1. 1 Dosimetric Optimization of Interstitial Gene Therapy Delivery Systems The Gynecologic Disease Program 1 Georgetown University Med. Ctr. 2 Walter Reed Army Med. Ctr. Kenneth H. Wong 1, PhD; Mira Jung 1, PhD; Anatoly Dritschilo 1, MD; G. Larry Maxwell 2, MD,

2. Oak Ridge National Lab BSEC Feb 18, 2009 2 Limits on Current Cancer Therapy Cancer is fundamentally a genetic disease. Gene therapy is biologically targeted, but distribution is difficult to control. Bystander and systemic effects pose major limitations.

3. Oak Ridge National Lab BSEC Feb 18, 2009 3 Limits on Current Cancer Therapy Radiation therapy can be highly conformal, but also biologically indiscriminate. How can we devise an effective combination therapy? cyberknifeinstamford.com graveslab.stanford.edu

4. Oak Ridge National Lab BSEC Feb 18, 2009 4 GeneSeeds are small hollow titanium tubes which can be implanted like brachytherapy seeds. Multiple seeds with regular spacing enables treatment of larger regions or organs. GeneSeed Concept

5. Oak Ridge National Lab BSEC Feb 18, 2009 5 GeneSeeds were originally designed to express constitutively (always on). GeneSeed Concept pIEX-1TNF-α The GeneSeed payload can now be linked to different promoters, allowing enhanced control of gene expression. Radiation Inducible Promoter

6. Oak Ridge National Lab BSEC Feb 18, 2009 6 GeneSeed Effect on Tumor Growth

7. Oak Ridge National Lab BSEC Feb 18, 2009 7 Brachytherapy Tools www.micknuclear.com www.cfpc.ca/cfp www.oncura.net

8. Oak Ridge National Lab BSEC Feb 18, 2009 8 Ultrasound imaging

9. Oak Ridge National Lab BSEC Feb 18, 2009 9 Cone beam CT guidance Siemens DynaCT

10. Oak Ridge National Lab BSEC Feb 18, 2009 10 Seed Geometry L D d z1z1 θ z r

11. Oak Ridge National Lab BSEC Feb 18, 2009 11 Diffusion Model 1.Divide region into 100 micrometer voxels. 2.Compute concentration gradients. 3.Transport plasmid, repeat

12. Oak Ridge National Lab BSEC Feb 18, 2009 12 Model results

13. Oak Ridge National Lab BSEC Feb 18, 2009 13 Monte Carlo Model 1.Vector as a particle with randomly chosen direction and path length. 2.Opening in the seed modeled as a line source of vectors.

14. Oak Ridge National Lab BSEC Feb 18, 2009 14 Reporter gene expression Microtome slices for microscopy & immunohistochemistry Excised tumor

15. Oak Ridge National Lab BSEC Feb 18, 2009 15 Gene v. Radiation Seed

16. Oak Ridge National Lab BSEC Feb 18, 2009 16 Dose Simulations – Effect of Seed Misplacement 0 1 3 2

17. Oak Ridge National Lab BSEC Feb 18, 2009 17 Mechanical Analysis Applied Loads Hollow Cylinder Perforated Cylinder Truss

18. Oak Ridge National Lab BSEC Feb 18, 2009 18 opticsplanet.com Westerlund Telescope, Uppsala Univ. www.astro.uu.se/grundutb/wt/

19. Oak Ridge National Lab BSEC Feb 18, 2009 19 Finite element model

20. Oak Ridge National Lab BSEC Feb 18, 2009 20 Discussion  Inhomogeneity represents a major challenge, as tissues can be very different.  Diffusion weighted MRI may be useful in providing additional treatment planning data.  Could create a tough (interesting) problem for dose optimization.

21. Oak Ridge National Lab BSEC Feb 18, 2009 21 Summary  GeneSeeds represent a promising anti- cancer combination therapy  Dosimetry models have been constructed –Next step: Validation in large animal model  Modified cylinder or truss is compatible with mechanical needs –Challenge may be material retention