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Therapeutic Gene Therapy for Cancer with Interleukin-23

Reay, Ja'Nean Christine (2010) Therapeutic Gene Therapy for Cancer with Interleukin-23. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Th1-polarizing cytokine IL-12 exhibits potent anti-tumor activity in multiple cancer models; however, therapeutic use of this cytokine is limited due to severe IFN-ã-mediated toxicity. To reduce the amount of IL-12 needed to elicit a therapeutic response, and thereby decrease associated toxicity, it is necessary to characterize novel cytokines to use in conjunction with IL-12. Newly described IL-12 family member IL-23 shares the IL-12 p40 subunit and promotes Th1 immunity by inducing IFN-ã expression and specifically stimulating proliferation of memory CD4+ T-cells. I have demonstrated that injection of an adenovirus expressing IL-23 (Ad.IL-23) into the tumor microenvironment results in significantly enhanced survival and tumor rejection in 40 percent of animals, with concomitant induction of protective anti-tumor immunity. Furthermore, the anti-tumor activity of IL-23 is dependent on IL-12, IFN-ã and CD4+ and CD8+ T-cells, indicating generation of a Th1 response. Delivery of adenovirus expressing IL-12 (Ad.IL-12) into the tumor microenvironment also results in enhanced survival and tumor rejection in up to 90 percent of animals. In contrast to Ad.IL-23, Ad.IL-12 anti-tumor activity requires only IFN-ã and induces protective immunity only 50 percent of the time, suggesting activation primarily of innate immunity. Due to the similar, yet divergent, effector mechanisms used in Ad.IL-12 and Ad.IL-23 anti-tumor effects, I hypothesized that use of these two viruses together would result in synergistic enhancement of tumor eradication. Surprisingly, Ad.IL-12 and Ad.IL-23 do not synergistically enhance anti-tumor effects over use of either cytokine alone, possibly due to IL-23 p19 sequestration of p40. To circumvent this possibility, adenovirus expressing single chain IL-23 (Ad.scIL-23) was constructed and characterized. Ad.scIL-23 expresses greater levels of cytokine than Ad.IL-23 and treatment of tumor bearing mice results in tumor rejection in 90 percent of animals. However, Ad.scIL-23 does not synergize with Ad.IL-12. Overall, I have shown that IL-23 does possess therapeutic anti-tumor effects, but does not synergize with IL-12 to enhance tumor eradication. Future studies could include characterizing CD4+ T-cell infiltrate of tumors treated with both Ad.IL-12 and Ad.IL-23 to elucidate the mechanism behind the lack of synergy between these two cytokines.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Reay, Ja'Nean
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairRobbins, Paulprobb@pitt.eduPROBB
Committee MemberGambotto, Andreagambottoa@upmc.eduAGAMB
Committee MemberOkada,
Committee MemberKolls,
Committee MemberStorkus, Walterstorkuswj@upmc.eduSTORKUSW
Date: 25 May 2010
Date Type: Completion
Defense Date: 12 May 2010
Approval Date: 25 May 2010
Submission Date: 20 May 2010
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Molecular Virology and Microbiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: adenovirus; cancer; gene therapy; IL-12; IL-23
Other ID:, etd-05202010-125900
Date Deposited: 10 Nov 2011 19:45
Last Modified: 19 Dec 2016 14:36


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