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

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Presentation transcript:

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)

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

Mice! Female C57BL/6 MyD88 -/- TLR4 -/- WT Chimeric WT and GFP +/+ WT and TLR2 -/-

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

T cells necessary in tumor regression

DCs come from bone marrow

TLR2 expression by BMDC necessary in tumor regression

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

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

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

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

References 1. Curtin J.F., Liu N., Candolfi M., et al HMB1 Mediate Endogenous TLR2 Activation and Brain Tumor Regression. PLoS Medicine. 6(1): 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 Accessed 11/4/ 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 Stevenson, P. Immunological Memory. The Australian Naturopathic Network. Revised 5/18/2002. Available online at Accessed 11/3/ Multitudes of Wikipedia pages