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Immune Response and Fighting Brain Cancer with Gene Therapy

Immune Response and Fighting Brain Cancer with Gene Therapy. Abbie Hunt November 10, 2009. 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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Immune Response and Fighting Brain Cancer with Gene Therapy

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  1. Immune Response and Fighting Brain Cancer with Gene Therapy Abbie Hunt November 10, 2009

  2. 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)

  3. Challengers Ad-TK Ad-Flt3L Ad0 Returning Champions GL26 GL261 B16-F10 LLc1 Cell lines, etc.

  4. Mice! • Female C57BL/6 • MyD88-/- • TLR4-/- • WT • Chimeric • WT and GFP+/+ • WT and TLR2-/- http://brainwindows.files.wordpress.com/2008/10/image-gfp-mouse-crop-copy.jpg

  5. GL26 GL261 B16-F10 Ad0 Ad-Flt3L + Ad0 Ad-TK + Ad0 Ad-Flt3L + Ad-TK GCV Saline Rechallenged Glioma Models

  6. T cells necessary in tumor regression

  7. DCs come from bone marrow

  8. TLR2 expression by BMDC necessary in tumor regression

  9. HMGB1 mediates TLR2-dependent glioma tumor regression • Increased levels of HMGB1 from GL26 treated with Ad-TK+GCV in vitro • Increased serum levels in mice • Blocked with glycyrrhizin or specific anti-HMGB1 antibodies

  10. HMGB1 released from tumor cells with Ad-TK+GCV, chemotherapy, or radiation therapy

  11. Ad-TK(+GCV) + Ad-Flt3L = Survival and Increased HMGB1

  12. 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-TK+GCV, chemotherapy, or radiation therapy • Ad-TK (+GCV) and Ad-Flt3L therapy results in GL261 and B16-F10 tumor regression and increased HMGB1 levels

  13. 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/PMC2659706/ 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.htmAccessed 11/3/09. • 5. Multitudes of Wikipedia pages

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