Safety, Antiviral Effects, and Quantitative Measurement of Modified CD4 T Cells Trafficking to Gut Lymphoid Tissue in a Phase I/II Open-label Clinical Trial Evaluating Multiple Infusions of Lentiviral Vector-modified CD4 T Cells Expressing Long env Antisense
Ronald Collman*1, F Shaheen1, J Boyer1, G Binder1, L Zifchak1, F Aberra1, G McGarrity2, B Levine1, P Tebas1, and C June1
1Univ of Pennsylvania, Philadelphia, US and 2VIRxSYS Corp, Gaithersburg, MD, US
Background: †Gene therapy with long antisense RNA
effectively blocks HIV replication in vitro. The lymphoid trafficking,
antiviral effects and safety of multiple infusions of lentiviral vector
transduced cells expressing env antisense are unknown.
Methods: †In an ongoing phase I/II trial, HIV-1-infected
subjects fully suppressed on ART received over 14 weeks until 6 infusions each
of 1010 autologous CD4 T cells transduced ex vivo with a
lentiviral vector encoding a 937nt env antisense construct (VRX496). At
week 18, eligible subjects underwent scheduled treatment interruption to
evaluate effects on viral load and CD4 count during viremia. Rectal biopsies
were obtained at baseline, after the third and sixth infusions, and 6 weeks
post-scheduled treatment interruption. Intraepithelial lymphocytes were
isolated and CD4 cells quantitated by flow cytometry. Vector copies per CD4
cell were measured in Intraepithelial lymphocytes and blood. Average viral load
at 10 and 14 weeks post scheduled treatment interruption was compared to the
subjectís pre treatment set point when available. Patients were monitored for
vector-derived replication competent lentivirus and immunogenicity, and T cell
receptor (TCR) diversity.
Results: †Of the total, 12 subjects completed infusions
and 7 underwent scheduled treatment interruption. Vector was detected in
Intraepithelial lymphocytes from 8 of 10 patients. VRX496-transduced T cells
persisted following scheduled treatment interruption in 4 and 6 of 7 evaluable
subjects in gut and blood, respectively. Vector copy number per CD4 T cell in
Intraepithelial lymphocytes and blood were strongly correlated (p = 0.0004).
CD4 cells increased concomitant with dosing in the blood but not the gut.
Following scheduled treatment interruption, all subjects had rebound viremia
and decreased blood CD4 counts, whereas mucosal CD4 cells were lower than blood
at baseline and did not decrease following scheduled treatment interruption.
Viral load set points decreased by 0.27 to 1.03 log in 3 patients; 4 patients
had low nadir CD4 and discontinued scheduled treatment interruption prior to
establishing set points. Half of patients developed antibodies against vesicular
stomatitis virus-G (VSV-G), which did not correlate with adverse events or loss
of vector modified cells. No TCR oligoclonality or replication competent
lentivirus was detected, and there were no safety concerns associated with
Conclusions: †Gene-modified CD4 T cells ex vivo
traffic to gut lymphoid tissue in most patients, persist following treatment
interruption, and are correlated with persistence in blood. Multiple infusions
of lentiviral vector modified cells increase CD4 counts prior to scheduled
treatment interruption and may decrease viral load set-point post-scheduled
treatment interruption. The protocol has been amended and repowered to further
evaluate this aspect.