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

Safety and Feasibility Study of Allotransplantation of CRISPR/Cas9 CCR5 Gene Modified CD34+ Hematopoietic Stem/Progenitor Cells in HIV-infected Subjects With Hematological Malignances

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.

Study Overview

• Status: Unknown
• Conditions: HIV-1-infection
• Intervention / Treatment: Genetic: CCR5 gene modification

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.

• Study Type: Interventional
• Enrollment (Anticipated): 5
• Phase: Not Applicable

Contacts and Locations

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100071
      • Recruiting
      • 307 Hospital of PLA (Affiliated Hospital of Academy to Military Medical Sciences)
      • Contact: Bin Zhang, MD, PhD; Phone Number: +86-10-66947625; Email: zb307ctc@163.com
      • Contact: Lei Xu, MD, PhD; Email: xulei800@hotmail.com
      • Principal Investigator: Hu Chen, MD, PhD
      • Principal Investigator: Hongkui Deng, PhD
      • Principal Investigator: Hao Wu, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Persistence of CCR5 gene disruption in engrafted cells	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.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CD34+ cell number	The CD34+ cell number pre-infusion	the first month

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gene disruption efficiency of bone marrow cells	The percentage of disrupted CCR5 gene alleles in genome from bone marrow cells detected by sequencing.	Up to Month 12
CCR5 gene disruption efficiency of peripheral blood cells	The percentage of disrupted CCR5 gene alleles in genome of peripheral blood cells by sequencing.	Up to Month 12
Hematopoietic cell engraftment	Measurement of multi-lineage hematopoietic cell engraftment time after transplantation to evaluate the hematological recovery	Up to Year 3
HIV-1 RNA level	Level change of HIV-1 RNA in plasma after transplantation	Up to Year 3
CD4+ T cell number	Level change of the CD4+ T cell number after transplantation	Up to Year 3
The ratio change of CD4/CD8	The ratio change of CD4/CD8 in peripheral blood after transplantation	Up to Year 3
HIV-1 RNA levels during ATI	HIV-1 RNA levels in plasma during ATI.	Every two weeks, until the end of ATI or up to 3 months
HIV-1 DNA level	Changes of proviral DNA in PBMC pre- transplantation and 12 month post-transplantation	Up to Month 12

Collaborators and Investigators

• Sponsor: Affiliated Hospital to Academy of Military Medical Sciences
• Collaborators: Peking University; Capital Medical University

Publications and helpful links

General Publications

• Xu L, Wang J, Liu Y, Xie L, Su B, Mou D, Wang L, Liu T, Wang X, Zhang B, Zhao L, Hu L, Ning H, Zhang Y, Deng K, Liu L, Lu X, Zhang T, Xu J, Li C, Wu H, Deng H, Chen H. CRISPR-Edited Stem Cells in a Patient with HIV and Acute Lymphocytic Leukemia. N Engl J Med. 2019 Sep 26;381(13):1240-1247. doi: 10.1056/NEJMoa1817426. Epub 2019 Sep 11.

Study record dates

Study Major Dates

• Study Start (Anticipated): May 30, 2017
• Primary Completion (Anticipated): May 20, 2019
• Study Completion (Anticipated): May 20, 2021

Study Registration Dates

• First Submitted: May 18, 2017
• First Submitted That Met QC Criteria: May 22, 2017
• First Posted (Actual): May 23, 2017

Study Record Updates

• Last Update Posted (Actual): May 23, 2017
• Last Update Submitted That Met QC Criteria: May 22, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Other Study ID Numbers: 307-HSPC-R5

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No