Persistent Off-the-Shelf meACE2-CAR-IL-15 NK Cells Derived from CD34(+) Cord Blood Stem Cells to Prevent and Treat COVID-19

The novel coronavirus disease (COVID-19), caused by SARS-CoV-2, has escalated to a pandemic and effective therapies are still needed. Although vaccines and therapeutics are available, the pandemic is still ongoing and becoming worse in some countries. One of the most promising new therapies is immunotherapy; however, it has not been developed for COVID-19 treatment. One immunotherapy that has shown promise in the clinic is genetically-modified natural killer (NK) cells with a molecule on its surface called a chimeric antigen receptor (CAR), referred to as CAR-NK cells. The CAR-NK cells that we made can seek and specifically destroy SARS-CoV-2-infected cells, while sparing normal cells. By expressing a CAR molecule on its surface, NK cells can specifically recognize a viral protein present on SARS-CoV-2-infected cells. Cord blood is a rich source of stem cells that can be used to make CAR-NK cells. While being more effective and less toxic than other CAR-immune cell therapies, another advantage is that the cells can be made ahead of time and frozen for storage, thus providing an “off-the-shelf” therapy for patients with virus infections such as COVID-19. One cord blood donation can generate many doses of CAR-NK cell therapy for hundreds of patients, which dramatically reduces costs. In our study, we generated ready-to-use CAR-NK cells specific for targeting SARS-CoV-2 infection, which we found are potent in killing SARS-CoV-2-infected cells in test tubes as well as in mice. Approximately half of SARS-CoV-2-infected mice treated with our CAR-NK cells recover completely, while all infected mice without the treatment die quickly with COVID-19 symptoms. We hope our CAR-NK cells will be translated into the clinic to treat severe COVID-19 patients or prevent infection. Our frozen, ready-to-use CAR-NK cell strategy may not only help limit the current pandemic but should also be suitable for a subsequent pandemic involving another coronavirus expressing the same surface molecule on infected cells.