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Safety of Transplantation of CRISPR CCR5 Modified CD34+ Cells in HIV-infected Subjects With Hematological Malignances
This study is currently recruiting participants.
Verified May 2017 by Chen Hu, Affiliated Hospital to Academy of Military Medical Sciences
Sponsor:
Affiliated Hospital to Academy of Military Medical Sciences
Collaborators:
Peking University
Capital Medical University
Information provided by (Responsible Party):
Chen Hu, Affiliated Hospital to Academy of Military Medical Sciences
ClinicalTrials.gov Identifier:
NCT03164135
First received: May 18, 2017
Last updated: May 22, 2017
Last verified: May 2017
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Purpose
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 | Intervention |
|---|---|
| HIV-1-infection | Genetic: CCR5 gene modification |
| Study Type: | Interventional |
| Study Design: | Intervention Model: Single Group Assignment Intervention Model Description: CD34+ hematopoietic stem/progenitor cells from donor are treated with CRISPR/Cas9 before transplantation into the patient. Masking: No maskingPrimary Purpose: Treatment |
| 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 |
Resource links provided by NLM:
Further study details as provided by Chen Hu, Affiliated Hospital to Academy of Military Medical Sciences:
Primary Outcome Measures:
- Persistence of CCR5 gene disruption in engrafted cells [ Time Frame: 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 [ Time Frame: the first month ]The CD34+ cell number pre-infusion
Other Outcome Measures:
- Gene disruption efficiency of bone marrow cells [ Time Frame: 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 [ Time Frame: Up to Month 12 ]The percentage of disrupted CCR5 gene alleles in genome of peripheral blood cells by sequencing.
- Hematopoietic cell engraftment [ Time Frame: Up to Year 3 ]Measurement of multi-lineage hematopoietic cell engraftment time after transplantation to evaluate the hematological recovery
- HIV-1 RNA level [ Time Frame: Up to Year 3 ]Level change of HIV-1 RNA in plasma after transplantation
- CD4+ T cell number [ Time Frame: Up to Year 3 ]Level change of the CD4+ T cell number after transplantation
- The ratio change of CD4/CD8 [ Time Frame: Up to Year 3 ]The ratio change of CD4/CD8 in peripheral blood after transplantation
- HIV-1 RNA levels during ATI [ Time Frame: 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 [ Time Frame: Up to Month 12 ]Changes of proviral DNA in PBMC pre- transplantation and 12 month post-transplantation
| Estimated Enrollment: | 5 |
| Anticipated Study Start Date: | May 30, 2017 |
| Estimated Study Completion Date: | May 20, 2021 |
| Estimated Primary Completion Date: | May 20, 2019 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
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.
|
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.
Eligibility| Ages Eligible for Study: | 18 Years to 60 Years (Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
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.
Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study.
To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.
For general information, see Learn About Clinical Studies.
Please refer to this study by its ClinicalTrials.gov identifier: NCT03164135
Please refer to this study by its ClinicalTrials.gov identifier: NCT03164135
Contacts
| Contact: Bin Zhang, MD, PhD | +86-10-66947625 | zb307ctc@163.com | |
| Contact: Hu Chen, MD, PhD | +86-10-66947108 | chenhu217@aliyun.com |
Locations
| China, Beijing | |
| 307 Hospital of PLA (Affiliated Hospital of Academy to Military Medical Sciences) | Recruiting |
| Beijing, Beijing, China, 100071 | |
| Contact: Bin Zhang, MD, PhD +86-10-66947625 zb307ctc@163.com | |
| Contact: Lei Xu, MD, PhD xulei800@hotmail.com | |
| Principal Investigator: Hu Chen, MD, PhD | |
| Principal Investigator: Hongkui Deng, PhD | |
| Principal Investigator: Hao Wu, MD, PhD | |
Sponsors and Collaborators
Affiliated Hospital to Academy of Military Medical Sciences
Peking University
Capital Medical University
More Information
| Responsible Party: | Chen Hu, Study Director, Affiliated Hospital to Academy of Military Medical Sciences |
| ClinicalTrials.gov Identifier: | NCT03164135 History of Changes |
| Other Study ID Numbers: |
307-HSPC-R5 |
| Study First Received: | May 18, 2017 |
| Last Updated: | May 22, 2017 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | No |
| Studies a U.S. FDA-regulated Drug Product: | No | |
| Studies a U.S. FDA-regulated Device Product: | No | |
ClinicalTrials.gov processed this record on July 17, 2017