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

HIV-1-infection Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03164135
• Other study ID #: 307-HSPC-R5
• Status: Recruiting
• Phase: N/A
• First received: May 18, 2017
• Last updated: May 22, 2017
• Start date: May 30, 2017
• Est. completion date: May 20, 2021

Study information

• Verified date: May 2017
• Source: Affiliated Hospital to Academy of Military Medical Sciences
• Contact: Bin Zhang, MD, PhD
• Phone: +86-10-66947625
• Email: zb307ctc[@]163.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 5
• Est. completion date: May 20, 2021
• Est. primary completion date: May 20, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

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.

Related Conditions & MeSH terms

• HIV-1-infection

Intervention

Genetic:
• CCR5 gene modification
CD34+ hematopoietic stem/progenitor cells from donor are treated with CRISPR/Cas9 targeting CCR5 gene.

Locations

Country	Name	City	State
China	307 Hospital of PLA (Affiliated Hospital of Academy to Military Medical Sciences)	Beijing	Beijing

Sponsors (3)

Lead Sponsor	Collaborator
Affiliated Hospital to Academy of Military Medical Sciences	Capital Medical University, Peking University

Country where clinical trial is conducted

China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Other	Hematopoietic cell engraftment	Measurement of multi-lineage hematopoietic cell engraftment time after transplantation to evaluate the hematological recovery	Up to Year 3
Other	HIV-1 RNA level	Level change of HIV-1 RNA in plasma after transplantation	Up to Year 3
Other	CD4+ T cell number	Level change of the CD4+ T cell number after transplantation	Up to Year 3
Other	The ratio change of CD4/CD8	The ratio change of CD4/CD8 in peripheral blood after transplantation	Up to Year 3
Other	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
Other	HIV-1 DNA level	Changes of proviral DNA in PBMC pre- transplantation and 12 month post-transplantation	Up to Month 12
Primary	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	CD34+ cell number	The CD34+ cell number pre-infusion	the first month