: 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.
Methods: We conducted a Phase 1 clinical trial at the University of Pennsylvania evaluating the use of genetically modified CD4 T cells with SB-728-T (a CCR5 directed ZFN).
Results: 6 immunologic responders (IR) with CD4>=450 were infused with 1010 genetically modified cells. At week 4, all participants underwent a 12-week HAART treatment interruption (TI). In addition 6 immunological non responders (NIR) were also infused. The mean CD4 and SB-728-T count increased by 1533/[micro]L (range 216 to 3025) and 83/[micro]L, respectively, on D7. Increases in CD4 over time correlated with SB-728-T engraftment (= 0.78, p <0.0001). SB-728-T was detected in the gut mucosa of all 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 32 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. HIV proviral DNA was evaluated using a new Digital Droplet qPCR method. The levels of HIV proviral DNA returned quickly to baseline levels after the resumption of ART. SB-728-T infusions were well tolerated with only mild reversible infusion-related adverse events. SB-728-T infusion increases CD4 counts that persist over time both in IR and NIR. SB-728-T expands rapidly and home to the gut. In one subject with the highest level of CCR5 modification, viral load was controlled for 12 weeks.
Conclusions: These data suggest that in addition to the previously documented increases in CD4 cell, SB-728-T may also suppress HIV replication.
(C) 2013 Lippincott Williams & Wilkins, Inc.