HIV
Conditions
Keywords
Gene therapy, Acquired Immunodeficiency Syndrome, HIV Infections, Retroviridae Infections, RNA Virus Infections, Virus Diseases, Sexually Transmitted Diseases, Viral, Sexually Transmitted Diseases, Immunologic Deficiency Syndromes, Immune System Diseases, Busulfan, Pharmacologic Actions
Brief summary
The purpose of the study is to evaluate the safety and feasibility of administering SB-728mR-HSPC after conditioning with busulfan.
Detailed description
The objective of the study is to evaluate the safety and feasibility of giving autologous SB-728mR-HSPC to HIV-1 (R5) infected patients who are being treated with cART and have undetectable virus but suboptimal CD4+ cell levels. To strengthen the possibility that CCR5-disrupted HSPCs engraft, patients will receive either a two- or three-day (Cohort 1 or Cohort 2) course of busulfan (dose targeting AUC of 4000 µM/day) before being infused with the genetically modified cells. At 9-12 months after SB-728mR-HSPC infusion, subjects who are aviremic with CD4 cell counts ≥600 cells/µL and have ≥1% CCR5-modified CD4 cells within the peripheral blood detected by pentamer PCR will undergo an ATI.
Interventions
GENETICSB-728mR-HSPC Infusion 3 days following busulfan conditioning
Sponsors
Sangamo Therapeutics
California Institute for Regenerative Medicine (CIRM)
City of Hope Medical Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Maximum age 75 years for cohort 1 and 65 years for cohort 2. * HIV-1 R5 seropositive with no evidence of CXCR4-tropic virus. * On cART with undetectable HIV-1 (\<20 gc/ml HIV-1 RNA) for at least 12 months prior to screening evaluations. * CD4+ T-cell counts ≥200 cells/µL and ≤750 cells/µL. * No psychosocial conditions that would hinder study compliance and follow-up. * Absence of clinically significant cardiomyopathy, congestive heart failure. Secondary Eligibility Criteria (for registration): * Complete G-CSF/Plerixafor mobilization of HSPC. * Collect ≥7.5 x 10\^6 CD34+ cells/kg in two aphereses. * The SB-728mR-HSPC product passed all release testing
Exclusion criteria
* Use of AZT or maraviroc in the cART regimen. * History of significant hematologic diseases such as leukemia, myelodysplasia, coagulopathy, and thromboembolism. * Any AIDS-related opportunistic infection occurring within the past year such as tuberculosis, cryptococcosis and for which treatment has been unsuccessful as determined by the Principal Investigator. * AIDS-related syndromes, infectious or otherwise, if perceived to cause excessive risk for morbidity post-HSPC infusion, as determined by the Principal Investigator. * Patients with active HBV or HCV infection, i.e., HBV DNA and HCV RNA in blood, are excluded. Those with inactive, but past infection with HBV (positive HBV surface antigen or HBV surface antibody) or inactive HCV (positive HCV antibody), must have no cirrhosis, as determined by abdominal ultrasound with elastography. * Active CMV retinitis or other active CMV-related organ dysfunction. * CXCR4-tropic virus. * Pregnant or nursing women. * Any history of HIV-associated encephalopathy; dementia of any kind; seizures in the past 12 months; any perceived inability to directly provide informed consent. * Participants may not be receiving any other investigational agents, or concurrent biological, chemotherapy, or radiation therapy. Participation in prior investigational drug or medical device study within the previous 45 days. * Current or history of immunomodulatory agent or steroid use. * Prior therapy with HIV vaccine or gene therapy product. * History of alcohol or substance abuse for the previous 12 months. * Participants with active malignancies. However, participants with skin cancers, namely basal cell or squamous cell carcinoma, and malignancies treated with curative intent having no known active disease present for ≥2 years, may be eligible.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Toxicity in subjects who received SB-728mR-HSPC after each busulfan dose level | 18 months |
Secondary
| Measure | Time frame |
|---|---|
| Number of CD34+ HSPC collected, gene modified, and released throughout the manufacturing process | Approximately first 1-2 months on study |
Other
| Measure | Time frame |
|---|---|
| Changes in CD4+ T-cell percentage after SB-728mR-HSPC infusion | Up to Year 5 |
| Changes in CD4+ T-cell number after SB-728mR-HSPC infusion | Up to Year 5 |
| Changes in CD4/CD8 ratio after SB-728mR-HSPC infusion | Up to Year 5 |
| Detection of CCR5 modified HSPC in bone marrow | Up to Month 12 |
| HIV-1 RNA levels in plasma during the treatment interruption of antiretroviral medicines | ATI Day 0 and weeks 2, 4, 6, 8, 10, 12, 14, 16 and 28 |
| Longitudinal changes of proviral DNA in PBMC | 18 months |
| Pharmacokinetic analysis of busulfan (AUC levels) | pre-busulfan and at 15, 30, 60, 180 and 240 min after end of infusion |
| Detection of CCR5-modified PBMC in blood over time | Up to Year 5 |
| Time to hematological recovery as measured by neutrophil and platelet engraftment time | Up to Year 5 |
Countries
United States
Outcome results
None listed