An NCI-designated Comprehensive Cancer Center
By Letisia Marquez | May 29, 2020
As City of Hope’s research to find better treatments for cancer and diabetes continues during the COVID-19 pandemic, the institution’s renowned physician-scientists are also using their expertise to attack the deadly virus on multiple research fronts.
 
“As City of Hope physician-scientists who both lead research against deadly viruses with similarities to COVID-19 and treat cancer patients with weakened immune systems, we are using our expertise to drive innovative COVID-19 research that we hope will lead to new treatments and prevention against the virus,” said Steven Rosen, M.D., City of Hope’s provost and chief scientific officer and the Morgan & Helen Chu Director’s Chair of the Beckman Research Institute. “City of Hope is working tirelessly to contribute to the world’s fight against this dangerous virus.”
 
Research efforts include developing two potential COVID-19 vaccines, testing possible new therapies and finding better screening/testing approaches.
 
One vaccine is being developed by Don Diamond, Ph.D., viral immunologist with City of Hope’s Department of Immuno-Oncology. Larry W. Kwak, M.D., Ph.D., deputy director of City of Hope’s comprehensive cancer center and the Dr. Michael Friedman Professor in Translational Medicine, is working on a unique DNA-based vaccine that builds on one he developed for lymphoma.

Harnessing natural killer cells

Natural killer (NK) cells comprise a group of innate immune cells that can attack cancer and viral infections, and City of Hope scientists are investigating if they can work against COVID-19.
 
Patients infected with the virus lose their immune system’s ability to attack the virus, and their percentage of NK cells also decreases.
 
One research team has engineered NK cells with both IL-15 (a cytokine that ensures long persistence of NK cells) and a CAR (“a set of eyes”) targeting the virus’s "spike" protein. ACE2, found on the surface of SARS-CoV-2 infected cells, which cause COVID-19, also was added to the NK cells so the CAR could recognize the virus and kill it.
 
The team is led by Jianhua Yu, Ph.D., City of Hope’s founding director of the Natural Killer Cell Biology Research Program within the Hematologic Malignancies Research Institute; Michael Caligiuri, M.D., the Deana and Steve Campbell Physician-in-Chief Distinguished Chair and president of City of Hope National Medical Center; and John Williams, Ph.D., professor in City of Hope’s Department of Molecular Medicine.
 
“If my lung cells are infected with the virus, the spike protein may come out on these cells’ surface,” Yu said. “Because the NK cell now has ACE2 on its surface, the CAR can find the spike protein and destroy those cells before it has the chance to spread throughout the body and make the patient sick.”
 
Yu emphasized that this type of treatment would need to be used as soon as patients become infected with COVID-19. The treatment could be crucial in treating patients who are at an increased risk of developing serious complications from COVID-19, including cancer patients and the elderly.

Blocking the Virus’s Male Spike

COVID-19 appears to be deadlier in men than women, according to global data. Although COVID-19 enters through the respiratory tract, the infection may quickly become amplified in other parts of our body. In fact, a male’s testicles, prostate, kidneys and other organs have high expression levels of the enzyme ACE2 (compared with the ovaries, which have low levels of ACE2 expression).
 
The culprit in this escalation is called coronavirus spike glycoprotein, which uses ACE2 for entry into cells like a burglar uses an open window.
 
Led by Yu with Caligiuri as a co-investigator, scientists are using COVID-19 survivors' B cells, and a type of lymphocyte, to make antibodies that would block the spike glycoprotein from locking onto ACE2.
 
“The thinking is COVID-19 survivors’ B cells must have made antibodies against the virus,” Caligiuri said. “We are testing a variety of antibodies to determine which could block the spike from latching onto ACE2.”
 
Next steps include laboratory testing of effective antibodies. A clinical trial testing those antibodies in patients could occur within the year.
 
Williams and Translational Genomics Research Institute investigators Paul Keim, Ph.D., and Bridget Barker, Ph.D., are also involved in the research.

antiviral therapy

City of Hope’s Kevin Morris, Ph.D., is working on an antiviral therapy that one day could be taken by patients infected with COVID-19 when they first start to show symptoms. This could prevent the disease from becoming full-blown — similar to what Tamiflu does for the common flu.
 
The therapy could also be used later on to decrease viral infection and, as a result, lessen the inflammation that makes it necessary for COVID-19 patients to be put on respirators, said Morris, professor and associate director of City of Hope’s Center for Gene Therapy.
 
“While most scientists are developing therapies that target COVID-19 symptoms, our group is focused on the source of the problem: the SARS-CoV-2 virus,” Morris said. “The bottom line is it may take a year or longer to develop a vaccine, but a molecular therapy could potentially be available to people who need it much sooner, and it would be a lot less expensive to develop.”
 
The innovative approach the Morris lab is working on would engineer nanoparticles to be delivered through the nose or intravenously so that they home in on the lungs, where the new coronavirus appears to do the most damage. This treatment would target up to three distinct regions of the SARS-CoV-2 RNA simultaneously, enhancing potency while limiting the virus’s potential to evolve resistance against the treatment. By targeting the Achilles’ heel of SARS-CoV2, a conserved region in the virus required for viral replication, the treatment could inhibit the growth and spread of viral genes — ultimately containing the disease within a box that continually shrinks until the virus is completely dead.
 
As a next step, the Morris lab will determine how potent the therapy is, as well as the potential dosage and side effects. By June, he expects to have collected enough data to apply for Food and Drug Administration approval for clinical trials. With more research, this platform could prove useful as a next-generation targeted lung therapy that goes well beyond SARS-CoV-2 viral infection and could be used to treat other RNA viruses that can cause an epidemic such as MERS, SARS, Zika or Ebola.

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