immune response and fighting brain cancer with gene therapy abbie hunt november 10, 2009
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-/-
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