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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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COVID-19

Intervention / Treatment
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* Biological: NK cells,IL15-NK cells,NKG2D CAR-NK cells,ACE2 CAR-NK cells,NKG2D-ACE2 CAR-NK cells


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NK cells<br>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<br>* The CAR-NK cells are universal off the shelf NK cells enriched from umbilical cord blood and engineered genetically.<br>|
| Experimental: IL15-NK cells<br>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<br>* The CAR-NK cells are universal off the shelf NK cells enriched from umbilical cord blood and engineered genetically.<br>|
| Experimental: NKG2D CAR-NK cells<br>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<br>* The CAR-NK cells are universal off the shelf NK cells enriched from umbilical cord blood and engineered genetically.<br>|
| Experimental: ACE2 CAR-NK cells<br>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<br>* The CAR-NK cells are universal off the shelf NK cells enriched from umbilical cord blood and engineered genetically.<br>|
| Experimental: NKG2D-ACE2 CAR-NK cells<br>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<br>* The CAR-NK cells are universal off the shelf NK cells enriched from umbilical cord blood and engineered genetically.<br>|

What is the study measuring?
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Primary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NKG2D-ACE2 CAR-NK, IL15 superagonist, GM-CSF-neutralizing scFv, COVID-19