1. Froelich, Warren

Article Content

Immunotherapy drugs used to treat cancer patients do not increase harmful complications associated with COVID-19 infection, according to preliminary data from researchers at the University of Cincinnati (UC) Cancer Center.

COVID-19. COVID-19... - Click to enlarge in new windowCOVID-19. COVID-19

The early findings-presented during a virtual COVID-19 and Cancer conference by the American Association for Cancer Research (AACR)-conflict with some other studies suggesting that immunotherapy for cancer may predispose an increased risk of hospitalization resulting from COVID-19 infection.


"Many patients with cancer are treated with immunotherapy, which activates the immune system against cancer to destroy it," said Layne Weatherford, PhD, a UC postdoctoral fellow who presented the findings at the AACR meeting. "In patients with both COVID-19 and cancer, our team thought immunotherapy might increase the immune system response, which could already be overactive because of the COVID-19 infection."


Indeed, the UC researchers initially suspected that infection with the SARS-CoV-2, the virus that causes COVID-19, would trigger a "cytokine storm" in patients already being treated with immunotherapy drugs, yielding serious and sometimes fatal complications including respiratory failure. Cytokines are small proteins that coordinate the body's response against infection. But sometimes the body's response goes into hyperdrive, releasing uncontrolled levels of cytokines and inflammation that can harm and even kill the patient.


But contrary to their hypothesis, the team did not see any worsening in the immune response in studies using patient blood samples.


"There was concern that immunotherapy may increase harmful cytokines," said Trish Wise-Draper, MD, PhD, Associate Professor of Medicine in the Division of Hematology and Oncology at the UC College of Medicine. "However, when we used the combination ex vivo, we did not see an increase suggesting the combination did not increase the risk. But, as stated throughout the presentation, the data is early and should be taken as such."


Unlike more traditional treatments that target tumor cells, immunotherapy regimens such as immune checkpoint inhibitors block proteins made by T cells and some cancer cells from binding, unleashing the body's immune system to attack and destroy cancer cells. One class of immunotherapy drug called PD-1 inhibitor (programmed cell death 1) has been linked to cytokine storms alone. PD-1 inhibitors block the interaction between PD-1 checkpoints on immune cells and its ligand PD-L1 (programmed cell death ligand 1) on tumor cells, allowing for the reversal of immune evasion and immune activation, as well as the release of cytokines.


"PD-1 inhibitors have become a mainstay in cancer treatment and recent reports from Memorial Sloan Kettering Cancer Center have suggested increased risk for severe disease if given within 90 days of COVID-19 infection," said Weatherford.


"However, other studies have shown no increased risk involved with immune checkpoint inhibitor treatment on COVID-19 patients," he added in an interview. "So there appears to be 'no slam dunk' paper that could put this idea to rest."


Research Details

To better understand what's happening, the UC team performed several experiments, including ex vivo studies with plasma samples from patients with head and neck cancer taken from the UC COVID-19 biorepository at the UC College of Medicine.


In an early test, the team exposed peripheral blood mononuclear cells (PBMC) (any peripheral blood cell having a round nucleus) from head and neck cancer patients, and healthy controls to the SARS-CoV-2 spike protein, the crown-like protrusion that represents the key point of entry for the virus into a human cell. Following two separate assays taken 6 hours and 24 hours after exposure, both sets of cells exhibited an increase in interleukin-6 (IL-6), considered a critical culprit in a COVID-19 cytokine storm.


The team then performed the same experiment, adding a PD-1 immune checkpoint inhibitor to COVID-19 infected PBMCs, in addition to head and neck cancer cell lines. As with the previous test, the team noted increased secretion of IL-6, with a higher release of the cytokine compared to healthy controls.


Overall, however, the preliminary experiments suggested that anti-PD-1 therapy did not exacerbate or increase IL-6 secretion. Further examination of other important cytokines is under way, the researchers said.


"From our preliminary ex vivo experiments, we believe that immunotherapy is not causing an increase in cytokine levels in COVID-19 patients," said Weatherford, a member of Wise-Draper's lab. "An alternative hypothesis is that immunotherapy could actually be protective against COVID-19 infection since it boosts the immune system.


"There is some evidence in severe COVID-19 disease there are fewer T cells and those still in circulation are exhausted, meaning they have PD-1 expression. Anti-PD-1 therapy could reactivate these exhausted T cells, which could improve the immune response to infection. I'm not aware of this hypothesis being tested yet."


Wise-Draper and Weatherford said they are now examining potential available agents that might decrease inflammatory cytokines. Toward that end, the team is testing to see if an anti-diabetic drug, metformin, can reduce production of cytokines by immune cells of COVID-19 patients.


Prior data from their lab showed that metformin could significantly reduce the secretion of some cytokines that are important for COVID-19 cytokine storm. Preliminary data show that metformin can reduce production of these proteins by immune cells of COVID-19 patients.


"These are promising, initial findings. Additional research is needed, but our results show that we might be able to treat COVID-19 complications with metformin or a similar drug one day," Wise-Draper noted.


Warren Froelich is a contributing writer.