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

Affiliated Hospital to Academy of Military Medical Sciences5 enrolled

Overview

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.

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

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

HIV-1-infection

Eligibility

Sex: ALLMin age: 18 YearsMax age: 60 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

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.

Time frame: 12 months

Secondary Outcomes

CD34+ cell number

The CD34+ cell number pre-infusion

Time frame: the first month