Link to the University of Pittsburgh Homepage
Link to the University Library System Homepage Link to the Contact Us Form

Induction of anti-tumor responses via adoptively transferred, cytokine-gene transduced A-NK cells

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 (Unpublished)

Primary Text

Download (12MB) | Preview


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.


Social Networking:
Share |


Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Goding, Stephen R.
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairBasse, Perbasse@imap.pitt.eduBASSE
Committee MemberGambotto, Andreagambottoa@upmc.eduAGAMB
Committee MemberGorelik, Eliesergorelik@pitt.eduGORELIK
Committee MemberVujanovic, Nikolavujanovicnl@upmc.eduVUJANOVI
Committee MemberKalinski, Pawelkalinskip@upmc.eduPAK5
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:, etd-07162008-204724
Date Deposited: 10 Nov 2011 19:51
Last Modified: 19 Dec 2016 14:36


Monthly Views for the past 3 years

Plum Analytics

Actions (login required)

View Item View Item