A Phase I Study of T-Cells Genetically Modified at the CCR5 Gene by Zinc Finger Nucleases SB-728mR in HIV-Infected Patients

Inclusion Criteria

• •HIV-1 infection, as documented by a rapid HIV test or any FDA-approved HIV-1 Enzyme or Chemiluminescence Immunoassay (E/CIA) test kit and confirmed by Western blot at any time prior to study entry or HIV antigen, plasma HIV-1 RNA, or second antibody test by a method other than rapid HIV and E/CIA. Alternatively, if a rapid HIV test or any FDA-approved HIV-1 Enzyme or Chemiluminescence Immunoassay (E/CIA) test kit is not available, two HIV-1 RNA values ≥ 2000 copies/mL at least 24 hours apart performed by any laboratory that has CLIA certification, or its equivalent, may be used to document infection.
• •CD4+ T cell count of ≥450 cells/mm3 at screen; and a documented CD4 nadir of not lower than 200 cells/mm3.
• •Adequate venous access and no other contraindications for leukapheresis.
• •Laboratory values obtained at screen:
• •1. Hemoglobin: ≥ 10.0 (males); ≥ 9.5 (females) g/dL
• •2. Absolute neutrophil count (ANC): ≥ 1000/mm3
• •3. Platelet count: ≥ 100,000/mm3
• •4. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT): ≤ 2.5 times the upper limit of normal (ULN).
• •Subjects must be willing to comply with study-mandated evaluations; including not changing their antiretroviral regimen (unless medically indicated) for 2 months in step 2 or until undergoing the analytical treatment interruption.
• •Be male or female, 18 years of age and older.
• •Ability and willingness of subject to provide informed consent.
• •Have a Karnofsky Performance Score of 70 or higher.
• •Have no polymorphisms in the CCR5 ZFN target region as determined by Cel I snp assay at screening.
• •Subjects in Cohorts 2 and 3: LVEF \> or equal to 40%
• •Clinically stable on their first or second HAART regimen. Changes while the patient HIV viral load is undetectable does not count toward the number of ART regimens used, only changes made for virologic failure (for example an individual switching from an NNRTI-based regimen to an integrase inhibitor based regimen while the HIV viral load is undetectable will still be in their first regimen). Site investigator anticipates that a fully active alternative ART regimen could be constructed in the event of virologic failure on the current ART regimen. The current regimen should have no changes within 4 weeks of enrollment. Subjects must be willing to continue on current antiretroviral therapy for the duration of the study except for the duration of the 16 week analytical treatment interruption. NOTE: Subject's ART regimen must be in accordance with the Department of Health and Human Services Document "Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents."
• •HIV-1 RNA undetectable by ultrasensitive assay copies/ml obtained at study screening visit or within 60 days prior to study screening visit performed with an ultrasensitive HIV-1 PCR assay. All subjects must have received at least 18 months of therapy and have HIV-1 RNA \<50 copies/mL using a FDA-approved assay for at least 48 weeks prior to enrollment. HIV-1 RNA must be measured at least once in the 24 weeks prior to enrollment and at least 3 days before the screening measure. Single determinations that are between ≥50 and \<500copies/mL (i.e., blips) are allowed as long as the preceding and subsequent determinations are \<50 copies/mL. The screening value may serve as the subsequent determination \<50 copies/mL following a blip. NOTE: subjects who have participated in other trials using ATI's will be permitted since detectable virus during the interruption does not represent virologic failure. These subjects should have at least 24 weeks of VL \<50 copies/mL.
• •Have a recorded viral load set point