Gene therapy of disseminated malignancy is limited by a lack of targeted vectors that can cross multiple tissue boundaries to reach all tumor deposits. Specific CTLs, however, can be generated against tumor antigens, and are able to cross tissue barriers and to specifically recognize tumor cells. We wish to combine the mobility and targeting functions of T cells with the capacity of adenovirus to efficiently transduce tumor cells and deliver oncolytic genes. As our model we will use CTL targeted to Epstein Barr Virus (EBV), since this virus contributes both to Hodgkin Disease and to immunoblastic lymphomas in the immunocompromised host. We have already infected EBV specific-CTLs with a Moloney derived retrovirus containing the adenovirus E1 gene under CD40L promoter control. This promoter is strictly regulated by T cell activation. When transduced with a therapeutic E1 deleted-Ad5F35 vector, E1-modified EBV specific-CTL produce an active adenovector only following specific engagement of their antigen specific receptors by EBV infected lymphoma cells. The CTL thereby deliver vector directly to tumor cells. In this application, we will test the hypothesis that the EBV-CTLs will traffic to the site of the EBV tumor, will express E1A upon antigen-mediated activation, replicate the adenovector they contain and infect adjacent tumor cells. In three specific Aims we will: 1) optimize the individual components of this system to obtain the largest adenoviral """"""""burst"""""""" size consistent with retention of antigen specific regulation 2) Compare the oncolytic activity of an Ad5F35 thymidine kinase (Tk) vector and a conditionally replication competent vector made by the EBV-CTL """"""""producer"""""""" cells 3) Determine the anti-tumor effects of """"""""producer"""""""" EBV-CTL in a NOD/SCID mouse model of EBV-positive lymphoma. At the conclusion of this study we will have in place an approach that could be implemented to allow truly targeted delivery of therapeutic vectors to disseminated malignancies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Small Research Grants (R03)
Project #
5R03DK067264-03
Application #
7091543
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Rankin, Tracy L
Project Start
2004-07-01
Project End
2008-06-30
Budget Start
2006-07-01
Budget End
2008-06-30
Support Year
3
Fiscal Year
2006
Total Cost
$146,963
Indirect Cost
Name
Baylor College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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Yotnda, P; Zompeta, C; Heslop, H E et al. (2004) Comparison of the efficiency of transduction of leukemic cells by fiber-modified adenoviruses. Hum Gene Ther 15:1229-42