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

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Grant Award Details

Grant Type:

Discovery Research Projects

Grant Number:

DISC2COVID19-11947

Investigator(s):

Name:

Dr Jianhua Yu

Institution:

City of Hope, Beckman Research Institute

Type:

Disease Focus:

COVID-19, Infectious Disease

Human Stem Cell Use:

Adult or Tissue Stem Cell

Award Value:

$150,000

Status:

Closed

Progress Reports

Reporting Period:

Year 1

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.

Grant Application Details

Application Title:

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

Public Abstract:

Research Objective

To develop and characterize meACE-2-CAR-IL15 NK cells expressing a mutated ACE2 and IL-15, allowing specific killing of SARS-CoV-2-infected cells and long in vivo persistence of the engineered cells.

Impact

To provide a timely, novel, and effective cell therapy for COVID-19, which has no FDA-approved vaccines and only remdesivir has received an emergency-use approval.

Major Proposed Activities

To further optimize expansion of umbilical cord blood (UCB) hematopoietic stem cells (HSCs) and engineer the expanded with the meACE2-CAR-IL15 retrovirus.
To differentiate UCB HSCs transduced with meACE2-CAR-IL15 into NK cells, followed by cell expansion.
Proof of concept: In vitro evaluation of meACE2-CAR-IL15 NK cells.
Proof of concept: In vivo evaluation of meACE2-CAR-IL15 NK cells.
Manuscript submission for publication & preparation for an INTERACT meeting with the FDA.
N/A

Statement of Benefit to California:

SARS has presented as a major public health threat in the past. A new SARS, COVID-19, started in December 2019 has rapidly disseminated to worldwide including California with mortality as high as 20% in the elderly and other more vulnerable populations. At present, worldwide COVID-19 patients have over 3.6 million with over 250,000 deaths. Currently, there are no approved COVID-19 vaccines and only remdesivir has received an FDA-approval for the treatment of COVID-19.