Immune Response and Fighting Brain Cancer with Gene Therapy

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Immune Response and Fighting Brain Cancer with
Gene Therapy

• Abbie Hunt
• November 10, 2009

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Overview

• Glioblastoma multiforme (GBM)
• Dendritic Cells (DC)
• Fms-like tyrosine kinase 3 ligand (Flt3L)
• Toll-like receptors (TLR)
• Bone-marrow derived DCs (BMDC)
• High-mobility-group box 1 (HMGB1)

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Cell lines, etc.

• Challengers
• Ad-TK
• Ad-Flt3L
• Ad0

• Returning Champions
• GL26
• GL261
• B16-F10
• LLc1

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Mice!

• Female C57BL/6
• MyD88-/-
• TLR4-/-
• WT
• Chimeric
• WT and GFP/
• WT and TLR2-/-

http//brainwindows.files.wordpress.com/2008/10/im
age-gfp-mouse-crop-copy.jpg
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Glioma Models

• GL26
• GL261
• B16-F10

• Ad0
• Ad-Flt3L Ad0
• Ad-TK Ad0
• Ad-Flt3L Ad-TK
• GCV
• Saline
• Rechallenged

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T cells necessary in tumor regression
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DCs come from bone marrow
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TLR2 expression by BMDC necessary in tumor
regression
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HMGB1 mediates TLR2-dependent glioma tumor
regression

• Increased levels of HMGB1 from GL26 treated with
  Ad-TKGCV in vitro
• Increased serum levels in mice
• Blocked with glycyrrhizin or specific anti-HMGB1
  antibodies

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HMGB1 released from tumor cells with Ad-TKGCV,
chemotherapy, or radiation therapy
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Ad-TK(GCV) Ad-Flt3L Survival and Increased
HMGB1
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Recap

• T cells necessary in tumor regression
• DCs come from bone marrow
• TLR2 expression by BMDC necessary in t.r.
• HMGB1 mediates TLR2-dependent glioma t.r.
• HMGB1 released from tumor cells with Ad-TKGCV,
  chemotherapy, or radiation therapy
• Ad-TK (GCV) and Ad-Flt3L therapy results in
  GL261 and B16-F10 tumor regression and increased
  HMGB1 levels

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References

• 1. Curtin J.F., Liu N., Candolfi M., et al.
  2009. HMB1 Mediate Endogenous TLR2 Activation and
  Brain Tumor Regression. PLoS Medicine. 6(1)
  84-104.
• 2. Southgate T., Kroeger K.M., Liu C., Lowenstein
  P.R. (2008). Gene transfer into meural cells in
  vivo using adenoviral vectors. Published online
  at Wiley Interscience. Available online at
  http//www.ncbi.nlm.nih.gov/pmc/articles/PMC265970
  6/ Accessed 11/4/09.
• 3. Sandmair A., Vapalahti M., Yla-Herttuala S.
  (2000). Adenovirus-Mediated Herpes Simplex
  Thymidine Kinase Gene Therapy for Brain Tumors.
  Cancer Gene Therapy Past Achievements and Future
  Challenges. Plenum Publishers, New York.
  163-170.
• 4. Stevenson, P. Immunological Memory. The
  Australian Naturopathic Network. Revised
  5/18/2002. Available online at http//www.ann.com.
  au/MedSci/immunolo.htm Accessed 11/3/09.
• 5. Multitudes of Wikipedia pages