Background: Administration of CCR5 modified autologous CD4 cells (SB-728-T) is safe and well-tolerated and results in increases in total CD4 counts. The modified cells traffic to lymphoid tissues and have a selective survival advantage during ART treatment interruption (TI). Studies in CCR5 Δ32 heterozygote HIV subjects showed VL reductions during TI correlated with levels of engraftment of circulating bi-allelic CCR5-modified cells supporting the importance of maximizing engraftment of modified cells. We have previously presented preliminary data on the use of low dose cyclophosphamide (CTX) to enhance this process. We now report the final results of this dose ranging study.
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 well tolerated with low grade GI side-effects 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. 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 in the table is expressed as Mean + SE; changes as Day 7 relative to pre-treatment baseline.
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 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 40.5+5.6% CD4 and 46.9+6.4% CD8 T cells. CD8 count increased by a mean of 2590/uL at 7 days in the 2 subjects with data available for analysis. The VL in the first subject remains undetectable 5 weeks after TI initiation versus a median duration of 15+3 days in subjects who received only SB-728T.
Conclusions: CTX conditioning is 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.
|CTX 100 mg/m2||CTX 500 mg/m2||CTX 1 g/m2||CTX 2 g/m2||CTX 1.5 g/m2|
|ΔCD4 (cells/uL)||776 ± 502||1695 ± 518||2700 ± 966||1370 ± 721||1396 ± 367|
|ΔCD8 (cells/uL)||98 ± 49||180 ± 117||-210 ± 7||-424 ± 63||-164 ± 161|
|Bi-allelic (cells/uL)||55 ± 42||102 ± 24||169 ± 67||142 ± 30||180 ± 25|