Tumor  Biotherapy  肿瘤生物治疗 Limin Zheng E-mail: zhenglm@mail.sysu.edu.cn
<ul><li>60.  Gene therapy ( 基因治疗) </li></ul><ul><li>61.  Cancer vaccines  ( 肿瘤疫苗 ) </li></ul><ul><li>62.  Cell transfer th...
Most active research area for cancer treatment Hundreds protocols are in clinic trials  Why tumor Bio-therapy? Current ant...
<ul><li>Problems with chemotherapy:  </li></ul><ul><li>Most drugs target nucleic acid synthesis or mitosis, affect both tu...
Tumor Bio-therapy <ul><li>Influence of specific genes </li></ul><ul><li>Antisense oligo or SiRNA, </li></ul><ul><li>Gene t...
Gene Therapy: A Brief History Jesse Gelsinger , 1999 Ashanti de Silva , 1990 Alain Fischer , 2003 1990  Ashanti de Silva ,...
Gene Therapy <ul><li>Genetic Disease , single gene related </li></ul><ul><li>Present: most in Tumor (Multiple genes) </li>...
<ul><li>Target Genes : </li></ul><ul><li>regulate immune response: cytokine, tumor Ag … etc </li></ul><ul><li>Differential...
Obstacles in Gene Therapy - vector <ul><li>The major problem is the carrier ( vector ) , </li></ul><ul><li>not the Genes <...
High immunogenecity of vector 载体免疫原性强和靶向性差 Immunogenecity of Adenovirus Adenovirus
Target - specificity The problem with Gene therapy is mainly due to  vector (immunogenic and low specificity for tumor)
Tumor Bio-therapy <ul><li>Influence of specific genes </li></ul><ul><li>Antisense oligo or SiRNA, </li></ul><ul><li>Gene t...
The elimination phase of Cancer Immunoediting Dunn et al,  Nature Immunology, 2002; 3:991
Effective immune responses eliminate tumor Tumors must escape from immune recognition Dunn et al,  Nature Immunology, 2002...
<ul><li>Mechanisms with host immune system </li></ul><ul><li>Ignorance: Immune system does not recognize the low levels of...
Tumor Vaccine  ( treatment, not prevention) Cell based vaccine:  Best and most widely used so far tumor cell based vaccine...
Anti-tumor effector arms of the immune response
Tumor vaccines: Use Dendritic cells, the most powerful APC, to elicit anti-tumor immune responses DC DC Tc
Interaction between DC and lymphocytes
<ul><li>DC uptake tumor cells,  digest and processed tumor Ag into smaller peptide, form a complex with MHC, and present t...
Ex vivo  loading of DC with tumor Ag
<ul><li>Some Facts about Tumor Antigens </li></ul><ul><li>Complete repertoire of tumor Ags and their encoding genes is far...
<ul><li>Use a single Tumor antigen to load DC, can easily generate tumor cells that loss this Ag (immune pressure/selectio...
Adaptive immune responses can be divided into two related activities—recognition and response . require co-operation betwe...
Activation of T cells by dendritic cells
 
 
<ul><li>Antigen-presentation  alone is NOT sufficient   </li></ul><ul><li>to trigger immune response </li></ul><ul><li>The...
危险? 自己人? 抗原 处理抗原 摄取抗原 S1 S2 效应细胞 APC 免疫应答 APC 双信号 ? Can we use adjuvant ( 佐剂) to activate APC,  (increase the co-stimulato...
 
 
Tumor Vaccine :   Limited success obtained in clinic, more challenges remain <ul><li>Other Vaccines: </li></ul><ul><li>DNA...
Get more “fighter”? culture immune cells in vitro ( >10 10 ) Problem:  functional activity? Reach the tumor?
In vivo, only high affinity CD8+ CTL can response to low levels of Tumor Ag, proliferate, and provide protective immunity;...
<ul><li>Cytokines: </li></ul><ul><li>Interferon ( 干扰素 ),  activate NK cells, M  </li></ul><ul><li>IL-2 ,  IL-12:  activat...
篦麻毒素
<ul><li>Problems in using Antibody to treat cancer: </li></ul><ul><li>Difficulty of Ab to penetrate into solid tumor </li>...
Cancer immunotherapy: moving beyond current vaccines NATURE MEDICINE  2004 , 10 : 909-915 <ul><li>Great progress has been ...
<ul><li>Promising, Great efforts still needed </li></ul>
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5 tumor biotherapy

  1. 1. Tumor Biotherapy 肿瘤生物治疗 Limin Zheng E-mail: zhenglm@mail.sysu.edu.cn
  2. 2. <ul><li>60. Gene therapy ( 基因治疗) </li></ul><ul><li>61. Cancer vaccines ( 肿瘤疫苗 ) </li></ul><ul><li>62. Cell transfer therapy ( 免疫细胞 ) </li></ul><ul><li>Antiangiogenesis agents ( 抗血管生成 ) </li></ul><ul><li>64. Focused ultrasound </li></ul><ul><li>65. Antisense inhibition of gene expres. </li></ul>DeVita Cancer: Principles and Practice of Oncology Part IV: Newer Approaches in Cancer Treatment (most of them are tumor biotherapy)
  3. 3. Most active research area for cancer treatment Hundreds protocols are in clinic trials Why tumor Bio-therapy? Current anti-tumor therapy used in Clinic: Surgery: primary tumor, No metastases Radiation : surface, small and localized tumors Chemotherapy: liquid tumor, metastases Tumor Bio-therapy
  4. 4. <ul><li>Problems with chemotherapy: </li></ul><ul><li>Most drugs target nucleic acid synthesis or mitosis, affect both tumor and normal dividing cells, cause side-effects on patients. </li></ul><ul><li>Tumor cells: genetic instability, heterogeneous, drug-resistant cells can survive and grow </li></ul><ul><li>Abnormal vessel structures & high pressure in tumor resulted in lower drug concentration in the lesion. </li></ul>
  5. 5. Tumor Bio-therapy <ul><li>Influence of specific genes </li></ul><ul><li>Antisense oligo or SiRNA, </li></ul><ul><li>Gene therapy ( deliver target genes into tumor cells through vector) </li></ul><ul><li>Immuno-therapy </li></ul><ul><li>Tumor vaccines, Cytokines, Antibodies, </li></ul><ul><li>Anti-Angiogenesis </li></ul><ul><li>Signal transduction: More active in Cancers </li></ul><ul><li>e.g. STI-571 (inhibit Bcr-Abl tyrosine kinase) </li></ul>
  6. 6. Gene Therapy: A Brief History Jesse Gelsinger , 1999 Ashanti de Silva , 1990 Alain Fischer , 2003 1990 Ashanti de Silva , USA (ADA 所致联合免疫缺陷) 1999 Jesse Gelsinger , USA 2003 Alain Fischer , France 2003 Adrian Thrasher , UK
  7. 7. Gene Therapy <ul><li>Genetic Disease , single gene related </li></ul><ul><li>Present: most in Tumor (Multiple genes) </li></ul><ul><li>Method Ex vivo : modify target cell in vitro </li></ul><ul><li>In situ : directly introduce into local tumors </li></ul><ul><li>( most commonly used; p53-AV ) </li></ul><ul><li>In vivo : injected into blood (immune-genes) </li></ul><ul><li>Key : target gene; vector; efficiency </li></ul>
  8. 8. <ul><li>Target Genes : </li></ul><ul><li>regulate immune response: cytokine, tumor Ag … etc </li></ul><ul><li>Differential expressed: TSG, apoptosis, angiogenesis etc. </li></ul><ul><li>How to introduce Genes into cells: </li></ul><ul><li>naked DNA , liposome , receptor … </li></ul><ul><li>Virus vector: replicate-deficient </li></ul><ul><li>(for transfection; no replication in human) </li></ul><ul><li>widely used: adenovirus (AV), AAV, Retrovirus </li></ul>
  9. 9. Obstacles in Gene Therapy - vector <ul><li>The major problem is the carrier ( vector ) , </li></ul><ul><li>not the Genes </li></ul><ul><li>Lack the efficient and specific vector. </li></ul><ul><li>The most widely used vector is virus vector </li></ul><ul><li>(adenovirus 腺病毒载体 ) </li></ul><ul><li>Major drawback of AV vector is </li></ul><ul><li>High immunogenecity and </li></ul><ul><li>low specificity for tumors </li></ul>
  10. 10. High immunogenecity of vector 载体免疫原性强和靶向性差 Immunogenecity of Adenovirus Adenovirus
  11. 11. Target - specificity The problem with Gene therapy is mainly due to vector (immunogenic and low specificity for tumor)
  12. 12. Tumor Bio-therapy <ul><li>Influence of specific genes </li></ul><ul><li>Antisense oligo or SiRNA, </li></ul><ul><li>Gene therapy </li></ul><ul><li>Immuno-therapy </li></ul><ul><li>Tumor vaccines, Cytokines, Antibodies… </li></ul><ul><li>Angiogenesis ( 抗血管生成 ): </li></ul><ul><li>block new blood vessel (血管) formation </li></ul><ul><li>Signal transduction: More active in Cancers </li></ul><ul><li>e.g. STI-571 (inhibit Bcr-Abl tyrosine kinase) </li></ul>
  13. 13. The elimination phase of Cancer Immunoediting Dunn et al, Nature Immunology, 2002; 3:991
  14. 14. Effective immune responses eliminate tumor Tumors must escape from immune recognition Dunn et al, Nature Immunology, 2002; 3:991
  15. 15. <ul><li>Mechanisms with host immune system </li></ul><ul><li>Ignorance: Immune system does not recognize the low levels of TAA at early phases of tumor </li></ul><ul><li>Tolerance of T cells to TAA, resulted from T-cell anergy or deletion (caused by host APC, T-reg) </li></ul><ul><li>Suppression of T cells: tumor-derived factors, immunosuppressive myeloid cells or T-reg </li></ul><ul><li>Defects in antigen presentation by professional antigen-presenting cells </li></ul>
  16. 16. Tumor Vaccine ( treatment, not prevention) Cell based vaccine: Best and most widely used so far tumor cell based vaccine: hard to get enough cells; DC ( 树突状细胞) based vaccine widely used in clinic
  17. 17. Anti-tumor effector arms of the immune response
  18. 18. Tumor vaccines: Use Dendritic cells, the most powerful APC, to elicit anti-tumor immune responses DC DC Tc
  19. 19. Interaction between DC and lymphocytes
  20. 20. <ul><li>DC uptake tumor cells, digest and processed tumor Ag into smaller peptide, form a complex with MHC, and present to the effectors ( 效应细胞 ). </li></ul><ul><li>Two Critical factors that affect DC vaccine </li></ul><ul><li>Antigen loading </li></ul><ul><li>Stimulating effective anti-tumor immunity (high affinity CD8+ CTL) </li></ul>
  21. 21. Ex vivo loading of DC with tumor Ag
  22. 22. <ul><li>Some Facts about Tumor Antigens </li></ul><ul><li>Complete repertoire of tumor Ags and their encoding genes is far from being fully defined. </li></ul><ul><li>The gene profiles from different types of cancers or even from the same type in different individuals are significantly diversified. </li></ul><ul><li>Only a small fraction of genes have been repeatedly cloned from different cDNA libraries prepared from distinct, or even the same type of cancer in different individuals. </li></ul>
  23. 23. <ul><li>Use a single Tumor antigen to load DC, can easily generate tumor cells that loss this Ag (immune pressure/selection) </li></ul><ul><li>So, whole cells antigens are used in most studies/clinical trials. </li></ul><ul><li>Include: tumor cell lysates, apoptotic tumor cells, necrotic tumor cells, tumor-DC fusion </li></ul>
  24. 24. Adaptive immune responses can be divided into two related activities—recognition and response . require co-operation between Lymphocytes and Ag presenting cell (APC, 抗原递呈细胞 )
  25. 25. Activation of T cells by dendritic cells
  26. 28. <ul><li>Antigen-presentation alone is NOT sufficient </li></ul><ul><li>to trigger immune response </li></ul><ul><li>The host immune response is tightly regulated by </li></ul><ul><li>Inhibitory ( 抑制 ) signals (e.g for NK cells ) </li></ul><ul><li>Co-stimulatory ( 共刺激 ) factors ( two signals ): </li></ul><ul><li>without them, Ag presentation resulted in </li></ul><ul><li>Anergy ( 无反应 ) or immuno-tolerance ( 耐受 ) </li></ul><ul><li>3. Danger Signals </li></ul>
  27. 29. 危险? 自己人? 抗原 处理抗原 摄取抗原 S1 S2 效应细胞 APC 免疫应答 APC 双信号 ? Can we use adjuvant ( 佐剂) to activate APC, (increase the co-stimulatory signals), during the Ag loading?
  28. 32. Tumor Vaccine : Limited success obtained in clinic, more challenges remain <ul><li>Other Vaccines: </li></ul><ul><li>DNA vaccine </li></ul><ul><li>Protein/peptide vaccine (8-12 AA): tumors may not express peptide (heterogeneity 异质性 ) </li></ul><ul><li>Others: virus, xenogeneic ( 异种) vaccine etc </li></ul>
  29. 33. Get more “fighter”? culture immune cells in vitro ( >10 10 ) Problem: functional activity? Reach the tumor?
  30. 34. In vivo, only high affinity CD8+ CTL can response to low levels of Tumor Ag, proliferate, and provide protective immunity; Generation of these CTL dependent on the expression of co-stimulatory molecules on DC Thus , effective loading of tumor Ag, helping the maturation and expression of co-stimulatory molecules on DC simultaneously ( 同时) are the dreams of tumor-immunologists.
  31. 35. <ul><li>Cytokines: </li></ul><ul><li>Interferon ( 干扰素 ), activate NK cells, M  </li></ul><ul><li>IL-2 , IL-12: activate T-cells; </li></ul><ul><li>TNF: direct or via M  and CTL to kill tumor </li></ul><ul><li>These cytokines are Not specific for tumor cells </li></ul><ul><li>Usually need high doses; with side-effects </li></ul><ul><li>Mainly used as assistant therapy </li></ul><ul><li>Antibody: several Ab are in clinic use </li></ul><ul><li>(e.g., for Her-2 in breast cancer) </li></ul>
  32. 36. 篦麻毒素
  33. 37. <ul><li>Problems in using Antibody to treat cancer: </li></ul><ul><li>Difficulty of Ab to penetrate into solid tumor </li></ul><ul><li>Only minority of tumor cells express the targeted Ag, due to heterogeneity of tumor cell population </li></ul><ul><li>3. Blocking effect of high circulating tumor Ag </li></ul><ul><li>4. Formation of anti-IgG Ab and toxicity of immune complexes </li></ul>
  34. 38. Cancer immunotherapy: moving beyond current vaccines NATURE MEDICINE 2004 , 10 : 909-915 <ul><li>Great progress has been made in the field of tumor immunology in the past decade, but ....... </li></ul><ul><li>In our cancer vaccine trials of 440 patients (NCI), the objective response rate was low (2.6%), and comparable to the results obtained by others. </li></ul>
  35. 39. <ul><li>Promising, Great efforts still needed </li></ul>

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