A Phase I/II Study of Universal Off-the-shelf NKG2D-ACE2 CAR-NK Cells for Therapy of COVID-19

Sponsor

Chongqing Public Health Medical Center (Other)

Overall Status

Recruiting

CT.gov ID

NCT04324996

Collaborator

Chongqing Sidemu Biotech (Other), Zhejiang Qixin Biotech (Other)

Enrollment

Location

Arms

30.3

Anticipated Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

SARS-CoV-2 infection mainly leads to interstitial pneumonia. The patients with low immunity have more serious conditions. At present, there is no specific drug/therapy available for COVID-19. NK cells are the major cells of the natural immune system, which are essential for innate immunity and adaptive immunity, and are indispensable in the defense of virus infection. NKG2D is an activating receptor of NK cells, which can recognize and thus clear virus infected cells. NK cells modified by CAR play a role in targeted cell therapy, and have benn demonstrated very safe without severe side effects such as cytokine releasing syndromes. The survival time of NK cells will be very short if there is no IL-15-sustained support after adoptive transfer into the body. In comparison with natural IL-15 in vivo, IL-15 superagonist (sIL-15/IL-15Rɑ chimeric protein) has increased the activity by nearly 20 times and as well as improved pharmacokinetic characteristics with longer persistence and enhanced target cytotoxicity. CAR-T cell-mediated cytokine release syndrome (CRS) and neurotoxicity have been shown to be abrogated through GM-CSF neutralization. ACE2 is the receptor of SARS-CoV-2 and binds to S protein of the virus envelope. We have constructed and prepared the universal off-the-shelf IL15 superagonist- and GM-CSF neutralizing scFv-secreting NKG2D-ACE2 CAR-NK derived from cord blood. By targeting the S protein of SARS-CoV-2 and NKG2DL on the surface of infected cells with ACE2 and NKG2D, respectively, and with the strong synergistic effect of IL15 superagonist and CRS prevention through GM-CSF neutralizing scFv, we hope that the SARS-CoV-2 virus particles and their infected cells can be safely and effectively removed, thus providing a safe and effective cell therapy for COVID-19. In addition, ACE2 CAR-NK cells can competitively inhibit SARS-CoV-2 infection of type II alveolar epithelial cells and other important organ or tissue cells through ACE2 so as to make SARS-CoV-2 abortive infection (i.e., no production of infectious virus particles).

This project is an open, randomized, parallel, multicenter phase I/II clinical trial. The NKG2D-ACE2 CAR-NK cells secreting super IL15 superagonist and GM-CSF neutralizing scFv are going to be give by intravenous infusion (108 cells per kilogram of body weight, once a week) for the treatment of 30 patients with each common, severe and critical type COVID-19, respectively.

Condition or Disease	Intervention/Treatment	Phase
COVID-19	Biological: NK cells,IL15-NK cells,NKG2D CAR-NK cells,ACE2 CAR-NK cells,NKG2D-ACE2 CAR-NK cells	Phase 1/Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

90 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

A Phase I/II Study of Universal Off-the-shelf NKG2D-ACE2 CAR-NK Cells Secreting IL15 Superagonist and GM-CSF-neutralizing scFv for Therapy of COVID-19

Actual Study Start Date :

Feb 21, 2020

Anticipated Primary Completion Date :

Feb 20, 2022

Anticipated Study Completion Date :

Aug 31, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: NK cells The NK cells are going to be give by intravenous infusion (10E8 cells per kilogram of body weight, once a week) .	Biological: NK cells,IL15-NK cells,NKG2D CAR-NK cells,ACE2 CAR-NK cells,NKG2D-ACE2 CAR-NK cells The CAR-NK cells are universal off the shelf NK cells enriched from umbilical cord blood and engineered genetically.
Experimental: IL15-NK cells The NK cells secreting super IL15 superagonist are going to be give by intravenous infusion (10E8 cells per kilogram of body weight, once a week) .	Biological: NK cells,IL15-NK cells,NKG2D CAR-NK cells,ACE2 CAR-NK cells,NKG2D-ACE2 CAR-NK cells The CAR-NK cells are universal off the shelf NK cells enriched from umbilical cord blood and engineered genetically.
Experimental: NKG2D CAR-NK cells The NKG2D CAR-NK cells are going to be give by intravenous infusion (10E8 cells per kilogram of body weight, once a week).	Biological: NK cells,IL15-NK cells,NKG2D CAR-NK cells,ACE2 CAR-NK cells,NKG2D-ACE2 CAR-NK cells The CAR-NK cells are universal off the shelf NK cells enriched from umbilical cord blood and engineered genetically.
Experimental: ACE2 CAR-NK cells The ACE2 CAR-NK cells are going to be give by intravenous infusion (10E8 cells per kilogram of body weight, once a week).	Biological: NK cells,IL15-NK cells,NKG2D CAR-NK cells,ACE2 CAR-NK cells,NKG2D-ACE2 CAR-NK cells The CAR-NK cells are universal off the shelf NK cells enriched from umbilical cord blood and engineered genetically.
Experimental: NKG2D-ACE2 CAR-NK cells The NKG2D-ACE2 CAR-NK cells secreting IL15 superagonist and GM-CSF-neutralizing scFv are going to be give by intravenous infusion (10E8 cells per kilogram of body weight, once a week).	Biological: NK cells,IL15-NK cells,NKG2D CAR-NK cells,ACE2 CAR-NK cells,NKG2D-ACE2 CAR-NK cells The CAR-NK cells are universal off the shelf NK cells enriched from umbilical cord blood and engineered genetically.

Outcome Measures

Primary Outcome Measures

Clinical response [Up to 28 days]
the efficacy of NKG2D-ACE2 CAR-NK cells in treating severe and critical 2019 new coronavirus (COVID-19) pneumonia
Side effects in the treatment group [Up to 28 days]
the safety and tolerability of NKG2D-ACE2 CAR-NK cells in patients with severe and critical 2019 new coronavirus (COVID-19) pneumonia

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Sign written informed consent;
Age ≥18 years;
Conforms to the NCP Critical and Critical Diagnostic Standards, namely "Pneumonitis Diagnosis and Treatment Scheme for New Coronavirus Infection (Trial Version 6)". Comprehensive judgment based on epidemiological history, clinical manifestations and etiological examination;
The course of disease is within 14 days after the onset of illness;
Willing to collect nasopharyngeal or oropharyngeal swabs before administration.

Exclusion Criteria:

Patients participating in clinical trials of other drugs;
pregnant or lactating women;
ALT / AST> 5 times ULN, or neutrophils <0.5 * 109 / L, or platelets less than 50 * 109 / L;
Expected survival time is less than 1 week;
A clear diagnosis of rheumatism-related diseases;
Long-term oral anti-rejection drugs or immunomodulatory drugs;
Patients hypersensitive to NK cells and their preservation solution.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Chongqing Public Health Medical Center	Chongqing		China	400036

Sponsors and Collaborators

Chongqing Public Health Medical Center
Chongqing Sidemu Biotech
Zhejiang Qixin Biotech

Investigators

Principal Investigator: Min Liu, A.B, Chongqing Public Health Center
Principal Investigator: Jimin Gao, Zhejiang Qixin Biotech

Study Documents (Full-Text)

None provided.

More Information

Publications

Responsible Party:

Chongqing Public Health Medical Center

ClinicalTrials.gov Identifier:

NCT04324996

Other Study ID Numbers:

ChongqingPublicHMC

First Posted:

Mar 27, 2020

Last Update Posted:

Nov 17, 2020

Last Verified:

Nov 1, 2020

Individual Participant Data (IPD) Sharing Statement:

Plan to Share IPD:

Studies a U.S. FDA-regulated Drug Product:

Studies a U.S. FDA-regulated Device Product:

Keywords provided by Chongqing Public Health Medical Center

NKG2D-ACE2 CAR-NK

IL15 superagonist

GM-CSF-neutralizing scFv

COVID-19

Additional relevant MeSH terms:

COVID-19

Study Results

No Results Posted as of Nov 17, 2020