Antiviral effects of autologous CD4 T cells genetically modified with a conditionally replicating lentiviral vector expressing long antisense to HIV

• Published in: Blood Vol. 121; no. 9; pp. 1524 - 1533
• Main Authors: Tebas, Pablo, Stein, David, Binder-Scholl, Gwendolyn, Mukherjee, Rithun, Brady, Troy, Rebello, Tessio, Humeau, Laurent, Kalos, Michael, Papasavvas, Emmanouil, Montaner, Luis J., Schullery, Daniel, Shaheen, Farida, Brennan, Andrea L., Zheng, Zhaohui, Cotte, Julio, Slepushkin, Vladimir, Veloso, Elizabeth, Mackley, Adonna, Hwang, Wei-Ting, Aberra, Faten, Zhan, Jenny, Boyer, Jean, Collman, Ronald G., Bushman, Frederic D., Levine, Bruce L., June, Carl H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 28.02.2013; American Society of Hematology
• Subjects: Adoptive Transfer - methods; Adult; Antiviral Agents - adverse effects; Antiviral Agents - metabolism; Antiviral Agents - pharmacology; CD4-Positive T-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - physiology; CD4-Positive T-Lymphocytes - transplantation; Clinical Trials and Observations; Female; Gene Therapy; Genetic Therapy - adverse effects; Genetic Therapy - methods; Genetic Vectors - adverse effects; Genetic Vectors - metabolism; Genetic Vectors - pharmacology; HIV Infections - genetics; HIV Infections - immunology; HIV Infections - therapy; HIV-1 - genetics; HIV-1 - immunology; Human immunodeficiency virus; Humans; Immunobiology; Lentivirus - genetics; Lentivirus - metabolism; Lentivirus - physiology; Male; Middle Aged; Oligonucleotides - administration & dosage; Oligonucleotides - genetics; Oligonucleotides, Antisense - administration & dosage; Oligonucleotides, Antisense - adverse effects; Oligonucleotides, Antisense - genetics; Oligonucleotides, Antisense - pharmacology; Transduction, Genetic - methods; Viral Load - drug effects; Virus Replication - genetics
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2012-07-447250

We report the safety and tolerability of 87 infusions of lentiviral vector–modified autologous CD4 T cells (VRX496-T; trade name, Lexgenleucel-T) in 17 HIV patients with well-controlled viremia. Antiviral effects were studied during analytic treatment interruption in a subset of 13 patients. VRX496-T was associated with a decrease in viral load set points in 6 of 8 subjects (P = .08). In addition, A → G transitions were enriched in HIV sequences after infusion, which is consistent with a model in which transduced CD4 T cells exert antisense-mediated genetic pressure on HIV during infection. Engraftment of vector-modified CD4 T cells was measured in gut-associated lymphoid tissue and was correlated with engraftment in blood. The engraftment half-life in the blood was approximately 5 weeks, with stable persistence in some patients for up to 5 years. Conditional replication of VRX496 was detected periodically through 1 year after infusion. No evidence of clonal selection of lentiviral vector–transduced T cells or integration enrichment near oncogenes was detected. This is the first demonstration that gene-modified cells can exert genetic pressure on HIV. We conclude that gene-modified T cells have the potential to decrease the fitness of HIV-1 and conditionally replicative lentiviral vectors have a promising safety profile in T cells. This study is registered at www.clinicaltrials.gov as number NCT00295477. •Adoptive transfer of autologous lentiviral-engineered T cells expressing an antisense is safe in chronic HIV infection.•Conditionally replicating lentiviral vector was associated with antiviral effects in patients as assessed by viral evolution and viral load.