An NCI-designated Comprehensive Cancer Center
By City of Hope | June 15, 2020
As the total number of COVID-19 cases continues to rise in the U.S., our renowned physician-scientists are taking numerous research approaches to swiftly work toward scientific answers needed to combat this deadly pandemic.

Blocking the Virus’ Male Spike

Researchers are speculating whether high levels of cellular enzyme Angiotensin Converting Enzyme 2 (ACE2) expression in male organs and tissues (the testicles and prostate) in comparison to female organs (ovaries) may be one reason global COVID-19 mortality rates are higher in men than women. Identifying antibodies that will block the target antigen, the viral spike glycoprotein, from attaching to ACE2 and gaining subsequent entry into cells to begin viral replication is the focus of principal investigators Michael Caligiuri, M.D., Deana and Stebe Campbell Physician-in-Chief Distinguished Chair, and Jianhua Yu, Ph.D., founding director of the National Killer Cell Biology Research Program alongside co-investigator John Williams, Ph.D., professor in the Department of Molecular Medicine.
 
Using blood samples from patients who’ve recovered from SARS-CoV-2 infection, the team extracted peripheral blood lymphocytes and began identifying those that were producing specific antibodies against the spike glycoprotein. In order to generate diverse immune antibody phage display libraries, the team is using samples from 12 different donors.
 
The team is also using instrumentation that allows them to shorten the lead time on identifying functional antibody therapeutic candidates. Instead of three to four weeks, the team can “do this overnight. As fast as we can load them onto the instrument, we can get … antibodies against the virus,” said Caligiuri/ president of City of Hope National Medical Center.
 
Using an established hACE2 transgenic mouse model, the group will test the antibodies specificity and efficacy. The City of Hope team is partnering with TGen North and Northern Arizona University to complete this phase of the research. If the team identifies antibodies that prevent viral progression in mice inoculated with the virus, they hope to begin clinical trials within the year.

Developing a New CAR NK Cell Therapy

With one of the most comprehensive chimeric antigen receptor (CAR) T cell programs in the world, City of Hope scientists are well-versed in the methodology of using an immunotherapy to treat cancer. This has allowed our experts to adapt tenets of this approach to develop a treatment for COVID-19. Using natural killer (NK) cells engineered with a CAR for the spike glycoprotein of the SARS-CoV-2 virus and ACE2 surface receptor Caligiuri, Yu and Williams are investigating these cells’ ability to target SARS-CoV-2 or attach to cells infected with the virus and kill it.      
           
Research is currently moving from laboratory testing into mouse models. Since NK cells can be generated en masse and given to anyone, this research may provide an alternative or additional option to other treatments currently being pursued. Yu recently received a grant from the California Institute for Regenerative Medicine that will help further this research.

Developing a COVID-19 Vaccine Using A Proven Platform

To construct a vaccine that will confer protective, long-lasting immunity against the COVID-19 disease, Don J. Diamond , Ph.D., Professor in the Department of Hematology & Hematopoietic Cell Transplantation and co-investigators Flavia Chiuppesi , Ph.D., and Felix Wussow , Ph.D., both research professors, are turning toward a subunit strategy for vaccine development. To generate potential vaccine candidates, the group identifies and makes synthetic copies of immunogenic components of the virus that get inserted into a carrier virus. Vaccine candidates have been built, and pre-clinical studies have been ongoing since March. A manuscript describing the successful strategy will be submitted in June. 
 
The platform has been used by the group in the past to develop a novel Triplex vaccine against cytomegalovirus as well as a therapeutic vaccine against solid tumors. These previous coronavirus studies alongside data from past immunological research have given Diamond’s team an early start in addressing COVID-19. They are slated to begin clinical manufacturing in mid-July and to apply to the FDA for permission for a fall 2020 clinical trial.

Naked DNA Provides a High-Throughput Path Toward a Vaccine

Having spent years pioneering a therapeutic vaccine for the treatment of non-Hodgkin lymphoma and also working on a potential HIV vaccine, Larry W. Kwak , M.D., Ph.D. has the infrastructure in place to quickly move forward with the creation of a vaccine for the novel coronavirus. The group takes DNA sequences that encode SARS-CoV-2 protein and fuses them with a chemokine adjuvant in order to stimulate a strong immune response. Because this type of vaccine relies on genetic sequences rather than live or attenuated virus, there’s no risk of causing viral infection.
 
Since the basic delivery platform has already passed FDA approvals, Kwak hopes to expedite clinical trials since his team already has a clinical vector developed.

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