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

• ClinicalTrials.gov Identifier: NCT04324996
• Recruitment Status: Recruiting
• First Posted: March 27, 2020
• Last Update Posted: November 17, 2020
• Sponsor: Chongqing Public Health Medical Center
• Collaborators: Chongqing Sidemu Biotech; Zhejiang Qixin Biotech
• Information provided by (Responsible Party): Chongqing Public Health Medical Center

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 (Clinical Trial)
• Estimated 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: February 21, 2020
• Estimated Primary Completion Date: February 20, 2022
• Estimated Study Completion Date: August 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 :

1. 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
2. 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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Contacts

Contact: Min Liu, A.B; 86-13668072999; gwzxliumin@foxmail.com

Contact: Jimin Gao, M.D., Ph.D.; 86-577-86699341; jimingao@yahoo.com

Locations

China

Chongqing Public Health Medical Center; Recruiting

Chongqing, China, 400036

Contact: Min Liu, A.B 086-13668072999 gwzxliumin@foxmail.com

Contact: Jimin Gao, M.D.,Ph.D. 086-577-86699341 jimingao@yahoo.com

Principal Investigator: Jimin Gao, M.D.,Ph.D.

Principal Investigator: Min Liu, A.B.

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

More Information

Publications:

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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. Review.

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. Review.

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. Review.

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. Review.

Mortier E, Quéméner A, Vusio P, Lorenzen I, Boublik Y, Grötzinger 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. Epub 2005 Nov 11.

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.

• Responsible Party: Chongqing Public Health Medical Center
• ClinicalTrials.gov Identifier: NCT04324996
• Other Study ID Numbers: ChongqingPublicHMC
• First Posted: March 27, 2020
• Last Update Posted: November 17, 2020
• Last Verified: November 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Chongqing Public Health Medical Center:

NKG2D-ACE2 CAR-NK; IL15 superagonist; GM-CSF-neutralizing scFv; COVID-19