alive and out of intensive care units.
Ponatinib is currently under patent protection so there is no generic available. But Gujral said it could be cheap to manufacture and patients can take it orally, as opposed to via infusion, saving time and money.
“All of the drugs we identified are daily pills,” Gujral said. “Our collaborator Rachel [Bender Ignacio, who leads the Hutch’s COVID-19 Clinical Research Center, or CCRC] was very excited about that. It could potentially decrease hospitalization.”
The CCRC opened in October of 2020 to address the need for COVID-19 therapies.
An epidemiologist, internist, infectious disease expert and the CCRC’s medical director, Bender Ignacio worked with the collaborators to create a mockup of a clinical trial to test this potential therapy in COVID-19 patients.
“It’s really fantastic that they’ve found something that seems to be more potent in this specific interaction than the drugs so far tested clinically,” Bender Ignacio said.
CCRC is currently running a handful of COVID-19 therapy clinical trials, but Bender Ignacio said more trials are absolutely needed, not just for therapies to alleviate the hyperinflammation of cytokine storms, but for those who contract long COVID-19.
While COVID-19 therapy trials are challenging for many reasons, therapies are coming.
“The pipeline is working,” she said, adding that Gujral’s drug-discovery platform could feed into that by identifying promising approved drugs for long-haul COVID-19 and other conditions that lack effective treatment.
Using FDA-approved drugs in a trial would also mean much faster results. Gujral said they hope to do a combined safety and efficacy trial of ponatinib in 100-150 patients at multiple sites. While the drug has side effects if used for a long period of time (cancer patients, on it for 25 to 30 months, have experienced blood clots), patients in a COVID-19 trial would take it for only five to seven days. And the trial could conceivably start as soon as patients are available.
There’s only one problem. They can’t access the drug, at least not yet.
Gujral said his team has had conversations with the manufacturer but they decided not to go forward with a clinical trial, provide any funding nor donate the drug for a trial funded entirely by donations.
“That was a setback,” he said. “But we are going to try knocking on their door again and also pursue other companies.”
Ponatinib wasn’t the only promising candidate from Gujral’s screen. But finding the interest and financing to fund new trials of generic drugs is a perennial problem, Holland noted.
Even so, trials must be conducted to know for sure if ponatinib or any other likely-looking compound has real lifesaving potential, he said.
“This could be a great place for philanthropy, or people who really want to make a difference to fund trials, to figure out if these drugs really could be used to save people’s lives,” he said.
Another promising aspect of the work is that this therapy might work in other storm scenarios.
“The [cytokine storm] phenomenon we studied is not specific to COVID,” Gujral said. “It’s how immune cells respond to a threat. It could be a viral assault, or bacterial, or cancer. What we’re studying is a response of the immune cell. It doesn’t matter where the threat comes from.”
Chan, lead author on the paper, said the versatility of the platform is also significant.
“We now have the ability to define a very specific assay that can measure the phenotype you want,” she said. “The phenotype is the problem you’re trying to solve for, in this case, it’s the cytokine release from immune cells. Then you couple that with this machine learning platform to screen for FDA-approved drugs that will block the phenotype you’re trying to measure. I think that’s very powerful.”
Gujral, Chan and team put the drug’s cytokine storm-dampening effect to the test with a mouse that developed sepsis, another type of storm, following a lung infection.
“It cleared the infection,” Gujral said.
But the researchers cautioned that “there’s a fine balance” between suppressing a cytokine storm and suppressing necessary immune function.
“You want the immune system to fight the virus or whatever the threat is,” Gujral said. “You want to show that you’re not suppressing it indefinitely, that you’re not suppressing all the immune cells.”
To that end, in collaboration with Hutch virology experts McNevin and McElrath, who holds the Joel D. Meyers Endowed Chair, the team tested how ponatinib worked against cytokine release by two different types of immune cells: monocytes and T cells.
“We found the drugs affected the ability of the monocytes to secrete cytokines,” Gujral said. “But they had little effect on T cells.”
Bender Ignacio said it was important to inhibit the hyperinflammatory response triggered by a subset of immune cells while theoretically allowing preservation of the parts of the immune system needed to fight the virus. The steroids currently being used to suppress the immune response are a “blunt tool,” she said.
“Looking at these precision tools is very important and may allow them to be used earlier in some cases,” she said. “There’s also potential for using them in people who never develop severe disease, to either prevent or treat long COVID.”
The Hutch team is thrilled by the success; Gujral called it a “a nice validation of the drug-discovery approach.”
Chan added that coming up with fast answers mid-pandemic felt incredibly rewarding.
“Whether this can have a translational impact depends on many stakeholders,” she said. “But this is an unprecedented time. As a scientist, I’m very excited that we can apply our platform to this crisis and find a solution. It feels very rewarding and also shows how versatile and flexible research can be.”
Best of all, it’s just the start.
“This really opens up a new area for biologists to look at the role of kinases in various diseases,” he said. “To find effective drugs or drug combinations that can block cytokine release. We also want to look at the mechanism and how this knowledge could be translated to other diseases, including cancer.”
This work was supported by generous donations to the Fred Hutch COVID-19 Research Fund.
Diane Mapes is a staff writer at Fred Hutchinson Cancer Research Center. She has written extensively about health issues for NBC News, TODAY, CNN, MSN, Seattle Magazine and other publications. A breast cancer survivor, she blogs at doublewhammied.com and tweets @double_whammied. Email her at email@example.com. Just diagnosed and need information and resources? Check out our patient treatment and support page.
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