By KRISTI BIRCH
KU Medical Center News
When 2020 began, Gregory Gan, M.D., Ph.D., was all set to dive into new research on treatment resistance and metastasis in head and neck cancer. A few months and a global pandemic later, he's partnered with pulmonologist Deepika Polineni, M.D., MPH, and they have launched a trial together exploring a drug to fight COVID-19.
From cancer to COVID
Since becoming an assistant professor of radiation oncology at the University of Kansas Cancer Center in July 2019, Gan had spent months getting his lab up and running. He'd also been awarded a National Institutes of Health COBRE (Centers for Biomedical Research Excellence) grant through the Kansas Institute for Precision Medicine (KIPM) to support the focus of his research: how a certain protein can regulate inflammation, growth and treatment resistance in cancer.
But then he had two setbacks. In January, he had identified a drug developed by Aclaris Therapeutics, Inc., that specifically targeted the protein he was researching. Gan wanted to see if it could prevent or slow metastasis in cancer. But at the time, Aclaris was focused on evaluating the drug for an immuno-inflammatory condition, rheumatoid arthritis.
And then in March, the coronavirus made its way to Kansas City, shutting down laboratories across the University of Kansas Medical Center as Kansas City implemented stay-at-home orders. Along with other researchers from KU Medical Center and around the country, Gan used the time at home to write and read about research findings in his field as well as to read up on the biology of the deadly new coronavirus.
And that's when it hit him. The same drug that he had wanted to study in cancer might also be effective in curtailing the "cytokine storm" that leads to respiratory failure and deaths of COVID-19 patients.
"I guess it's true what they say about lemons and lemonade," said Gan. "I'm lucky in that the pathway I'm already studying actually may have a role for managing COVID-19."
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That's when he contacted Polineni, an associate professor of medicine at KU Medical Center. Polineni, a fellow NIH COBRE grant recipient through KIPM and a physician-scientist in adult pulmonary medicine, was working with her laboratory to study patterns of inflammation and anti-inflammatory response in cystic fibrosis (CF), a genetic pulmonary disease and long-standing focus of her research. Polineni had also temporarily shut down her lab and was actively seeking ways to contribute in the pandemic. Gan wanted to discuss with his colleague the plausibility of therapeutic application of the drug he was studying in COVID-19-related pulmonary disease.
After reviewing the data for the drug, Polineni and Gan decided that the evidence supported testing it in COVID-19 patients.
This month, Gan and Polineni began enrolling patients in their clinical trial to evaluate if Aclaris's new investigational drug (ATI-450) can be used to halt respiratory failure in patients hospitalized with COVID-19. If successful, this could potentially keep those patients from needing mechanical ventilation.
Making the connection
The specific protein that Gan studies is known as MAP kinase-activated protein kinase-2 (MK2). For three years, he has been researching the role of MK2 on treatment resistance in head and neck cancer. Recently, his work has expanded into studying how this protein plays a role in cancer metastasis, the disease process where cancer spreads from one part of the body to another.
MK2 helps the body produce inflammatory cytokines, types of proteins released both by the body's immune system and tissue. MK2 is also important in a process known as epithelial-to-mesenchymal transition (EMT), in which epithelial cells transform into a type of stem-like cell that helps organs develop and repairs damaged tissue. Both inflammation and EMT are necessary processes in healthy tissue. However, in cancer, both processes become overactive. Excessive inflammatory cytokines can stimulate cancer growth, treatment resistance, immune suppression and changes to normal tissue function. Overactive EMT can similarly suppress the immune system, enhance cancer resistance to therapy and transform cancer into a more invasive tumor capable of spreading to distant parts of the body.
Gan had previously done research showing that blocking the MK2 pathway in tumor cells engrafted into mice could sensitize them to the effects of radiation, reduce inflammation and slow down tumor metastasis. The next step was testing whether blocking the MK2 pathway would have the same result in humans. The question was how.
That's what led to his interest in ATI-450, an investigational oral compound produced by Aclaris. ATI-450 inhibits MK2, and had already been through a Phase 1 trial to assess its safety in healthy people.
Gan knew immediately that he wanted to test its use in sensitizing cancer to radiation and chemotherapy.
"I thought this was a perfect opportunity. This company has this new super-cool drug that could potentially benefit my cancer patients," he said. "But when I spoke to the company, they indicated that they were going to be focusing on evaluating the drug for rheumatoid arthritis."
That was in January.
In March, Gan was home reading about the coronavirus when he realized something: patients with severe COVID-19 infections experience abnormally high levels of inflammation that lead to rapid lung deterioration and the need to be put on a ventilator. Interestingly, the inflammatory cytokines Gan had been studying in cancer were the same ones in COVID-19, which led him to surmise that the MK2 pathway might similarly be activated. That overactive immune response, commonly known as a "cytokine storm," damages the lungs and is a major reason that some COVID-19 patients develop acute respiratory distress syndrome and do not survive.
Excited as he realized ATI-450 might be a potential treatment for hospitalized patients with COVID-19, Gan reached out to Polineni and asked her to collaborate with him. Gan had heard her deliver a presentation and knew about her research in CF, inflammation and lung function.
Polineni had spent years studying differences in inflammatory responses in people with chronic lung disease in CF, and how these differences correlate with better or worse outcomes.
"The same cytokines this drug targets are also important to the inflammatory processes of lung disease I study in CF," said Polineni. "In the setting of infection, even with a virus like SARS-CoV-2 [the virus that causes COVID-19], some inflammation is required to aid in clearing infection, but a hyper-inflammatory response can lead to accelerated lung injury and worsened outcomes. When Greg approached me, trials of cytokine inhibition had just recently commenced in COVID-19. While a precedent had been set, ATI-450 further represented a novel therapeutic opportunity with an expanded profile of cytokine inhibition mirroring key players in COVID-19. I told him, ‘It makes sense.'"
Together, the two researchers reached out to Aclaris about supporting a clinical trial to evaluate the potential of ATI-450 to treat people hospitalized with COVID-19, in conjunction with standard-of-care treatment.
This time, the answer was an enthusiastic "yes."
Gan and Polineni then had to work quickly to get approval from the Food and Drug Administration to use the drug in a clinical trial, a feat they accomplished in just six weeks after designing the protocol for the trial.
"This kind of collaboration between the KU Cancer Center and the KU School of Medicine's Department of Internal Medicine — engaging partnerships of faculty and study teams across all levels — isn't new, but it's something that I, as a CF researcher, and Dr. Gan, who hasn't been at KU long, hadn't had the chance to participate in before," noted Polineni. "It's been wonderful to see what we can do working together."
Cool collaborations
The phase-2 trial will evaluate the safety and efficacy of ATI-450 in patients who are hospitalized with COVID-19, in conjunction with standard-of-care treatment, and see if the drug can abate respiratory failure in these patients and reduce the likelihood that they will need to be put on a ventilator. Ventilators are necessary for the sickest of the sick, and those patients often need them for weeks. Unfortunately, many who need them do not survive.
ATI-450 is not the only cytokine-inhibiting drug being tested to treat COVID-19, but many potential treatments target a single type of cytokine. Because ATI-450 attacks multiple types of cytokines, the researchers surmise it may have more of an impact.
For this trial, the goal is to enroll 36 patients at least 18 years of age who are hospitalized with COVID-19 and have respiratory symptoms. (There are some rare cases of COVID-19 that have cardiac involvement but little respiratory involvement.) The participants will be consenting patients being treated at The University of Kansas Health System.
Half the patients will be randomized to receive the drug, and half will be randomized to receive a placebo. All patients will receive standard-of-care treatment during the trial, in addition to the drug or placebo. The researchers are primarily interested in the proportion of patients who are not suffering from respiratory failure at the end of 14 days.
They will also be taking blood samples to measure cytokine levels so that they can correlate those levels with the patients' condition at the end of the trial. In addition, Gan and Polineni, who were able to return to their labs in May, will be doing further lab work on those blood samples to see what's happening to specific cell types, such as neutrophils, mononuclear cells, and T-cells, that are involved in the body's immune response.
If this trial shows Gan and Polineni that ATI-450 can be effective at stopping the progression of COVID-19 and keeping people from needing mechanical ventilation, the investigators will be discussing next steps with Aclaris regarding the clinical development of this drug as a potential treatment for inpatients with COVID-19.
The researchers also plan to use what they learn from the trial to inform their other, separate research projects on cancer and CF.
"As physicians, we always want to advance the public good, and as scientists, we want to remain productive. All the lessons we're going to learn from studying COVID-19 will hopefully help us design smarter studies in our respective areas and tell us a little bit more about the drug that we're studying," said Gan. "And that is, I think, the best I could have hoped for in the middle of a pandemic crisis."