Dosimetric Optimization of Interstitial Gene Therapy Delivery Systems

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Dosimetric Optimization of Interstitial Gene
Therapy Delivery Systems
Kenneth H. Wong1, PhD Mira Jung1, PhD Anatoly
Dritschilo1, MD G. Larry Maxwell2, MD,

• The Gynecologic Disease Program
• 1Georgetown University Med. Ctr.
• 2Walter Reed Army Med. Ctr.

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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.

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Limits on Current Cancer Therapy
cyberknifeinstamford.com
graveslab.stanford.edu

• Radiation therapy can be highly conformal, but
  also biologically indiscriminate.
• How can we devise an effective combination
  therapy?

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GeneSeed Concept

• 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.

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GeneSeed Concept

• GeneSeeds were originally designed to express
  constitutively (always on).

Radiation Inducible Promoter
The GeneSeed payload can now be linked to
different promoters, allowing enhanced control of
gene expression.
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GeneSeed Effect on Tumor Growth
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Brachytherapy Tools
www.micknuclear.com
www.oncura.net
www.cfpc.ca/cfp
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Ultrasound imaging
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Cone beam CT guidance

• Siemens
• DynaCT

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Seed Geometry
r
z
?
L
D
d
z1
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Diffusion Model

1. Divide region into 100 micrometer voxels.
2. Compute concentration gradients.
3. Transport plasmid, repeat

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Model results
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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.

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Reporter gene expression
Excised tumor
Microtome slices for microscopy
immunohistochemistry
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Gene v. Radiation Seed
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Dose Simulations Effect of Seed Misplacement
1
0
2
3
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Mechanical Analysis
Applied Loads
Hollow Cylinder
Perforated Cylinder
Truss
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opticsplanet.com
Westerlund Telescope, Uppsala Univ. www.astro.uu.s
e/grundutb/wt/
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Finite element model
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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.

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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