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Safety of Transplantation of CRISPR CCR5 Modified CD34+ Cells in HIV-infected Subjects With Hematological Malignances

This study is currently recruiting participants.
Verified May 2017 by Chen Hu, Affiliated Hospital to Academy of Military Medical Sciences
Sponsor:
ClinicalTrials.gov Identifier:
NCT03164135
First Posted: May 23, 2017
Last Update Posted: May 23, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborators:
Peking University
Capital Medical University
Information provided by (Responsible Party):
Chen Hu, Affiliated Hospital to Academy of Military Medical Sciences
  Purpose
The investigators performed this study to evaluate the safety and feasibility of transplantation with CRISPR/Cas9 CCR5 gene modified CD34+ hematopoietic stem/progenitor cells for patients that develop AIDS and hematological malignances. Patients will be treated with antiviral therapy (ART) to achieve undetectable HIV-1 virus in peripheral blood before conditioning. CD34+ cells from donors will be infused into the patients after treatment with CRISPR/Cas9 to ablate CCR5 gene.

Condition Intervention
HIV-1-infection Genetic: CCR5 gene modification

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Intervention Model Description:
CD34+ hematopoietic stem/progenitor cells from donor are treated with CRISPR/Cas9 before transplantation into the patient.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Safety and Feasibility Study of Allotransplantation of CRISPR/Cas9 CCR5 Gene Modified CD34+ Hematopoietic Stem/Progenitor Cells in HIV-infected Subjects With Hematological Malignances

Resource links provided by NLM:


Further study details as provided by Chen Hu, Affiliated Hospital to Academy of Military Medical Sciences:

Primary Outcome Measures:
  • Persistence of CCR5 gene disruption in engrafted cells [ Time Frame: 12 months ]
    Participants will be transplanted with CD34+ cells which are treated using the CRISPR/Cas9 system to disrupt CCR5 gene. The persistence of CCR5 gene disruption in engrafted cells will be evaluated by sequencing.


Secondary Outcome Measures:
  • CD34+ cell number [ Time Frame: the first month ]
    The CD34+ cell number pre-infusion


Other Outcome Measures:
  • Gene disruption efficiency of bone marrow cells [ Time Frame: Up to Month 12 ]
    The percentage of disrupted CCR5 gene alleles in genome from bone marrow cells detected by sequencing.

  • CCR5 gene disruption efficiency of peripheral blood cells [ Time Frame: Up to Month 12 ]
    The percentage of disrupted CCR5 gene alleles in genome of peripheral blood cells by sequencing.

  • Hematopoietic cell engraftment [ Time Frame: Up to Year 3 ]
    Measurement of multi-lineage hematopoietic cell engraftment time after transplantation to evaluate the hematological recovery

  • HIV-1 RNA level [ Time Frame: Up to Year 3 ]
    Level change of HIV-1 RNA in plasma after transplantation

  • CD4+ T cell number [ Time Frame: Up to Year 3 ]
    Level change of the CD4+ T cell number after transplantation

  • The ratio change of CD4/CD8 [ Time Frame: Up to Year 3 ]
    The ratio change of CD4/CD8 in peripheral blood after transplantation

  • HIV-1 RNA levels during ATI [ Time Frame: Every two weeks, until the end of ATI or up to 3 months ]
    HIV-1 RNA levels in plasma during ATI.

  • HIV-1 DNA level [ Time Frame: Up to Month 12 ]
    Changes of proviral DNA in PBMC pre- transplantation and 12 month post-transplantation


Estimated Enrollment: 5
Anticipated Study Start Date: May 30, 2017
Estimated Study Completion Date: May 20, 2021
Estimated Primary Completion Date: May 20, 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: CCR5 gene modification
CD34+ hematopoietic stem/progenitor cells from donor are treated with CRISPR/Cas9 before transplantation into the patient.
Genetic: CCR5 gene modification
CD34+ hematopoietic stem/progenitor cells from donor are treated with CRISPR/Cas9 targeting CCR5 gene.

Detailed Description:
The primary objective of this study is to determine the safety of the infusion of CD34+ cells which are treated with CRISPR/Cas9 to disrupt the CCR5 gene. The secondary objective is to evaluate the resistance to HIV-1(R5) in infected patients after infusion of modified CD34+ cells with or without an antiretroviral therapy interruption (ATI). After the transplantation, the reconstitution time and frequency of multi-lineage hematopoietic cell will be analyzed against previously reported HSCT in HIV-1 patients. After the detection of high CD4+ T cells reconstitution (over 600 cells/μL) and CCR5 negative cells (over 1%) in peripheral blood, subjects will undergo an ATI. HIV-1 RNA level and CD4+ cell counts will be monitored biweekly for at least one month.
  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age between 18 to 60, male of female;
  2. Hematological neoplasms;
  3. HIV-1 R5 tropic virus with no CXCR4-tropic or R5/X4 dual-tropic HIV;
  4. On ART with undetectable HIV-1 level (<40gc/ml, HIV-1 RNA);
  5. Availability of a consenting HLA-matched donor;
  6. No cardiomyopathy or congestive heart failure;
  7. CD4+ T-cell counts ≥200 cells/µL and ≤750 cells/µL;
  8. Absence of psychosocial conditions and be willing to comply with study-mandated evaluations for 2 years;
  9. Life expectancy of at least 1 year.

Exclusion Criteria:

  1. Acute or chronic hepatitis B or hepatitis C infection;
  2. Any cancer or malignancy other than hematological neoplasms;
  3. Subject with CMV retinitis or other active CMV infection related diseases;
  4. Subject with organ dysfunction;
  5. Non-pregnant and non-nursing;
  6. Drug or alcohol abuse or dependence;
  7. Currently enrolled in another clinical trial or underwent cell therapy;
  8. Donor incapable for HSPC mobilization;
  9. in the opinion of the site investigator, would interfere with adherence to study requirements.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03164135


Contacts
Contact: Bin Zhang, MD, PhD +86-10-66947625 zb307ctc@163.com
Contact: Hu Chen, MD, PhD +86-10-66947108 chenhu217@aliyun.com

Locations
China, Beijing
307 Hospital of PLA (Affiliated Hospital of Academy to Military Medical Sciences) Recruiting
Beijing, Beijing, China, 100071
Contact: Bin Zhang, MD, PhD    +86-10-66947625    zb307ctc@163.com   
Contact: Lei Xu, MD, PhD       xulei800@hotmail.com   
Principal Investigator: Hu Chen, MD, PhD         
Principal Investigator: Hongkui Deng, PhD         
Principal Investigator: Hao Wu, MD, PhD         
Sponsors and Collaborators
Affiliated Hospital to Academy of Military Medical Sciences
Peking University
Capital Medical University
  More Information

Responsible Party: Chen Hu, Study Director, Affiliated Hospital to Academy of Military Medical Sciences
ClinicalTrials.gov Identifier: NCT03164135     History of Changes
Other Study ID Numbers: 307-HSPC-R5
First Submitted: May 18, 2017
First Posted: May 23, 2017
Last Update Posted: May 23, 2017
Last Verified: May 2017
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


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