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

Phase 1

• Conditions: COVID-19
• Interventions: Biological: NK cells,IL15-NK cells,NKG2D CAR-NK cells,ACE2 CAR-NK cells,NKG2D-ACE2 CAR-NK cells

• Registration Number: NCT04324996
• Lead Sponsor: Chongqing Public Health Medical Center

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2020-02-21
• Study First Submitted: 2020-03-25
• Study First Submitted QC: 2020-03-25
• Study First Posted: 2020-03-27
• Status Verified: 2020-11
• Last Update Submitted: 2020-11-16
• Last Update Posted: 2020-11-17
• Primary Completion: 2022-02-20
• Study Completion: 2022-08-31

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 90

Inclusion Criteria

1. Sign written informed consent;
2. Age ≥18 years;
3. 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;
4. The course of disease is within 14 days after the onset of illness;
5. Willing to collect nasopharyngeal or oropharyngeal swabs before administration.

Exclusion Criteria

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
ACE2 CAR-NK cells	NK cells,IL15-NK cells,NKG2D CAR-NK cells,ACE2 CAR-NK cells,NKG2D-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).
NK cells	NK cells,IL15-NK cells,NKG2D CAR-NK cells,ACE2 CAR-NK cells,NKG2D-ACE2 CAR-NK cells	The NK cells are going to be give by intravenous infusion (10E8 cells per kilogram of body weight, once a week) .
IL15-NK cells	NK cells,IL15-NK cells,NKG2D CAR-NK cells,ACE2 CAR-NK cells,NKG2D-ACE2 CAR-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) .
NKG2D-ACE2 CAR-NK cells	NK cells,IL15-NK cells,NKG2D CAR-NK cells,ACE2 CAR-NK cells,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).
NKG2D CAR-NK cells	NK cells,IL15-NK cells,NKG2D CAR-NK cells,ACE2 CAR-NK cells,NKG2D-ACE2 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).

Primary Outcome Measures

Name	Time	Method
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

Trial Locations

Locations (1)

Chongqing Public Health Medical Center; 🇨🇳 Chongqing, China