Cancer clinicians use their expertise to tackle the COVID-19 pandemic
April 20, 2020
An over-active immune response may contribute to the severity of illness experienced by some COVID-19 patients. In this era of fighting cancer with immunotherapy, cancer clinicians are applying their understanding of the immune system to the battle against the coronavirus. These physician-scientists have been ushered to the frontline and are using their knowledge to launch COVID-19 clinical trials in record time.
The University of Chicago Medicine Comprehensive Cancer Center is leading studies to understand the dramatically varied immune responses to this disease and collaborating on multiple treatment strategies to reduce the number of patients progressing to severe COVID-19 — including the testing of drugs that are currently approved for use in cancer patients.
Cancer clinicians understand two truths about the immune response, learned from treating cancer patients. First, the immune response is extremely diverse between individuals, due to genetic and environmental differences. Second, the immune response maintains a careful balance – a tightrope walk between an incomplete or excessive response. This understanding has placed these investigators in a unique position to steer lifesaving clinical trials for COVID-19 patients.
Mystifying variations in severity of COVID-19
Why do people have such different responses to COVID-19? Infected individuals range from asymptomatic, to moderate, to severe disease requiring intensive care and ventilation. The diverse reactions to infection are a result of complex environmental and genetic factors. Understanding the diversity of responses can help guide treatments now and provide a stronger base of knowledge in the event of a future pandemic.
To answer this question, medical oncologist Thomas F. Gajewski, MD, PhD, is leading a newly approved study to track and characterize the immune response of patients enrolled in COVID-19 drug trials. Gajewski and colleagues are collecting samples from patients to examine the levels of circulating cytokines, the molecules that trigger inflammation, and characterize their immune cells to see how these factors relate to a patient’s ability to fight the virus and respond to therapies.
“This translational research study is an outstanding example of the team science capabilities at UChicago Medicine, involving dozens of investigators with expertise in immunology, human genetics, clinical trial management, disease biomarkers, the microbiome, respiratory medicine and data science,” Gajewski said.
In addition to immune profiling of patients, this in-depth study will determine how other factors correlate with disease severity. The levels of virus-attacking antibodies will be measured. Gene expression analysis will be performed on patient immune cells to further characterize individual responses. Also, genetic tests will uncover differences in patient DNA that impact response. Each of these components will provide insight as to why patients have widely variable susceptibility to COVID-19.
Environmental factors will be taken into account as well. Since there is evidence that the bacteria in the normal lung can be helpful or harmful in cases of viral lung infections, the make-up of bacteria, or microbiota, in the airways and lungs will be analyzed. This extensive data will provide evidence as to whether treatments that alter the lung microbiota might improve outcomes.
Patients who are providing samples to the biobanking study may also take part in one of the treatment trials at UChicago Medicine. Ongoing trials for potential medications include testing different approaches to inhibit an over-activated immune respons and an investigational anti-viral drug. Each patient will be monitored closely, and their immune response will be analyzed to provide the best care for individuals and gain information to guide treatment for all patients.
Severe COVID-19 linked to an over-active immune response
During the severe immune response caused by some coronaviruses, the rapidly replicating virus triggers a massive inflammatory response in the lungs, including cytokine production and immune cell activation, resulting in extensive lung damage that can lead to difficulty breathing. In some patients, an overactive immune response can do more damage than the viral infection, causing damage to the lungs and even to other organs. This extreme immune response caused by COVID-19 is referred to as a cytokine storm, or cytokine release syndrome (CRS).
Cancer clinicians are all too familiar with CRS because it has been seen in cancer patients who receive immunotherapy. They predict that drugs used to treat CRS in cancer patients may also save the lives of patients with COVID-19. The hope is that treatments that suppress an unrelenting immune response may be able to reduce the number of patients needing critical care and ventilation and, ultimately, reduce deaths.
Tocilizumab blocks cytokine release syndrome in cancer patients
High levels of the inflammatory cytokine interleukin (IL)-6, are characteristic of CRS. Certain cancer treatments, such as CAR T-cell therapy, also cause CRS in patients, causing similar symptoms, including severe lung inflammation. Tocilizumab is an existing drug that successfully blocks IL-6 activity and is currently used to treat cancer patients with hyperinflammation following CAR T-cell therapy and has shown promise in the treatment of CRS and lung inflammation caused by COVID-19.
The trial is for hospitalized patients who are not in intensive care. The hope is that blocking an over-active immune response will aid in recovery and prevent patients from becoming critically ill and requiring ventilation. In addition to showing if tocilizumab can rapidly reduce COVID-19 symptoms, this trial will improve understanding of the role of IL-6 and the inflammatory response in COVID-19 disease.
Hydroxychloroquine — an anti-inflammatory drug used to treat auto-immune disease
Hydroxychloroquine inhibits production of inflammatory cytokines by immune cells, and overall immune cell activity, but in a non-specific, non-targeted fashion. It is currently used to treat lupus and rheumatoid arthritis, both auto-immune diseases. Hydroxychloroquine is thought to function by reducing activation of the immune system, and also may inhibit replication of the virus.
A clinical trial led by rheumatologist Reem Jan, MD, is testing hydroxychloroquine in COVID-19 patients. Ratain and Gajewski are also co-investigators on this study.
This trial is treating patients in the outpatient setting when disease is not yet severe, with the goal of preventing hospitalization. Patients are receiving a high dose for a short term with the hope of achieving a rapid response.
Remdesivir inhibits viral replication
Remdesivir is an anti-viral drug with low toxicity that has been tested against Ebola, SARS and MERS. Researchers hypothesize that remdesivir can help patients with COVID-19 rapidly defeat the virus.
Clinical trials led by Kathleen Mullane, DO, PharmD, an expert in the diagnosis and treatment of infections in immunocompromised patients, is testing the use of remdesivir in two different trials – one for patients with moderate disease and another for patients with severe COVID-19.
Each of these COVID-19 treatment trials at UChicago Medicine will provide samples from patients to be analyzed in the immune profiling study led by Gajewski. The comprehensive investigation of diverse responses to the virus and to treatments will help all patients receive the best options for care now and will have a long-term impact on improving treatments for all people.