All ETDs from UAB

Advisory Committee Chair

David T Curiel

Advisory Committee Members

Joel Glasgow

Zdenek Hel

John Mountz

Gene Siegal

Document Type

Dissertation

Date of Award

2013

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Adenoviruses are the most commonly used gene therapy vector for cancer therapy clinical trials. While adenovirus has shown a great track record in a variety of cancer therapeutics it has not progressed as a vector system for the modification of T lymphocytes. One of the major roadblocks towards utilizing adenovirus for T cell therapy is the lack of coxsackie virus and adenovirus receptor on the cell surface of T cell lineages. Exploitation of alternative receptors has allowed adenovirus vectors to be utilized in a variety of cell types that native adenovirus type 5 cannot infect. Thus, retargeting adenovirus to an alternative receptor expressed on T cells should allow for increased infectivity and full utilization of adenovirus as a gene therapy vector. There are a variety of retargeting strategies employed to retarget adenovirus to alternative cell types. Of the strategies available, we utilized the adapter-based strategy to retarget adenovirus to T cells. This strategy has a variety of advantages including its rapid development, lack of interference with adenovirus biology and assembly, and the ability to utilize secreted biological ligands. Within, we describe how resistance to adenovirus infection observed in T cells can be overcome utilizing a bi-specific adapter, sCAR-mIL-2, which retargets adenovirus to the murine interleukin 2 receptor. This adapter shows excellent ability to promote adenovirus infection in a murine T cell line, an increase was also observed in isolated primary murine T cells. These results show that alternative targeting strategies can bypass native biology and allow for the utilization of adenovirus in genetically modifying T cells for therapy.

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