25. A Dose Escalation Study of Cyclophophamide (CTX) to Enhance SB-728-T Engraftment

Background: CCR5 modified autologous CD4 cells (SB-728-T) are safe and increases total CD4 counts. The cells traffic to lymphoid tissues and have a selective survival advantage during ART treatment interruption (TI). Additional studies in CCR5 D32 heterozygote HIV subjects showed VL reductions during TI correlated with circulating bi-allelic CCR5-modified CD4 cells supporting the importance of maximizing engraftment. Low dose CTX has been successfully used to increase T cell engraftment. This study examines the effect of escalating doses of CTX on SB-728-T engraftment. Methods: A dose escalation study of IV CTX, with doses ranging from 100 mg/m2 to 2 g/m2 (n=3-6/cohort), administered 1-3 days prior to SB-728-T (>90% CD4, <1% CD8) infusion was performed in 18 aviremic, ART treated HIV subjects with CD4 T cells ≥500/uL. Results: CTX was generally well tolerated with low grade GI side-effects, managed with anti-emetics, at doses up to 1 g/m2. Grade 3 and 4 neutropenia requiring G-CSF developed at 1.5 and 2.0 g/m2 CTX. On Day 7, a dose-related increase in CD4 count and engraftment of bi-allelic CCR5 modified cells was observed with CTX doses up to 1 g/m2 but did not increase at 2.0 and 1.5 g/m2. By comparison, there was a progressive decline in CD8 cells with CTX dose escalation. Data is expressed as Mean +/- SE in Table 1.Table 1100 mg/m2500 mg/m21 g/m22 g/m21.5 g/m2ΔCD4 (cells/uL)776±5021695±5182700±9661370±7211396±367ΔCD8 (cells/uL)98±49180±117−210±7−424±63−164±161Bi-allelic (cells/uL)55±42102±24169±67142±30180±25 Open table in a new tab A 1-log VL reduction from peak was seen in 1 subject each at 100 and 500 mg/m2 of CTX while 1 subject each at the 1 and 1.5 g/m2 dose level had a 2-log decline during a TI. At the conclusion of the study, 3 additional subjects were conditioned with 1 g/m2 of CTX and administered CCR5 modified T cells containing 46.9+/-6.4% CD8 cells. CD8 count increased by 2236+/-967/uL (range 1029-4150/uL) with only modest increases in CD4 counts (733+/-233/uL; range 297-1096/uL) at 7 days in the 3 subjects. Two of the three subjects have had modest increases in VL to date during TI (<1000 copies/mL), suggesting an effect on viral control with the added CD8 T cells. Conclusion: CTX conditioning is generally well tolerated and was associated with increased engraftment of CCR5-modified T cells at doses up to 1 g/m2 in HIV subjects. CTX conditioning may be a useful strategy to maximize the engraftment and anti-viral effects of SB-728-T. The effects of co-administering CD8 cells with SB-728-T on VL will be presented.