Natural killer (NK) cells engineered with chimeric antigen receptor (CAR) cells to better fight COVID-19

City of Hope researchers have engineered an immunotherapy using natural killer cells with a specific molecule that can target the SARS-CoV-2 virus’ spike protein, providing a novel therapeutic pathway for the treatment of COVID-19 and other infections that include the spike protein, according to a study published in Nature Communications. The research adds to City of Hope’s leadership in using CAR T cell therapy, natural killer cells and other immunotherapies to help find better treatments against cancer and other diseases.

“The importance of this off-the-shelf therapy is that one does not need to use one’s own cells — the cells can be frozen and ready to go, locally or shipped anywhere around the world,” said Michael Caligiuri, M.D., president of City of Hope National Medical Center, the Deana and Steve Campbell Physician-in-Chief Distinguished Chair and one of the study’s authors.

Natural killer (NK) cells are lymphocytes in the body that recognize and rapidly target abnormal cells, including cells infected with viruses. Although NK cells are universal killers in the body’s immune response against certain viruses or tumors, they lack specificity against SARS-CoV-2. Studies have revealed that COVID-19 patients have significantly decreased numbers of NK cells. However, in this study, City of Hope researchers show that genetically modifying the NK cells with a chimeric antigen receptor or CAR that specifically “sees” the SARS-CoV-2 virus improves survival in animals infected with the virus.

The preclinical research study was led by Caligiuri and Jianhua Yu, Ph.D., City of Hope professor and director of the Natural Killer Cell Biology Research Program. Together, they have nearly 55 years of collective laboratory investigation of NK cells.

“Sadly, more than 1 million Americans have died from COVID-19. Therefore, more effective therapies are still needed,” Yu said. “Cellular immunotherapies for COVID-19 patients have not been approved yet, but they could be beneficial because they harness existing immunity to fight disease.”

For the study, the team isolated NK cells from umbilical cord blood and used them to manufacture CAR-NK cells. These cells were then engineered to express ACE2 receptors, a protein that the virus sees and attaches to in order to enter a cell. The CAR-NK cells use this ACE2 receptor to attach to the spike protein of SARS-CoV2, and then unleash their attack on the virus.

To prolong the survival of the NK cells, which typically have a short lifespan, the research team also engineered the CAR-NK cells to release IL-15, an immune hormone that can prolong NK cell survival in the body.

Next, the team administered the engineered NK cells to humanized mice infected with live SARS-CoV-2. The results showed a reduced viral load and prolonged survival in the animal models. The team also tested the same cells after cryopreserving, or freezing, them and found that they retained their activity. This finding, along with the global abundance of public umbilical cord blood banks for sourcing donor NK cells, would make the therapy more viable as an off-the-shelf therapy for COVID-19 patients.

“Our human CAR-NK cell product proved successful against COVID-19 in preclinical research,” Yu said. “Furthermore, this novel, ready-to-use immunotherapeutic approach for treating SARS-CoV-2 infection could possibly be used against future SARS outbreaks and other spike-expressing viruses.”

Still, there is much work to be done to ensure that the treatment is safe, well-tolerated and effective in humans, although now over 30 patients have received genetically modified NK cells for the treatment of cancer without serious, life-threatening side effects, Caligiuri noted. The research team hope to gain clearance to use their CAR-NK cell product in moderate to high-risk patients infected with SARS-CoV-2 in the near future.

About City of Hope

City of Hope's mission is to deliver the cures of tomorrow to the people who need them today. Founded in 1913, City of Hope has grown into one of the largest cancer research and treatment organizations in the U.S. and one of the leading research centers for diabetes and other life-threatening illnesses. As an independent, National Cancer Institute-designated comprehensive cancer center, City of Hope brings a uniquely integrated model to patients, spanning cancer care, research and development, academics and training, and innovation initiatives. Research and technology developed at City of Hope has been the basis for numerous breakthrough cancer medicines, as well as human synthetic insulin and monoclonal antibodies. A leader in bone marrow transplantation and immunotherapy, such as CAR T cell therapy, City of Hope’s personalized treatment protocols help advance cancer care throughout the world.

With a goal of expanding access to the latest discoveries and leading-edge care to more patients, families and communities, City of Hope’s growing national system includes its main Los Angeles campus, a network of clinical care locations across Southern California, a new cancer center in Orange County, California, scheduled to open in 2022, and Cancer Treatment Centers of America. City of Hope’s affiliated family of organizations includes Translational Genomics Research Institute and AccessHope^TM. For more information about City of Hope, follow us on Facebook, Twitter, YouTube, Instagram and LinkedIn.

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