The central theme of the proposal is to continue testing lentiviral engineered T cells for safety and efficacy in HIV infection. This proposal continues the progress made recent years by our group in developing immune restoration for HIV using adoptive T cell transfer and the development of lentiviral vectors to engineer intrinsic HIV resistance. We have recently completed the world's first pilot test of lentiviral gene transfer in humans. Results from the first five subjects are encouraging and warrant formal study to optimize the approach under this RFA. This proposal represents a strong and productive interaction between academia and the private sector that is highly motivated in bringing lentiviral vector technology, in general, and T cell gene transfer therapy in particular, to the bedside, and to do this in a safe and rigorous fashion. The overall goal is to carefully establish the safety or our innovative clinical trials by testing laboratory-based hypotheses, while pursuing additional basic investigation of lentiviral engineering for subsequent immunogene transfer trials for HIV/AIDS. The elements of this proposal are as follows: ? Clinical Trials Engine: Lentiviral Engineered T Cells for HIV (Project 1, C. June and P. Tebas). This project will test first and second generation lentiviral vectors that express anti-sense HIV for safety and efficacy and trafficking in phase l/ll trials. Effects of lentiviral engineered CD4 T cells on the host virus relationship will be determined using unique patient samples. ? Lentiviral Vector Integration in the Clinic (Project 2, F. Bushman): A comprehensive evaluation of lentiviral integration will be done to predict long term safety of lentiviral engineered T cells. ? Engineering Innate T Cell Resistance to HIV Infection (Project 3, J. Riley and R. Doms): Improved lentiviral vectors will be developed by targeting TRIMSa and other novel targets using zinc finger nucleases, and a SCID-hu model will be used to select an optimized vector for clinical testing. The program is supported by 3 cores: Core A, the Lentiviral GLP and GMP Vector Core; Core B, the Cell Engineering Core, and Core C, the Administrative and Biostatistics Core. Private sector interactions are established with ViRxSYS Corp. and Sangamo BioSciences, Inc. Together these studies will provide a comprehensive evaluation of the safety and antiviral efficacy of lentiviral vectors for HIIV/AIDS, and they will move the field forward by providing critical safety data for this new and exciting class of vectors. ? ? PROJECT 1: Clinical trials engine: lentiviral engineered T cells for HIV (June, C. H.) ? ? DESCRIPTION (provided by applicant): The principle that adoptively transferred T lymphocytes have therapeutic promise for HIV infection is well established. Our long range goals are to establish the safety of infusions of lentiviral engineered T cells, and to test second generation transgenes for safety and improved antiviral efficacy. Our long range objective is to obviate the need to take daily antiviral medications in patients with HIV infection. In a recently completed phase I pilot study, we have demonstrated the safety and feasibility of a single infusion of lentiviral engineered autologous CD4 T cells when administered to HIV infected subjects with late-stage, HAART resistant HIV infection. To date, there is no evidence of insert ional mutagenesis, and one subject has experienced a reduction in viral load. The engraftment and persistence of the gene-modified T cells is satisfactory and suggests that the VSV-G pseudotyped HIV-based lentiviral vector system is nonimmunogenic. Based on our previous studies of costimulated CD4 T cells, we now hypothesize that multiple infusions of lentiviral engineered autologous CD4 T cells that express the VRX496 antisense env transgene will lead to a sustained and higher level engraftment. We further hypothesize that the transgene will confer antiviral effects. Two clinical trials are proposed to test these hypotheses. First, we will perform a multiple dose phase l/ll study in patients whose viral replication is suppressed on HAART. Structured treatment interruption will be carried out to assess antiviral efficacy, and lymphoid biopsies will be used to determine tissue trafficking of the engineered CD4 T cells. In trial #2 we will test a lentiviral vector developed in project 3 that expresses a more potent antiviral product. We will compare the relative survival of the T cells transduced with the second generation vector to cells transduced with the original VRX496 vector tested in trial #1. Together, these trials will represent the first formal efficacy tests of lentiviral engineered T cells for their potential to serve as a potent antiviral therapy for treatment of HIV-1 infection. This project interacts with projects 2, and 3, and the project relies on Cores A and B for cGMP lentiviral vector manufacturing and for clinical grade T cell expansion and transduction technology. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI066290-02
Application #
7113712
Study Section
Special Emphasis Panel (ZAI1-TS-A (M2))
Program Officer
Voulgaropoulou, Frosso
Project Start
2005-09-01
Project End
2009-02-28
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
2
Fiscal Year
2006
Total Cost
$1,936,423
Indirect Cost
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Riley, James L; Montaner, Luis J (2017) Cell-Mediated Immunity to Target the Persistent Human Immunodeficiency Virus Reservoir. J Infect Dis 215:S160-S171
Levine, Bruce; Leskowitz, Rachel; Davis, Megan (2015) Personalized gene therapy locks out HIV, paving the way to control virus without antiretroviral drugs. Expert Opin Biol Ther 15:831-43
Richardson, Max W; Guo, Lili; Xin, Frances et al. (2014) Stabilized human TRIM5? protects human T cells from HIV-1 infection. Mol Ther 22:1084-1095
Tebas, Pablo; Stein, David; Tang, Winson W et al. (2014) Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. N Engl J Med 370:901-10
Maier, Dawn A; Brennan, Andrea L; Jiang, Shuguang et al. (2013) Efficient clinical scale gene modification via zinc finger nuclease-targeted disruption of the HIV co-receptor CCR5. Hum Gene Ther 24:245-58
Tebas, Pablo; Stein, David; Binder-Scholl, Gwendolyn et al. (2013) Antiviral effects of autologous CD4 T cells genetically modified with a conditionally replicating lentiviral vector expressing long antisense to HIV. Blood 121:1524-33
Gijsbers, Rik; Vets, Sofie; De Rijck, Jan et al. (2011) Role of the PWWP domain of lens epithelium-derived growth factor (LEDGF)/p75 cofactor in lentiviral integration targeting. J Biol Chem 286:41812-25
Mukherjee, Rithun; Plesa, Gabriela; Sherrill-Mix, Scott et al. (2010) HIV sequence variation associated with env antisense adoptive T-cell therapy in the hNSG mouse model. Mol Ther 18:803-11
June, Carl H; Blazar, Bruce R; Riley, James L (2009) Engineering lymphocyte subsets: tools, trials and tribulations. Nat Rev Immunol 9:704-16
Wang, Gary P; Levine, Bruce L; Binder, Gwendolyn K et al. (2009) Analysis of lentiviral vector integration in HIV+ study subjects receiving autologous infusions of gene modified CD4+ T cells. Mol Ther 17:844-50

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