Goding, Stephen R. L.
(2008)
Induction of anti-tumor responses via adoptively transferred, cytokine-gene transduced A-NK cells.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Despite successes in animals, cytokine gene expression selectively in human tumors is difficult to achieve due to lack of efficient delivery methods. We previously demonstrated that adoptively transferred, IL-2 activated natural killer (A-NK) cells are very effective in trafficking to, infiltrating and, subsequently, reducing B16 lung tumors in tumor-bearing animals. We therefore speculated that the tumor-seeking A-NK cells could be used for the delivery of cytokines selectively to the tumor microenvironment. However, tumor infiltration by A-NK cells depends on high and often toxic doses of IL-2 to support the transferred A-NK cells' survival and anti-tumor functions. To address this problem, we hypothesized that A-NK cells transduced to express pro-NK cell cytokines would become less dependent on high and potentially toxic amounts of IL-2. Assessments of transduction efficiency in vitro demonstrated that adenoviral transduction consistently resulted in high (>60%) transduction rates and substantial expression of transgenes such as GFP, luciferase, and mIL-12 for at least 4 days. In vivo experiments illustrated that mIL-12 transduced A-NK cells localized and survived significantly better than mock transduced cells within lung metastases than in the surrounding normal lung tissue when supported with low, non-toxic doses of IL-2. The intratumoral survival of non-transduced "bystander" A-NK cells also increased when they were co-injected with IL-12 gene-transduced A-NK cells. The enhanced survival of exogenously delivered, IL-12 gene-transduced A-NK cells resulted in greater anti-tumor responsiveness. This led to a 7-10 day increase in median survival time compared to tumor-bearing mice receiving mock-transduced A-NK cells. These data show that the presence of IL-12 around tumor-infiltrating A-NK cells enhances their anti-tumor activity while reducing their requirement for systemically administered IL-2. This A-NK cell delivered IL-12 has lead to an enhanced host anti-tumor reactivity, which appeared to be mediated through cytokine involvement, namely IFNγ, rather than T, B, and NK cellular activity. Thus, adoptive transfer of A-NK cells represents an efficient method for targeting products of genes to tumor sites and eliciting anti-tumor responses.
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
23 July 2008 |
| Date Type: |
Completion |
| Defense Date: |
24 June 2008 |
| Approval Date: |
23 July 2008 |
| Submission Date: |
16 July 2008 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Immunology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
gene therapy; natural killer cells; tumor immunotherapy |
| Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-07162008-204724/, etd-07162008-204724 |
| Date Deposited: |
10 Nov 2011 19:51 |
| Last Modified: |
19 Dec 2016 14:36 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/8403 |
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