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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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HIV-1-infection

Intervention / Treatment
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* Genetic: CCR5 gene modification


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age between 18 to 60, male of female; Hematological neoplasms; HIV-1 R5 tropic virus with no CXCR4-tropic or R5/X4 dual-tropic HIV; On ART with undetectable HIV-1 level (<40gc/ml, HIV-1 RNA); Availability of a consenting HLA-matched donor; No cardiomyopathy or congestive heart failure; CD4+ T-cell counts ≥200 cells/µL and ≤750 cells/µL; Absence of psychosocial conditions and be willing to comply with study-mandated evaluations for 2 years; Life expectancy of at least 1 year. Exclusion Criteria: Acute or chronic hepatitis B or hepatitis C infection; Any cancer or malignancy other than hematological neoplasms; Subject with CMV retinitis or other active CMV infection related diseases; Subject with organ dysfunction; Non-pregnant and non-nursing; Drug or alcohol abuse or dependence; Currently enrolled in another clinical trial or underwent cell therapy; Donor incapable for HSPC mobilization; in the opinion of the site investigator, would interfere with adherence to study requirements.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: CD34+ hematopoietic stem/progenitor cells from donor are treated with CRISPR/Cas9 before transplantation into the patient.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CCR5 gene modification<br>CD34+ hematopoietic stem/progenitor cells from donor are treated with CRISPR/Cas9 before transplantation into the patient. | Genetic: CCR5 gene modification<br>* CD34+ hematopoietic stem/progenitor cells from donor are treated with CRISPR/Cas9 targeting CCR5 gene.<br>|

What is the study measuring?
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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 |