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

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ClinicalTrials.gov Identifier: NCT04324996
Recruitment Status : Recruiting
First Posted : March 27, 2020
Last Update Posted : March 27, 2020
Sponsor:
Collaborator:
Chongqing Sidemu Biotechnology Technology Co.,Ltd.
Information provided by (Responsible Party):
Chongqing Public Health Medical Center

Tracking Information
First Submitted Date  ICMJE March 25, 2020
First Posted Date  ICMJE March 27, 2020
Last Update Posted Date March 27, 2020
Actual Study Start Date  ICMJE March 21, 2020
Estimated Primary Completion Date May 31, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 25, 2020)
  • Clinical response [ Time Frame: 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 [ Time Frame: 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
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Phase I/II Study of Universal Off-the-shelf NKG2D-ACE2 CAR-NK Cells for Therapy of COVID-19
Official Title  ICMJE 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
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 Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE COVID-19
Intervention  ICMJE 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.
Study Arms  ICMJE
  • Experimental: NK cells
    The NK cells are going to be give by intravenous infusion (10E8 cells per kilogram of body weight, once a week) .
    Intervention: Biological: NK cells,IL15-NK cells,NKG2D CAR-NK cells,ACE2 CAR-NK cells,NKG2D-ACE2 CAR-NK cells
  • 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) .
    Intervention: Biological: NK cells,IL15-NK cells,NKG2D CAR-NK cells,ACE2 CAR-NK cells,NKG2D-ACE2 CAR-NK cells
  • 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).
    Intervention: Biological: NK cells,IL15-NK cells,NKG2D CAR-NK cells,ACE2 CAR-NK cells,NKG2D-ACE2 CAR-NK cells
  • 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).
    Intervention: Biological: NK cells,IL15-NK cells,NKG2D CAR-NK cells,ACE2 CAR-NK cells,NKG2D-ACE2 CAR-NK cells
  • 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).
    Intervention: Biological: NK cells,IL15-NK cells,NKG2D CAR-NK cells,ACE2 CAR-NK cells,NKG2D-ACE2 CAR-NK cells
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 25, 2020)
90
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 30, 2020
Estimated Primary Completion Date May 31, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Min Liu, A.B 13668072999 gwzxliumin@foxmail.com
Contact: Jimin Gao, PhD 0577-86699341 jimingao64@163.com
Listed Location Countries  ICMJE China
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04324996
Other Study ID Numbers  ICMJE ChongqingPublicHMC
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Chongqing Public Health Medical Center
Study Sponsor  ICMJE Chongqing Public Health Medical Center
Collaborators  ICMJE Chongqing Sidemu Biotechnology Technology Co.,Ltd.
Investigators  ICMJE
Principal Investigator: Min Liu, A.B Chongqing Public Health Center
PRS Account Chongqing Public Health Medical Center
Verification Date March 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP