Background
TRAILBLAZER is a multi-center blinded, randomized trial of infusion of autologous zinc-finger endonuclease-modified CCR5-edited CD4+ lymphocytes (MC) compared to autologous infusion of unmodified CD4+ lymphocytes (UC). We hypothesized that abrogating CCR5 expression in CD4+ memory T cells would result in accelerated clearance of the replication competent HIV reservoir.
Methods
We enrolled PWH age 18-70 years on stable antiretroviral therapy (ART) with a CD4 count >350 c/mm3 and HIV-1 RNA < 50 copies/mL for ≥ 48 weeks. Participants were randomized (2:1) to receive a single intravenous infusion of 0.5 to 4×1010ex vivo expanded autologous CD4+ memory T cells that have been transduced with a zinc finger nuclease designed to knock out the CCR5 gene or unmodified CD4+ T cells. All participants received cyclophosphamide conditioning (1 gm/M2). The frequency of cells harboring intact HIV was estimated using the intact proviral DNA assay (IPDA, Accelevir) at entry, week 48 and 96.
Results
30 participants were enrolled (19 MC, 11 UC). The median age was 55 years (min, max: 28, 69 years); all were male sex at birth; 30% non-white race; median duration of ART 14 years; and a median CD4 count 650 cells/mm3 (357,1105 cells/mm3). There were no significant unanticipated side effects from the cyclophosphamide conditioning or study product infusion, and no Grade ≥3 treatment-related adverse events. Four participants had unevaluable IPDA data due to amplicon signal failure (all in CCR5-modified arm), 1 participant had undetectable IPDA at all time points, and 1 participant prematurely discontinued the study for reasons unrelated to the study. In the remaining 24 participants (N=13 MC; N=11 UC), IPDA had minimal changes over time (Figure), with mean changes between -0.1 and +0.1 log10 in both treatment arms. There was no evidence the CCR5-modified arm had greater changes in IPDA than the unmodified arm (p=0.48 week 96, primary endpoint). Mean changes in total provirus were between -0.08 to -0.05 log10, with no differences in the treatment arms (p=1.0 at week 96).
Conclusions
In this blinded randomized controlled trial of re-infusion of autologous CCR5-gene edited CD4+ memory T cells, there was no significant reduction in HIV reservoir as measured by intact or total HIV proviruses using the IPDA assay at weeks 48 or 96. It will be important to determine the threshold of CCR5-edited memory CD4+ T cells and tissue HIV reservoir to understand these results.