The clinical trial component of this proposal consists of a phase I study of lentiviral vector transduced T-cells expressing anti-HIV siRNA (J. Zaia, P.I.). This will be the first trial of anti-HIV siRNA in humans and will be performed at City of Hope with collaboration from C. June at UPENN and M. Jensen at COH. The goals of the study are to determine the feasibility and safety of lentiviral transduction and expansion of T-cells from AIDS patients who have failed HAART. The preclinical and the clinical aspects of T-cell function will be characterized by C. June after transduction and expression of anti-HIV RNAs. He will provide important GMP manufacturing scale up support for the clinical trial in Project 5 in the areas of expansion technology and analysis of the function of T-cell after transduction and selection. In anticipation of a T cell selection system, the effect of IMPDH on T cell function and the safety of lentivirus integration will be explored.
The specific aims are as follows:
Aim 1 : To determine the feasibility and safety of RNAi-lentivirus transduced T cell immunotherapy in the setting of AIDS: Study 1: The lentivirus vector, pHIV7-shII, has been selected for clinical phase I studies based on comparative anti-HIV effect in vitro (see PRELIMINARY RESULTS). This vector was developed in our current IPCP activity by J. Rossi and J.K. Yee, and it is a self-inactivating lentivirus vector encoding a short hair-pin RNAi targeting an exon in HIV-1 rev. The clinical grade T cell product will be characterized for immune function, TCR repertoire, and resistance to HIV before and after infusion into research patients. In this study, the T cell collection, transduction, and expansion will be performed at BRICOH in Core C, and the subjects will be treated in the GCRC. The biologic effect of this transduction on cells pre- and post-infusion will be evaluated. Study 2: To determine the safety and relative efficacy of a lentivirus encoding a multiplex RNAi developed in this IPCP. Using the first generation pHIV7-shlI lentivirus vector evaluated in aim 1 for comparison, a second clinical trial will evaluate the relative survival of T cells transduced with a multi-plexed RNAi vector developed in Projects 1-3. In this second clinical trial, subjects will receive combined T cells transduced with either the fast generation RNAi vector or with the improved vector and then observed for relative T cell survival in the presence of HIV.
Aim 2 : To characterize the function of T cells after in vitro expansion and selection: The immunologic function of T cells expanded after lentivirus RNAi transduction and after transduction with new vectors developed in Projects 1-3 will be studied. A particular focus of this work will be the effect of T cell selection and expansion, using either IMPDH2- or MGMT-based methods, on the immunologic function of these cells in vitro and on the anti-HIV effect. This will contribute to the safety phase of study #1 and to the pre-clinical phase of study #2.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI061839-03
Application #
7255462
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2006-08-01
Budget End
2007-07-31
Support Year
3
Fiscal Year
2006
Total Cost
$428,913
Indirect Cost
Name
City of Hope/Beckman Research Institute
Department
Type
DUNS #
027176833
City
Duarte
State
CA
Country
United States
Zip Code
91010
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Zheng, Weiyan; Wang, Yingjia; Chang, Tammy et al. (2013) Significant differences in genotoxicity induced by retrovirus integration in human T cells and induced pluripotent stem cells. Gene 519:142-9
Trobridge, Grant D; Horn, Peter A; Beard, Brian C et al. (2012) Large animal models for foamy virus vector gene therapy. Viruses 4:3572-88
Kiem, Hans-Peter; Ironside, Christina; Beard, Brian C et al. (2010) A retroviral vector common integration site between leupaxin and zinc finger protein 91 (ZFP91) observed in baboon hematopoietic repopulating cells. Exp Hematol 38:819-22, 822.e1-3
Trobridge, Grant D; Wu, Robert A; Hansen, Michael et al. (2010) Cocal-pseudotyped lentiviral vectors resist inactivation by human serum and efficiently transduce primate hematopoietic repopulating cells. Mol Ther 18:725-33
DiGiusto, David L; Krishnan, Amrita; Li, Lijing et al. (2010) RNA-based gene therapy for HIV with lentiviral vector-modified CD34(+) cells in patients undergoing transplantation for AIDS-related lymphoma. Sci Transl Med 2:36ra43
Beard, Brian C; Trobridge, Grant D; Ironside, Christina et al. (2010) Efficient and stable MGMT-mediated selection of long-term repopulating stem cells in nonhuman primates. J Clin Invest 120:2345-54
Trobridge, G D; Kiem, H-P (2010) Large animal models of hematopoietic stem cell gene therapy. Gene Ther 17:939-48
Kiem, H-P; Wu, R A; Sun, G et al. (2010) Foamy combinatorial anti-HIV vectors with MGMTP140K potently inhibit HIV-1 and SHIV replication and mediate selection in vivo. Gene Ther 17:37-49
Bonig, Halvard; Watts, Korashon L; Chang, Kai-Hsin et al. (2009) Concurrent blockade of alpha4-integrin and CXCR4 in hematopoietic stem/progenitor cell mobilization. Stem Cells 27:836-7

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