Safety of Transplantation of CRISPR CCR5 Modified CD34+ Cells in HIV-infected Subjects With Hematological Malignances
Study Details
Study Description
Brief Summary
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 or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
N/A |
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 Design
Arms and Interventions
| 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.
|
Outcome Measures
Primary Outcome Measures
- Persistence of CCR5 gene disruption in engrafted cells [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 [the first month]
The CD34+ cell number pre-infusion
Other Outcome Measures
- Gene disruption efficiency of bone marrow cells [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 [Up to Month 12]
The percentage of disrupted CCR5 gene alleles in genome of peripheral blood cells by sequencing.
- Hematopoietic cell engraftment [Up to Year 3]
Measurement of multi-lineage hematopoietic cell engraftment time after transplantation to evaluate the hematological recovery
- HIV-1 RNA level [Up to Year 3]
Level change of HIV-1 RNA in plasma after transplantation
- CD4+ T cell number [Up to Year 3]
Level change of the CD4+ T cell number after transplantation
- The ratio change of CD4/CD8 [Up to Year 3]
The ratio change of CD4/CD8 in peripheral blood after transplantation
- HIV-1 RNA levels during ATI [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 [Up to Month 12]
Changes of proviral DNA in PBMC pre- transplantation and 12 month post-transplantation
Eligibility Criteria
Criteria
Inclusion Criteria:
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Age between 18 to 60, male of female;
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Hematological neoplasms;
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HIV-1 R5 tropic virus with no CXCR4-tropic or R5/X4 dual-tropic HIV;
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On ART with undetectable HIV-1 level (<40gc/ml, HIV-1 RNA);
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Availability of a consenting HLA-matched donor;
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No cardiomyopathy or congestive heart failure;
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CD4+ T-cell counts ≥200 cells/µL and ≤750 cells/µL;
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Absence of psychosocial conditions and be willing to comply with study-mandated evaluations for 2 years;
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Life expectancy of at least 1 year.
Exclusion Criteria:
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Acute or chronic hepatitis B or hepatitis C infection;
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Any cancer or malignancy other than hematological neoplasms;
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Subject with CMV retinitis or other active CMV infection related diseases;
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Subject with organ dysfunction;
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Non-pregnant and non-nursing;
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Drug or alcohol abuse or dependence;
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Currently enrolled in another clinical trial or underwent cell therapy;
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Donor incapable for HSPC mobilization;
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in the opinion of the site investigator, would interfere with adherence to study requirements.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | 307 Hospital of PLA (Affiliated Hospital of Academy to Military Medical Sciences) | Beijing | Beijing | China | 100071 |
Sponsors and Collaborators
- Affiliated Hospital to Academy of Military Medical Sciences
- Peking University
- Capital Medical University
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 307-HSPC-R5