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Understanding cancer immunology for herbal research in cancer 施文远博士 Dr. Daniel Man-yuen SZE 1 Hong Kong Polytechnic University 2 Australian Collaborative Centre in TCM Cancer immunology 1. Novel anti-cancer TCM-related cytotoxic compounds (Endophytes) 2. Natural anti-cancer T-cell immunity 3. Defective blood dendritic cells in cancer 4. TCM targeting Cancer Stem Cells TCM herbs as sources of endophytes and anti-cancer compounds By Kristin Miller Supervisor Dr Daniel Sze background Yew Trees Screen TCM herbs for the presence of endophytes that have the potential to produce bioactive substances Bacterial and Fungal DNA PCR to amplify fungal and bacterial genes Plant DNA (NOT PLANT GENES) Bands of amplified DNA Identify plants which contain endophytes producing bioactives Identify plant samples positive for NRPS, PKS and Taxol biosynthetic genes Cancer immunology 1. Novel anti-cancer TCM-related cytotoxic compounds (Endophytes) 2. Natural anti-cancer T-cell immunity 3. Defective blood dendritic cells in cancer 4. TCM targeting Cancer Stem Cells Naturally Occurring Clinically Significant Anti-Cancer (Multiple Myeloma) Cytotoxic T cell Expansions Multiple Myeloma Pre Transplant 30 % of CD3 cells 20 T cell Expansions if >3SD of aged-matched controls. 10 0 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 TCR Vβ repertoire After 8 months thalomide 30 % of CD3 cells 20 10 0 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 TCRVβ repertoire Cancer immunology 1. Novel anti-cancer TCM-related cytotoxic compounds (Endophytes) 2. Natural anti-cancer T-cell immunity 3. Defective blood dendritic cells in cancer 4. TCM targeting Cancer Stem Cells Progression Free Survival 多发性骨髓瘤中特异性CD8+T细胞 與 ALLG- MM6 Thalidomide 沙利竇邁的臨床試驗 1.0 中位存活率 Thal and T cells Thal and No Tcells No Thal and T cells No Thal and No T cells χ2= 9.5; p=0.002 Progression free 0.5 0.0 0 10 20 30 40 50 60 Sze et al, Blood 2001; Sze et al, Leuk Lymphoma 2003; Months Median Survival Thal and T cells Thal and No T cells No Thal and Tcells No Thal and No T cells 40.1 months 28.3 months 21.3 months 15.9 months Effective anti-cancer multi-directional mechanisms 多向抗癌機理 Thalidomide 抗氧化 Anti-oxidant 抗 转移 Anti-metastasis 沙利竇邁 免疫調節 Immunomodulation 微環境調節 microenvironment modulation 殺滅腫瘤 Anti-tumour 抑制血管新生 Anti-angiogenesis Bruno et al (2004) Lancet Oncol 5:430 Sze et al (2006) Current Cancer Drug Targets. 6: 89 To kill Tumor cells To promote Anti-cancer T/NK cell activities Do selected (Chinese) herbal medicines exhibit this desirable differential cytotoxicty towards cancer cells versus normal cells (heart, liver, kidney, nerve, bone) including peripheral 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. Cancer immunology 1. Novel anti-cancer TCM-related cytotoxic compounds (Endophytes) 2. Natural anti-cancer T-cell immunity 3. Defective blood dendritic cells in cancer 4. TCM targeting Cancer Stem Cells Defective Dendritic cells in cancer can be corrected by Interferon-γ and IL-12 active TGFβ latent TGFβ IL-10 Immature DC Malignant Plasma cell Dysfunctional Dendritic cells NORMAL T cell Immature DC Mature DC = CD80
