Multiple Treatment Interruptions and Protecting HIV-Specific CD4 T-Cells Enables Durable CTL Response and Viral Control

BACKGROUNDThe cell and gene therapy product AGT103-T was evaluated (NCT04561258) for safety, immunogenicity, and persistence for up to 180 days post infusion. We sought to investigate the impact following analytical treatment interruptions (ATIs). METHODSSix patients suspended their antiretroviral therapy (ART) until their viral load reached 100,000 copies/mL in two successive visits, or their CD4 count fell below 300 cells/L. We measured the magnitude of viral rebound, the persistence of AGT103-T transduced CD4+ T-cells and the impact on HIV-specific immune responses. RESULTSDuring the ATI, all patients experienced logarithmic viral rebound followed by a 2-5-fold increase in total CD8 counts, that coincided with a rise in HIV-specific CD8 T-cells. This was attributed to the increase in antigen availability and memory recall. Thus, to determine if the immune response generated during this "auto-vaccination" event can contribute to viral suppression upon subsequent exposures, a second ATI was initiated. During the second ATI, the Gag-specific CD8 T cells were either maintained or rose and the peak viremia was substantially decreased with viral set-points ranging from 7,000-25,000 copies/mL. Upon ART resumption, faster viral control was demonstrated without any serious adverse events (SAEs) or drug resistance. CONCLUSIONAGT103-T gene therapy and multiple ATIs were not associated with SAEs and allowed subjects to establish a low viral set-point with relatively stable CD4 T cell counts. Additionally, multiple ATIs are beneficial for the study design when induction of CD8 T cells is required to establish viral control. REGISTRATIONClinicalTrials.gov NCT05540964 FUNDINGAmerican Gene Technologies International Inc.