Dose Escalation Study of Cyclophosphamide in HIV-Infected Subjects on HAART Receiving SB-728-T

• Effect of escalating doses of cyclophosphamide on SB-728-T engraftment as measured by pentamer PCR [ Time Frame: Up to 12 months after the last SB-728-T infusion ] [ Designated as safety issue: No ]
• Effect of SB-728-T on plasma HIV-1 RNA levels following HAART interruption [ Time Frame: Up to 12 months after the last SB-728-T infusion ] [ Designated as safety issue: No ]
• Change in CD4+ T-cell counts in peripheral blood after treatment with SB-728-T [ Time Frame: Up to 12 months after the last SB-728-T infusion ] [ Designated as safety issue: No ]

The purpose of the study is to evaluate the safety, tolerability and effect on HIV viral load, of escalating doses of cyclophosphamide administered 1 day prior to SB-728-T infusion.

The objectives of the study are to augment HIV-specific T-cells and to reverse or decrease the progressive destruction of CD4+ T-cells that leads to clinical AIDS. Levels of engraftment vary from negligible to about 10% of the CD4+ T-cells in the vascular compartment. Preliminary analyses of HAART TI suggest that an anti-HIV effect may correlate with the level of SB-728-T engraftment. Concurrently, non-myeloablative lymphodepletion with cyclophosphamide has been demonstrated to enhance engraftment of adoptively transferred T-cells through a variety of mechanisms. The study is being undertaken to increase SB-728-T engraftment through the administration of low non-myeloablative doses of cyclophosphamide.

• Genetic: SB-728-T
  Infusion will be 5 to 30 billion ZFN modified CD4+ T cells 1 day following IV cyclophosphamide 200 mg
  Other Name: cyclophosphamide
• Genetic: SB-728-T
  Infusion will be 5 to 30 billion ZFN modified CD4+ T cells 1 day following IV cyclophosphamide 0.5 g/m2
  Other Name: cyclophosphamide
• Genetic: SB-728-T
  Infusion will be 5 to 30 billion ZFN modified CD4+ T cells 1 day following IV cyclophosphamide 1.0 g/m2
  Other Name: cyclophosphamide

• Experimental: Cohort 1 - IV cyclophosphamide 200 mg
  Intervention: Genetic: SB-728-T
• Experimental: Cohort 2 - IV cyclophosphamide 0.5 g/m2
  Intervention: Genetic: SB-728-T
• Experimental: Cohort 3 - IV cyclophosphamide 1.0 g/m2
  Intervention: Genetic: SB-728-T

Inclusion Criteria:

• Male or female, 18 years of age or older with documented HIV diagnosis within 10 years of screening.
• Must be willing to comply with study-mandated evaluations; including discontinuation of current antiretroviral therapy during the treatment interruption.
• Must have received at least 6 months of continuous HAART therapy and have had undetectable VLs for the preceding 3 months.
• On stable antiretroviral medication (no changes to treatment within 4 weeks of screening.
• CD4+ T-cell count ≥500 cells/µL.
• Undetectable HIV-1 RNA obtained at screening.
• ANC ≥2500/µL
• Platelet count ≥200,000/µL

Exclusion Criteria:

• Acute or chronic hepatitis B or hepatitis C infection.
• Active or recent (in prior 6 months) AIDS defining complication.
• Any cancer or malignancy within the past 5 years, with the exception of successfully treated basal cell or squamous cell carcinoma of the skin or low grade (0 or 1) anal or cervical dysplasia.
• Current diagnosis of NYHA grade 3 or 4 CHF, uncontrolled angina or arrhythmias.
• History or any features on physical examination indicative of a bleeding diathesis.
• Received HIV experimental vaccine within 6 months prior to screening, or any previous gene therapy using an integrating vector.
• Use of chronic corticosteroids, hydroxyurea, or immunomodulating agents within 30 days prior to screening.
• Use of Aspirin, dipyridamole, warfarin or any other medication that is likely to affect platelet function or other aspects of blood coagulation during the 2 week period prior to leukapheresis.
• Currently participating in another clinical trial or participation in such a trial within 30 days prior to screening visit.
• Subjects who are currently taking maraviroc or have received maraviroc within 6 months prior to screening.