1. Understanding cancer immunology for herbal research in cancer Dr. Daniel Man-yuen SZE1 Hong Kong Polytechnic University 2 Australian Collaborative Centre in TCM

2. Cancer immunology 1. Novel anti-cancer TCM-related cytotoxiccompounds (Endophytes)2. Natural anti-cancer T-cell immunity3. Defective blood dendritic cells in cancer4. TCM targeting Cancer Stem Cells 3. backgroundTCM herbs as sources of endophytes and anti-cancercompounds ByKristin MillerSupervisor Yew Trees Dr Daniel Sze 4. Screen TCM herbs for the presence of endophytes that have the potential to produce bioactive substancesBacterial andFungal DNA PCR to amplify fungal and bacterial genes(NOT PLANT GENES)Plant DNABands of amplified DNAIdentify plants whichcontain endophytes producing bioactivesIdentify plant samplespositive for NRPS, PKSand Taxol biosyntheticgenes 5. Cancer immunology 1. Novel anti-cancer TCM-related cytotoxiccompounds (Endophytes)2. Natural anti-cancer T-cell immunity3. Defective blood dendritic cells in cancer4. TCM targeting Cancer Stem Cells 6. Naturally OccurringClinically SignificantAnti-Cancer(Multiple Myeloma) Cytotoxic T cell Expansions 7. Multiple Myeloma 8. Pre Transplant30 % of CD3 cellsT cell Expansions20 if >3SD ofaged-matched controls.100 1 2 3 5.1 5.2 5.3 7.1 8 9 11 12 13.1 13.614 16 17 18 20 21 22 23TCR V repertoireAfter 8 months thalomide30 % of CD3 cells20 100 1 2 3 5.1 5.2 5.3 7.1 8 9 11 12 13.1 13.614 16 17 18 20 21 22 23 TCRV repertoire 9. Cancer immunology 1. Novel anti-cancer TCM-related cytotoxiccompounds (Endophytes)2. Natural anti-cancer T-cell immunity3. Defective blood dendritic cells in cancer4. TCM targeting Cancer Stem Cells 10. Progression Free SurvivalCD8+T ALLG- MM6Thalidomide 1.0 Thal and T cells Progression free Thal and No Tcells No Thal and T cells No Thal and No T cells0.5 2= 9.5; p=0.002 Sze et al, Blood 2001;Sze et al, Leuk Lymphoma0.00 10 203040 50 60 2003;MonthsMedian Survival Thal and T cells 40.1 months Thal and No T cells28.3 months No Thal and Tcells 21.3 months No Thal and No T cells 15.9 months 11. Effective anti-cancer multi-directional mechanisms Thalidomide Anti-oxidant Anti-metastasis Immunomodulation microenvironment modulation Anti-tumour Anti-angiogenesis Bruno et al (2004) Lancet Oncol 5:430 Sze et al (2006) Current Cancer Drug Targets. 6: 89 12. To kill To promote Tumor Anti-cancer cells T/NK cell activities 13. Do selected (Chinese) herbal medicinesexhibit this desirable differential cytotoxictytowards cancer cells versus normal cells(heart, liver, kidney, nerve, bone) includingperipheral blood mononuclear cells (PBMCs)?Tan, A. & Sze, D.M. (2008) Indigenous herbs and Cancer. Journal of Complementary Medicine. 7, 48.High-throughput screening platform for anticancer therapeutic drug cytotoxicity. Sekhon BK, Roubin RH, Tan A, Chan WK, Sze DM. Assay Drug Dev Technol. 2008 Oct;6(5):711-22. 14. Cancer immunology 1. Novel anti-cancer TCM-related cytotoxiccompounds (Endophytes)2. Natural anti-cancer T-cell immunity3. Defective blood dendritic cells in cancer4. TCM targeting Cancer Stem Cells 15. Defective Dendritic cells in cancer can be corrected by Interferon- and IL-12 activeTGF Malignantlatent Plasma cellTGFIL-10 Immature DCDysfunctionalDendritic cellsNORMAL T cellImmature DCMature DC = CD80