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B107 Results of a phase 1 using CCR5 Deficiency with Zinc Finger Nuclease-modified Autologous CD4 T Cells (SB-728-T) in HIV-infected Subjects

Tebas Pablo; June, C; Stein, D; Wang, S; Lee, G; Levine, B; Tang, W; Ando, D
JAIDS Journal of Acquired Immune Deficiency Syndromes: April 2013
doi: 10.1097/01.qai.0000429208.01732.16
Abstracts: PDF Only

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/µL (range 216 to 3025) and 83/µL, 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.

© 2013 Lippincott Williams & Wilkins, Inc.