Background:  CCR5 is an important co-receptor for HIV entry and zinc finger nuclease (ZFN)-mediated modification of this receptor in CD4 T cells may render a survival advantage in HIV infection. We have previously reported preliminary data from 2 Phase 1 studies of SB-728-T. Here, we report additional data relating to safety, increases in CD4, persistence and trafficking of SB-728-T, and effect on HIV.

Methods:  In the Penn study, 6 immunologic responders (IR) with CD4 ≥450 cells/µL and 6 immunologic non-responders (INR) with CD4 ≤500 cells/µL were infused with 10¹⁰ cells. At week 4, IR underwent a 12-week HAART treatment interruption (TI). In the CA study, 9 INR (CD4 200 to 500 cells/µL) were enrolled into 3 cohorts that received 1x, 2x or 3x10¹⁰ cells. The median duration of follow up for both studies was 232 days (range 56 to 561).

Results:  The mean CD4 and SB-728-T count increased by 1533/µL (range 216 to 3025) and 83/µL, respectively, on D7 in IR and by 820/µL (range 133 to 4467) and 19/µL, respectively, in INR from the 2 studies. Increases in CD4 over time correlated with SB-728-T engraftment (г = 0.78, p <0.0001). SB-728-T was detected in the gut mucosa of all 18 subjects biopsied (median 6%). During TI, HIV-RNA dropped ~0.8 to 2.1 log from their peak levels in 3 subjects. In one CCR5 Δ32 heterozygous subject with a viral set point of 165K copies/mL, viral load peaked at 6247 during week 6 of TI and was undetectable by week 12. In the CA study, peripheral blood mononuclear cell HIV proviral DNA was evaluated using a new Digital Droplet qPCR method. Samples with previously undetectable levels using traditional qPCR now showed measurable proviral DNA. Three of 6 subjects with >11 months follow up had an ~1-log decrease over time. CD4 T cell interferon gamma (IFN-γ) ELISpots to HIV gag peptides performed at baseline showed stratification into a high and low (360 vs 130 SFC/10⁶) ELISpot group. One subject with high baseline IFN-γ ELISpot developed a high antibody response to env and gag in response to viremia along with >1-log drop from peak in HIV RNA during TI. SB-728-T infusions were well tolerated with only mild reversible infusion-related adverse events.

Conclusions:  SB-728-T infusion increases CD4 counts that persist over time. SB-728-T expands rapidly and home to the gut. Preliminary data suggest that SB-728-T may decrease proviral DNA. In one subject with the highest level of CCR5 modification, viral load was controlled (< limit of detection) without HAART. These data suggest that in addition to the previously documented increases in CD4 cell, SB-728-T may also suppress HIV replication.