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-/-

http://brainwindows.files.wordpress.com/2008/10/image-gfp-mouse-crop-copy.jpg

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. 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.htm Accessed 11/3/09.

5. Multitudes of Wikipedia pages