(Compound details obtained from ChemIDplus Advanced,1 Treatment Action Group website,2 and ClinicalTrials.gov3,4)
Mechanism of Action: Gene therapy product (lentiviral vector-modified autologous CD4 T cells). Lexgenleucel-T is a gene transfer product created by genetically modifying autologous CD4 T cells ex vivo with VRX496. VRX496 is a VSV-G (vesicular stomatitis virus glycoprotein) pseudotyped HIV-based lentiviral vector. VRX496 carries a 937-base-long antisense RNA sequence directed against the gp120 region of wild-type HIV-1 env. The mechanism by which VRX496 inhibits HIV replication may be mediated by the double-stranded RNA-specific adenosine deaminase (dsRAD) enzyme, which causes HIV transcripts to be trapped and degraded within the nucleus or modified in the cytoplasm. VRX496 does not contain genetic material encoding any viral proteins, making it replication defective. Furthermore, expression of the antisense gene occurs only after HIV infects VRX496-transduced cells.5-7
Lexgenleucel-T therapy is designed to provide individuals with HIV with a reservoir of CD4 T cells that can inhibit HIV replication and the production of new virions. Lexgenleucel-T may also support the survival of CD4 T cells in the body. It is intended to allow for viral load control in the absence of ART.6,8
Half-life (T½): In a Phase 1/2 study (NCT00295477) of 17 participants with HIV receiving three to six infusions of lexgenleucel-T, the estimated half-life of lexgenleucel-T in the blood was 5.28 weeks. In 13 participants, lexgenleucel-T stably persisted in the blood for up to 5 years.9
Resistance: VRX496 pressure on HIV env has resulted in the development of mutant HIV with deletions or A to G transitions in the envelope region. These mutants, however, were found to be incapable of replication in the presence of VRX496.7,9
Select Clinical Trials
Study Identifiers: Protocol 802456; NCT00295477
Sponsor: University of Pennsylvania
Status: This study has been completed.
Study Purpose: The purpose of this open-label study was to evaluate the safety and effects of repeated lexgenleucel-T infusions on viral load and CD4 counts.
- Participants were adults with HIV who were on a stable ART regimen for the past 4 weeks prior to study entry.
- Participants were willing to continue on their current ART regimen during the study and were willing to take part in an analytical treatment interruption of ART.
- Participants had undetectable viral loads (typically <20 copies/mL) and CD4 counts >450 cells/mm3 at screening.9,10
Selected Study Results: Results published in the journal Blood (2013) showed that infusions of lexgenleucel-T were associated with decreases in viral load set points after an analytical treatment interruption of ART. After lexgenleucel-T infusions, CD4 counts increased; however, during ART treatment interruption, participants’ CD4 counts decreased significantly from baseline compared to participants who did not undergo treatment interruption. The infusions of lexgenleucel-T were found to be safe with no treatment-related serious adverse events (SAEs).9
Additional Published Material:
- CROI, 2010: Prolonged control of viremia after transfer of autologous CD4 T cells genetically modified with a lentiviral vector expressing long antisense to HIV env (VRX496)
Study Identifiers: (1) VRX496-USA-05-002; NCT00131560 and (2) VRX496-USA-05-002-Rollover; NCT00622232
Sponsor: VIRxSYS Corporation
Status: These studies are ongoing, but not recruiting participants.
Study Purpose: VRX496-USA-05-002 is an open-label study designed to evaluate the safety and biological activity of single and repeated infusions of lexgenleucel-T. The purpose of the rollover study is to evaluate the safety and therapeutic effects of an additional infusion of VRX496 in participants who successfully complete the VRX496-USA-05-002 study.
- Participants are adults with HIV who have either failed or been intolerant to at least one triple combination ART regimen.
- Participants who are receiving ART at study entry are willing to continue their current therapy during the study, and those who are not receiving ART are willing to remain off of therapy for the duration of the study.
- Participants have a stable viral load (no significant changes) in the past 3 months prior to screening. They have a viral load between 5,000 and 200,000 copies/mL and CD4 counts ≥150 cells/mm3 at screening.3,4
Selected Study Results: Results published in Molecular Therapy (2010) (abstract 646) showed that single and multiple lexgenleucel-T infusions did not significantly reduce participants’ viral load levels at the one year post-infusion time point. In most participants, lexgenleucel-T had no consistent effect on CD4 counts; however, a single dose of lexgenleucel-T was found to significantly increase CD4 counts in a small number of participants. The infusions of lexgenleucel-T were found to be safe with no SAEs identified during the study.11
Additional Published Material:
- IAS, 2011: Autologous T-cell therapy based on a lentiviral vector expressing long antisense RNA targeted against HIV-1 env gene influences HIV replication and evolution in vivo
- Mol Ther, 2010 (abstract 803): Long term persistence of VRX496-modified CD4+ T lymphocytes following lexgenleucel-T infusions for the treatment of HIV/AIDS: results from a Phase 2 clinical trial
Adverse EventsProtocol 802456 (NCT0295477):
During this Phase 1/2 study, a safety analysis was done after a median of 5 years of participant follow-up. There were no SAEs or unexpected adverse events (AEs) related to study treatment. No emergence of a replication-competent lentivirus derived from the vector was detected. Safety issues related to multiple infusions were not reported. The most common AE was a garlic/creamed corn odor during infusion, which was caused by the cryopreservative DMSO. Other common treatment-related AEs were infusion site reactions, including stinging and cold sensation, and the development of VSV-G antibodies in approximately 50% of participants after three infusions.9,10,12
Analysis was done on VRX496 integration sites from preinfusion and postinfusion samples obtained from a subset of participants. In cell samples recovered at 28 to 32 weeks postinfusion and up to 24 months postinfusion, there was no evidence indicating that lexgenleucel-T-modified cells persisted or expanded as a result of integration near cancer-associated genes.9,13VRX496-USA-05-002 (NCT00131560); VRX496-USA-05-002-Rollover (NCT00622232):
In these Phase 2 studies, no SAEs related to lexgenleucel-T treatment have been reported. In 27 participants completing 3 years of postinfusion follow-up, no long-term safety concerns have emerged. VSV-G antibodies developed in 10 participants after they received repeated infusions, but the emergence of these antibodies did not result in any AEs. Furthermore, the development of VSV-G antibodies did not affect the potency, persistence, or effectiveness of lexgenleucel-T in vivo.11,14,15
Drug InteractionsDrug-drug interactions associated with lexgenleucel-T are currently unknown.
- United States National Library of Medicine. ChemIDplus Advanced: Lexgenleucel-T. https://chem.nlm.nih.gov/chemidplus/rn/1294006-17-9. Accessed August 11, 2022
- Treatment Action Group website. Research toward a cure trials. https://www.treatmentactiongroup.org/cure/trials/. Accessed August 11, 2022
- VIRxSYS Corporation. A Phase II, open-label, multicenter study to evaluate the safety, tolerability, and biological activity of single and repeated doses of autologous T cells transduced with VRX496 in HIV-positive subjects. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on August 16, 2005. NLM Identifier: NCT00131560. https://clinicaltrials.gov/ct2/show/NCT00131560. Accessed August 11, 2022
- VIRxSYS Corporation. A rollover study to evaluate safety and therapeutic effect of re-infusing subjects who completed participation in the VRX496-USA-05-002 trial with autologous T cells transduced with VRX496. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on February 11, 2008. NLM Identifier: NCT00622232. https://clinicaltrials.gov/ct2/show/NCT00622232. Accessed August 11, 2022
- Pasternak A, Korokhov N, Berkhout B, Lukashov V, Humeau L. Autologous T-cell therapy based on a lentiviral vector expressing long antisense RNA targeted against HIV-1 env gene influences HIV replication and evolution in vivo. Abstract presented at: 6th International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment, and Prevention; July 17-20, 2011; Rome, Italy. Abstract WEPDA0205. http://www.abstract-archive.org/Abstract/Share/8813. Accessed August 11, 2022
- VIRxSYS Corporation. FDA biological response modifiers advisory committee meeting briefing package—Autologous T cells transduced with VRX496, an HIV-1 based lentiviral vector for the treatment of patient-subjects infected with HIV-1; October 26th, 2001. https://web.archive.org/web/20180127035407/https://www.fda.gov/ohrms/dockets/ac/01/briefing/3794b3_13_sponsor.pdf. Accessed August 11, 2022
- Lu X, Yu Q, Binder GK, et al. Antisense-mediated inhibition of human immunodeficiency virus (HIV) replication by use of an HIV type 1-based vector results in severely attenuated mutants incapable of developing resistance. J Virol. 2004;78(13):7079-7088. doi:10.1128/JVI.78.13.7079-7088.2004
- Hartman TL, Buckheit RW. The continuing evolution of HIV-1 therapy: Identification and development of novel antiretroviral agents targeting viral and cellular targets. Mol Biol Int. Published online 2012. doi:10.1155/2012/401965
- Tebas P, Stein D, Binder-Scholl G, et al. Antiviral effects of autologous CD4 T cells genetically modified with a conditionally replicating lentiviral vector expressing long antisense to HIV. Blood. 2013;121(9):1524-1533. doi:10.1182/blood-2012-07-447250
- University of Pennsylvania. A Phase I/II, open-label, single center study to evaluate the tolerability, trafficking and therapeutic effects of repeated doses of autologous T cells transduced with VRX496 in HIV infected subjects. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on February 21, 2006. NLM Identifier: NCT00295477. https://clinicaltrials.gov/ct2/show/NCT00295477. Accessed August 11, 2022
- Rebello T, Stein D, Blick G, et al. Safety and efficacy of autologous CD4+ T cells transduced with a lentiviral vector delivering anti-HIV RNA antisense env in HIV+ subjects failing one or more HAART regimens. Mol Ther. 2010;18:S251-S252. doi:10.1016/S1525-0016(16)38087-X
- Tebas P, Stein D, Zifchak L, et al. Prolonged control of viremia after transfer of autologous CD4 T cells genetically modified with a lentiviral vector expressing long antisense to HIV env (VRX496). 17th Conference on Retroviruses and Opportunistic Infections (CROI); February 16-19, 2010; San Francisco, CA. Levin: Conference Reports for National AIDS Treatment Advocacy Project (NATAP); 2010. http://www.natap.org/2010/CROI/croi_182.htm. Accessed August 11, 2022
- Wang GP, Levine BL, Binder GK, et al. Analysis of lentiviral vector integration in HIV+ study subjects receiving autologous infusions of gene modified CD4+ T cells. Mol Ther. 2009;17(5):844-850. doi:10.1038/mt.2009.16
- Humeau LM, Andre K, Bengtson K, Zhang S, McGarrity G, Rebello T. Long term persistence of VRX496-modified CD4+ T lymphocytes following lexgenleucel-T infusions for the treatment of HIV/AIDS: results from a Phase 2 clinical trial. Mol Ther. 2010;18:S311. doi:10.1016/S1525-0016(16)38244-2
- Lemiale F, Shovlin L, Andre K, McGarrity G, Rebello T, Humeau L. Repeated autologous infusions of cells modified with VSV-G-pseudotyped lentiviral vector VRX496 can induce anti-VSV-G humoral response in humans without clinical consequence or effect on modified cells persistence: findings from lexgenleucel-T Phase 2 clinical trial. Mol Ther. 2010;18:S17-S18. doi:10.1016/S1525-0016(16)37482-2
Last Reviewed: August 11, 2022