Clinical trial NCT03164135: Safety of Transplantation of CRISPR CCR5 Modified CD34+ Cells in HIV-infected Subjects With Hematological Malignances
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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: HIV-1-infection
Lead sponsor: Affiliated Hospital to Academy of Military Medical Sciences
Sponsor class: OTHER
Collaborators: name: Peking University
name: Capital Medical University
First posted: 2017-05-23
Enrollment: 5
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: CD34+ hematopoietic stem/progenitor cells from donor are treated with CRISPR/Cas9 before transplantation into the patient.
Primary purpose: TREATMENT

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.

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 criteria: 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.

Primary outcomes:
measure: Persistence of CCR5 gene disruption in engrafted cells
timeFrame: 12 months
Secondary outcomes:
measure: CD34+ cell number
timeFrame: the first month
Other outcomes:
measure: Gene disruption efficiency of bone marrow cells
timeFrame: Up to Month 12
measure: CCR5 gene disruption efficiency of peripheral blood cells
timeFrame: Up to Month 12
measure: Hematopoietic cell engraftment
timeFrame: Up to Year 3
measure: HIV-1 RNA level
timeFrame: Up to Year 3
measure: CD4+ T cell number
timeFrame: Up to Year 3
measure: The ratio change of CD4/CD8
timeFrame: Up to Year 3
measure: HIV-1 RNA levels during ATI
timeFrame: Every two weeks, until the end of ATI or up to 3 months
measure: HIV-1 DNA level
timeFrame: Up to Month 12
Locations:
city: Beijing
country: China
facility: 307 Hospital of PLA (Affiliated Hospital of Academy to Military Medical Sciences)
state: Beijing
Study officials:
References:
citation: Xu L, Wang J, Liu Y, Xie L, Su B, Mou D, Wang L, Liu T, Wang X, Zhang B, Zhao L, Hu L, Ning H, Zhang Y, Deng K, Liu L, Lu X, Zhang T, Xu J, Li C, Wu H, Deng H, Chen H. CRISPR-Edited Stem Cells in a Patient with HIV and Acute Lymphocytic Leukemia. N Engl J Med. 2019 Sep 26;381(13):1240-1247. doi: 10.1056/NEJMoa1817426. Epub 2019 Sep 11.