A Single Infusion of Zinc Finger Nuclease CCR5 Modified Autologous CD4 T Cells (SB-728-T) Increases CD4 Counts and Leads to Decrease in HIV Proviral Load in an Aviremic HIV-infected Subject
Jay Lalezari*1, R Mitsuyasu2, S Wang3, G Lee3, M Giedlin3, W Tang3, K Spratt3, R Surosky3, N Dubois-Stringfellow3, and D Ando3
1Quest Clin Res, San Francisco, CA, US; 2Univ of California, Los Angeles, US; and 3Sangamo BioSci, Richmond, CA, US
Background: CCR5 is an important co-receptor for HIV entry. Modification of CCR5 in CD4 T cells with zinc finger nuclease (ZFN) may render a survival advantage. We have previously reported preliminary data from a Phase 1 study of SB-728-T in aviremic HIV+ subjects. Here, we report on one subject that showed data relating to increases in CD4, persistence and trafficking of SB-728-T and effect on proviral load (PVL).
Methods: Study SB-728-902 subject 01-104 (CD4 count 272, %CD4 27,) received 1x1010 SB-728-T (36% CCR5 modification). Peripheral blood and rectal biopsies were obtained at baseline, 14 days, 3, 6, and 12 months post-infusion.
Results: Subject 01-104 was infused with 1x1010 SB-728-T with no adverse effects. CD4 and SB-728-T counts increased by 268/μL and 17/μL at day 7, respectively. Homing to the gut mucosa was detected by day 14, composing 7.1% of the mucosal CD4, and increased to 21% by month 3. Histological analysis of the gut mucosa showed a corresponding increase in inflammation (p = 0.04) and elevated levels of activated CD4 and CD8 at month 3. At month 6, when SB-728-T peaked (>90%), both inflammation and activated lymphocyte levels began to trend lower. By month 12, SB-728-T in the mucosal CD4 decreased to 5.2%, coinciding with decreases in inflammation and activated lymphocytes to below baseline levels. Peripheral blood mononuclear cell PVL was evaluated using Digital Droplet qPCR method that allows for precise determination of low copy events. A ~1-log decrease over time (11 months duration) was observed.
Conclusions: SB-728-T infusion leads to a durable increase in CD4 and a decrease in peripheral PVL in an aviremic immunologic non-responder (INR) HIV subject. SB-728-T cells expand rapidly and home to the gut mucosa. Preliminary data suggest that SB-728-T leads to restoration of CD4-depleted population of the gut mucosa. In addition, the increase in CCR5 modified T cells over time during an inflammatory response at month 3, where SB-728-T increased from 7.1% to 90% (day 14 to month 6) and return to 5.2% (month 12) suggest that SB-728-T can respond to a gut inflammatory event.