Abstract

In collaboration with Sangamo, we have previously employed the use of zinc finger nucleases (ZFN) to edit the CCR5 gene to generate HIV resistant CD4+ T cells. Building upon that success, and mindful of it limitations, our study aims to protect CD4 cells by expressing C34- CXCR4 to render them resistant to both R5 and X4 HIV. The hypothesis of our study is that autologous CD4+ T cells genetically modified with an HR2, C34-peptide conjugated to the CXCR4 N-terminus using lentiviral vector will be resistant to HIV infection in vivo in the setting of an analytical treatment interruption and will preserve and enhance an immunological response to HIV. In close collaboration with Projects 2, 3 and 4, and Cores A and B, we will evaluate in vivo C34- CXCR4-modified autologous CD4+T cells with 3 Specific Aims SA1: Complete pre-clinical testing necessary to support manufacturing of C34-CXCR4-modified autologous CD4+T cells. SA2: Conduct a proof of concept clinical trial to determine the safety of C34-CXCR4-modified autologous CD4+T cells in patients with well controlled viral replication. SA3: Evaluate the host and virological response to C34-CXCR4-modified autologous CD4+T cells.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
1U19AI117950-01
Application #
8899247
Study Section
Special Emphasis Panel (ZAI1-BP-A (J3))
Project Start
Project End
Budget Start
2015-04-10
Budget End
2016-03-31
Support Year
1
Fiscal Year
2015
Total Cost
$576,249
Indirect Cost
$208,129

  Institution

Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104

  Publications

Fraietta, Joseph A; Nobles, Christopher L; Sammons, Morgan A et al. (2018) Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells. Nature 558:307-312
Medvec, Andrew R; Ecker, Christopher; Kong, Hong et al. (2018) Improved Expansion and In Vivo Function of Patient T Cells by a Serum-free Medium. Mol Ther Methods Clin Dev 8:65-74
Clarke, Erik L; Connell, A Jesse; Six, Emmanuelle et al. (2018) T cell dynamics and response of the microbiota after gene therapy to treat X-linked severe combined immunodeficiency. Genome Med 10:70
Stelekati, Erietta; Chen, Zeyu; Manne, Sasikanth et al. (2018) Long-Term Persistence of Exhausted CD8 T Cells in Chronic Infection Is Regulated by MicroRNA-155. Cell Rep 23:2142-2156
Ecker, Christopher; Riley, James L (2018) Translating In Vitro T Cell Metabolic Findings to In Vivo Tumor Models of Nutrient Competition. Cell Metab 28:190-195
Ecker, Christopher; Guo, Lili; Voicu, Stefana et al. (2018) Differential Reliance on Lipid Metabolism as a Salvage Pathway Underlies Functional Differences of T Cell Subsets in Poor Nutrient Environments. Cell Rep 23:741-755
Maldini, Colby R; Ellis, Gavin I; Riley, James L (2018) CAR T cells for infection, autoimmunity and allotransplantation. Nat Rev Immunol 18:605-616
Bengsch, Bertram; Ohtani, Takuya; Khan, Omar et al. (2018) Epigenomic-Guided Mass Cytometry Profiling Reveals Disease-Specific Features of Exhausted CD8 T Cells. Immunity 48:1029-1045.e5
Veenhuis, Rebecca T; Kwaa, Abena K; Garliss, Caroline C et al. (2018) Long-term remission despite clonal expansion of replication-competent HIV-1 isolates. JCI Insight 3:
Chen, Gang; Huang, Alexander C; Zhang, Wei et al. (2018) Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response. Nature 560:382-386

Showing the most recent 10 out of 27 publications