City of Hope physicians/scientists lead multiple, innovative COVID-19 research projectsMay 21, 2020
Chimeric antigen receptor (CAR)-NK cell therapy to treat the virus is one of more than two dozen COVID-19 research projects underway
DUARTE, Calif. — As City of Hope’s research on finding better treatments for cancer and diabetes continues during the COVID-19 pandemic, the institution’s renowned physician-scientists and basic 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.
Developing a COVID-19 vaccine with “naked DNA”
Larry W. Kwak, M.D., Ph.D., deputy director of City of Hope’s comprehensive cancer center and the Dr. Michael Friedman Professor of Translational Medicine, and his team are developing a COVID-19 vaccine that builds on one he pioneered for the treatment of lymphoma.
“We have a vested interest in preventing COVID-19 because most, if not all, of our patients are immunosuppressed and therefore, extremely vulnerable to this infection,” he said. “It touches directly on our mission of curing cancer.”
Kwak's previous experience developing a lymphoma vaccine, which showed positive results in a clinical trial, is expected to cut a faster path to clinical trials if his team’s efforts against the coronavirus find success.
“What gives us a speed advantage is that the basic delivery platform has already been allowed by the FDA,” said Kwak, who also is director of the Toni Stephenson Lymphoma Center within the Hematologic Malignancies and Stem Cell Transplantation Institute at City of Hope. “We’ll probably save about a year because we have the clinical vector in hand.”
Kwak’s prospective COVID-19 vaccine will work like many others by introducing elements of an infectious microbe to a person’s system so that the body’s natural defenses can recognize and destroy the invader. In this case, his technology deploys “naked DNA” — the source code of life — to fight disease.
His team will fuse genetic material that encodes proteins from the coronavirus with a sequence that encodes a type of immune molecule called a chemokine. The small proteins in this family serve to attract immune cells, mustering them to the site of infection, for instance. The engineered hybrid DNA would be delivered with an injection under the skin.
This approach is expected to impart two key advantages: speed of development and safety of delivery.
The payload for Kwak’s platform will rely upon the latest information from other research groups that are unraveling the genetic code of the coronavirus, as well as its mutated variations. Any lab looking to produce a vaccine would need to screen many coronavirus protein candidates in preclinical studies, searching for the most effective version. For Kwak’s team, switching out genetic sequences at this stage can be accomplished swiftly.
“This is high-throughput,” Kwak said. “Because it’s naked DNA, we can manipulate it very quickly to come up with the best candidate.”
Chimeric antigen receptor (CAR) natural killer (NK) cells to treat COVID-19
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 and Stem Cell Transplantation Institute, Michael Caligiuri, M.D., 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 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 TGen North investigators Paul Keim, Ph.D., and Bridget Barker, Ph.D., are also involved in the research.
An antiviral therapy to prevent COVID-19 from becoming full-blown
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 FDA 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.
Additional COVID-19 research at City of Hope
City of Hope’s scientists/doctors, as well as its affiliate Translational Genomics Institute (TGen) in Phoenix, Arizona, are conducting additional COVID-19 research. One collaboration is led by City of Hope's John Zaia, M.D., director of City of Hope's Center for Gene Therapy, and funded by the California Institute for Regenerative Medicine. Zaia will lead a clinical study to administer blood plasma from recovered COVID-19 patients to treat those with the virus. Zaia, the Aaron D. Miller and Edith Miller Chair for Gene Therapy is also collaborating with TGen to develop a COVID-19 virus antibody neutralization test.
To control the spread of COVID-19, City of Hope scientists and their colleagues at other institutions are using a 25-year-old landmark study — the California Teachers Study (CTS), originally developed to track breast cancer — to unearth new data on the pandemic. Having access to historical data on up to 133,477 study participants enables researchers to adjust for confounding risk factors such as diabetes, cancer and heart conditions so that a crisp image of COVID-19 is developed: where it’s spreading, who it’s affecting and their health outcomes. The seventh CTS study survey will also take place this fall and collect answers on COVID-19-related and healthy aging questions.
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About City of Hope
City of Hope is an independent biomedical research and treatment center for cancer, diabetes and other life-threatening diseases. Founded in 1913, City of Hope is a leader in bone marrow transplantation and immunotherapy such as CAR T cell therapy. City of Hope’s translational research and personalized treatment protocols advance care throughout the world. Human synthetic insulin and numerous breakthrough cancer drugs are based on technology developed at the institution. A National Cancer Institute-designated comprehensive cancer center and a founding member of the National Comprehensive Cancer Network, City of Hope is the highest ranked cancer hospital in the West, according to U.S. News & World Report’s Best Hospitals: Specialty Ranking. Its main campus is located near Los Angeles, with additional locations throughout Southern California. For more information about City of Hope, follow us on Facebook, Twitter, YouTube or Instagram.