1075. Phase I Clinical Trial Demonstrates Safety and Feasibility of Autologous Cellular Therapy with Lentiviral Modified CD4 T Cells Expressing Anti-HIV Antisense in Patients with HAART Resistant HIV-1 Infection

Abstract

Top of pageAbstract Emerging drug resistance raises concerns about HAART as a long-term therapy. We have developed an HIV-1-based lentiviral vector expressing a 937-base antisense gene against the HIV envelope for autologous T cell therapy for HIV/AIDS. The vector introduces no new sequences to an HIV-infected individual. In preclinical studies, HIV replication was inhibited over 95%, and up to 4 logs, in primary CD4 T lymphocytes isolated from HIV-infected patients. For evaluation of safety and tolerability of this therapy, a Phase I open-label non-randomized clinical trial has been carried out. Five patients who have failed at least two HAART regimens due to intolerance or resistance, and have CD4 counts above 150 cells/mm3 and a viral load greater than 5000 copies/ml, have been serially enrolled for a 6-month study with 21 day, 3, 6, 9, and 12-month monitoring points. Each patient was given a single i.v. dose of |[sim]| 1 |[times]| 1010 genetically-modified autologous T cells, and then monitored for viral load, CD4 count, replication competent lentivirus (RCL), outgrowth of vector-modified cells, immunological parameters, and adverse events. Serious adverse events (SAE) were defined in part by a sustained 30% increase in viral load, or sustained 0.5 log decrease in CD4 count within 3 weeks post dose. All five patients have been dosed, and have completed the critical 3-week safety timepoint. No SAEs related to the product have occurred, and all RCL tests have been negative, including a biological RCL assay performed on apheresed patient PBMCs at 6 months. Patients 1-3 have reached their 1 year follow-up and all three have demonstrated clinically significant (>0.5 log) reductions in their viral loads at 1 year at 0.78 log, 1.61 log, and 0.57 log, respectively. Furthermore, patients 2 and 3 have had a 20% and 30% increase in CD4 counts, respectively, while patient 1 has maintained a steady CD4 count. Patient 4 will reach his 9-month follow up in March, and Patient 5 has just completed his 3-month follow up. Circulating vector-modified cells was detected in patient 2 at one year, to month 9 in patients 1 and 3, and they remain detectable in patients 4 and 5. To date, 211 total integration sites from the transduced clinical products of all 5 patients have been analyzed; initial results indicate that VRX496 preferentially integrates into transcription units and disfavors integration into alphoid repeats, a pattern that is comparable to and indistinguishable from wild type HIV. These data support the safety and feasibility of lentiviral vector therapy in the setting of ex vivo cellular therapy.