NCT04324996

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.

Trial Health

43
At Risk

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Trial has exceeded expected completion date
Enrollment
90

participants targeted

Target at P50-P75 for phase_1 covid19

Timeline
Completed

Started Feb 2020

Longer than P75 for phase_1 covid19

Geographic Reach
1 country

1 active site

Status
unknown

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

Study Start

First participant enrolled

February 21, 2020

Completed
1 month until next milestone

First Submitted

Initial submission to the registry

March 25, 2020

Completed
2 days until next milestone

First Posted

Study publicly available on registry

March 27, 2020

Completed
1.9 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

February 20, 2022

Completed
6 months until next milestone

Study Completion

Last participant's last visit for all outcomes

August 31, 2022

Completed
Last Updated

November 17, 2020

Status Verified

November 1, 2020

Enrollment Period

2 years

First QC Date

March 25, 2020

Last Update Submit

November 16, 2020

Conditions

COVID-19

Keywords

NKG2D-ACE2 CAR-NKIL15 superagonistGM-CSF-neutralizing scFvCOVID-19

Outcome Measures

Primary Outcomes (2)

  • 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

Study Arms (5)

NK cells

EXPERIMENTAL

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

IL15-NK cells

EXPERIMENTAL

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

NKG2D CAR-NK cells

EXPERIMENTAL

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

ACE2 CAR-NK cells

EXPERIMENTAL

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

NKG2D-ACE2 CAR-NK cells

EXPERIMENTAL

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

Interventions

NK cells,IL15-NK cells,NKG2D CAR-NK cells,ACE2 CAR-NK cells,NKG2D-ACE2 CAR-NK cellsBIOLOGICAL

The CAR-NK cells are universal off the shelf NK cells enriched from umbilical cord blood and engineered genetically.

ACE2 CAR-NK cellsIL15-NK cellsNK cellsNKG2D CAR-NK cellsNKG2D-ACE2 CAR-NK cells

Eligibility Criteria

Age18 Years+
Sexall
Healthy VolunteersNo
Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

  • 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.

You may not qualify if:

  • 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.

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (1)

Chongqing Public Health Medical Center

Chongqing, 400036, China

RECRUITING

Related Publications (12)

  • Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, Si HR, Zhu Y, Li B, Huang CL, Chen HD, Chen J, Luo Y, Guo H, Jiang RD, Liu MQ, Chen Y, Shen XR, Wang X, Zheng XS, Zhao K, Chen QJ, Deng F, Liu LL, Yan B, Zhan FX, Wang YY, Xiao GF, Shi ZL. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020 Mar;579(7798):270-273. doi: 10.1038/s41586-020-2012-7. Epub 2020 Feb 3.

    PMID: 32015507BACKGROUND

  • Wu F, Zhao S, Yu B, Chen YM, Wang W, Song ZG, Hu Y, Tao ZW, Tian JH, Pei YY, Yuan ML, Zhang YL, Dai FH, Liu Y, Wang QM, Zheng JJ, Xu L, Holmes EC, Zhang YZ. A new coronavirus associated with human respiratory disease in China. Nature. 2020 Mar;579(7798):265-269. doi: 10.1038/s41586-020-2008-3. Epub 2020 Feb 3.

    PMID: 32015508BACKGROUND

  • Kuba K, Imai Y, Rao S, Jiang C, Penninger JM. Lessons from SARS: control of acute lung failure by the SARS receptor ACE2. J Mol Med (Berl). 2006 Oct;84(10):814-20. doi: 10.1007/s00109-006-0094-9. Epub 2006 Sep 19.

    PMID: 16988814BACKGROUND

  • Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, Zhao X, Huang B, Shi W, Lu R, Niu P, Zhan F, Ma X, Wang D, Xu W, Wu G, Gao GF, Tan W; China Novel Coronavirus Investigating and Research Team. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med. 2020 Feb 20;382(8):727-733. doi: 10.1056/NEJMoa2001017. Epub 2020 Jan 24.

    PMID: 31978945BACKGROUND

  • Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, Qiu Y, Wang J, Liu Y, Wei Y, Xia J, Yu T, Zhang X, Zhang L. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020 Feb 15;395(10223):507-513. doi: 10.1016/S0140-6736(20)30211-7. Epub 2020 Jan 30.

    PMID: 32007143BACKGROUND

  • Li Q, Guan X, Wu P, Wang X, Zhou L, Tong Y, Ren R, Leung KSM, Lau EHY, Wong JY, Xing X, Xiang N, Wu Y, Li C, Chen Q, Li D, Liu T, Zhao J, Liu M, Tu W, Chen C, Jin L, Yang R, Wang Q, Zhou S, Wang R, Liu H, Luo Y, Liu Y, Shao G, Li H, Tao Z, Yang Y, Deng Z, Liu B, Ma Z, Zhang Y, Shi G, Lam TTY, Wu JT, Gao GF, Cowling BJ, Yang B, Leung GM, Feng Z. Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia. N Engl J Med. 2020 Mar 26;382(13):1199-1207. doi: 10.1056/NEJMoa2001316. Epub 2020 Jan 29.

    PMID: 31995857BACKGROUND

  • Minetto P, Guolo F, Pesce S, Greppi M, Obino V, Ferretti E, Sivori S, Genova C, Lemoli RM, Marcenaro E. Harnessing NK Cells for Cancer Treatment. Front Immunol. 2019 Dec 6;10:2836. doi: 10.3389/fimmu.2019.02836. eCollection 2019.

    PMID: 31867006BACKGROUND

  • Liu H, Wang S, Xin J, Wang J, Yao C, Zhang Z. Role of NKG2D and its ligands in cancer immunotherapy. Am J Cancer Res. 2019 Oct 1;9(10):2064-2078. eCollection 2019.

    PMID: 31720075BACKGROUND

  • Wang W, Jiang J, Wu C. CAR-NK for tumor immunotherapy: Clinical transformation and future prospects. Cancer Lett. 2020 Mar 1;472:175-180. doi: 10.1016/j.canlet.2019.11.033. Epub 2019 Nov 29.

    PMID: 31790761BACKGROUND

  • Sarvaria A, Jawdat D, Madrigal JA, Saudemont A. Umbilical Cord Blood Natural Killer Cells, Their Characteristics, and Potential Clinical Applications. Front Immunol. 2017 Mar 23;8:329. doi: 10.3389/fimmu.2017.00329. eCollection 2017.

    PMID: 28386260BACKGROUND

  • Mortier E, Quemener A, Vusio P, Lorenzen I, Boublik Y, Grotzinger J, Plet A, Jacques Y. Soluble interleukin-15 receptor alpha (IL-15R alpha)-sushi as a selective and potent agonist of IL-15 action through IL-15R beta/gamma. Hyperagonist IL-15 x IL-15R alpha fusion proteins. J Biol Chem. 2006 Jan 20;281(3):1612-9. doi: 10.1074/jbc.M508624200. Epub 2005 Nov 11.

    PMID: 16284400BACKGROUND

  • Liu E, Marin D, Banerjee P, Macapinlac HA, Thompson P, Basar R, Nassif Kerbauy L, Overman B, Thall P, Kaplan M, Nandivada V, Kaur I, Nunez Cortes A, Cao K, Daher M, Hosing C, Cohen EN, Kebriaei P, Mehta R, Neelapu S, Nieto Y, Wang M, Wierda W, Keating M, Champlin R, Shpall EJ, Rezvani K. Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors. N Engl J Med. 2020 Feb 6;382(6):545-553. doi: 10.1056/NEJMoa1910607.

    PMID: 32023374BACKGROUND

MeSH Terms

Conditions

COVID-19

Condition Hierarchy (Ancestors)

Pneumonia, ViralPneumoniaRespiratory Tract InfectionsInfectionsVirus DiseasesCoronavirus InfectionsCoronaviridae InfectionsNidovirales InfectionsRNA Virus InfectionsLung DiseasesRespiratory Tract Diseases

Study Officials

  • Min Liu, A.B

    Chongqing Public Health Center

    PRINCIPAL INVESTIGATOR

  • Jimin Gao

    Zhejiang Qixin Biotech

    PRINCIPAL INVESTIGATOR

Central Study Contacts

Min Liu, A.B

CONTACT

86-13668072999gwzxliumin@foxmail.com

Jimin Gao, M.D., Ph.D.

CONTACT

86-577-86699341jimingao@yahoo.com

Study Design

Study Type
interventional
Phase
phase 1
Allocation
RANDOMIZED
Masking
QUADRUPLE
Who Masked
PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
Purpose
TREATMENT
Intervention Model
PARALLEL
Sponsor Type
OTHER
Responsible Party
SPONSOR

Study Record Dates

First Submitted

March 25, 2020

First Posted

March 27, 2020

Study Start

February 21, 2020

Primary Completion

February 20, 2022

Study Completion

August 31, 2022

Last Updated

November 17, 2020

Record last verified: 2020-11

Data Sharing

IPD Sharing
Will not share

Locations

CN(1)