Tumor immunotherapy

1. Tumor immunotherapy 张沛 张书铭 张黎明 赵宸 赵世刚

3. Tumour Immunotherapy: questions • Can immune stimulators combat cancer? • Which forms of immunotherapy can be used? • Is vaccination effective against established tumours? • Can anti-tumour responses be generated in vitro? • Can in vitro responses translate into in vivo effects? • What barriers are there to development of effective IT? • ……???

4. Tumor=Death?

6. Apoptosis induction Complement-mediated cytotoxicity ADCC Conjugated to toxin / isotope MØ NK N.o 1 ‘Passive’ immunotherapy • Adminstration of monoclonal antibodies which target either tumour-specific or over-expressed antigens. • Kill tumour cells in a variety of ways:

10. STRESSES N.o 2Heat Shock Proteins for Therapy HSPs protect the delicate functions of the cell.

11. COOH NH4 Heat Shock Proteins(HSP70) ATPase peptide-binding domain tumour peptide sequence

12. CTL Hsp70 or gp96 / peptide complex NK tumour peptides presented to CTL / NK cells via HLA Class I TAP system Transporter Associated with Peptide processing How is the anti-tumour effect produced? CD91 endocytosis receptor APC

13. Vaccination using HSP complexes Peripheral blood from CML patient Isolate HSP complexes from tumour cells APC Load APCwith HSP complexes in vitro Co-culture with patient T cells and expand effectors for infusion into patient Immunize patient directly with tumour antigen-primed APC

14. COOH NH4 Heat Shock Proteins(HSP70) ATPase peptide-binding domain tumour peptide sequence

15. Survival rates in a model of lymphoma Immunized with PBS () 40 µg HSP70 from liver () 20 µg HSP70 A20 cells () 40 µg HSP70 A20 cells ()

16. N.o 3 Dendritic cell therapy • Dendritic cells are key components of the adaptive immune response ,can activatenaive T cell • APC function with ability to direct IR (activation/tolerance) • Present in peripheral blood as circulating subtypes (<0.4% TWC)

17. DC developed from patient monocytes Pulsed with target antigens Stimulated to maturation and inoculated back into patient Tumour-specific immune responses measured DC-based therapy Currently in Phase II and Phase III trials for melanoma, prostatic carcinoma and lymphoma.

18. Common Myeloid Progenitor Haemopoietic Stem Cell Circulating Myeloid DC Monocyte CD34+ Stem Cell Ex vivo GM-CSF + IL-4 Immature mdDC Ex vivo GM-CSF + Flt-3 + TNF Maturation factors Mature mdDC CD34+ DC Dendritic cell sources for therapy Copland et al (2005) Cancer Immunol. Immunother. 54:297

19. HSP—peptide complex vaccine Dendritic cells vaccine------Active immunotherapy

20. N.o4 Adoptive immunotherapy Definition: Induce, activate or multiply the anti-tumor effective cells invitro.Then transfuse the cells to thepatients to cause anti-tumor function .

22. Common anti-tumor effective cells • LAK (lymphokine-activated killers) • TIL (tumor infiltrating lymphocytes) :higherspecificity • CD3AK (CD3 antibodty activated killers) • CTL cell

23. 复发 免疫治疗 手术 肿瘤消失 另一侧新生肿瘤

24. 肿瘤组织减少

25. N.o 5 Cytokine therapy The mechanism of cytokine therapy for tumor is that after being injected into body , the cytokine can regulate and increase the activity of immune cells ,and have enhance anti-tumor effect. So far, IL-2,IFN-r,TNF-a and CSF have been used for tumor treatment .

26. N.o 6 Gene therapy Tumor cells may lose some genes or express abnormal genes . Transduce target gene to body and restore the function of tumor cells help them to express normal products.

27. New pathways--gene therapy • Cytokines gene(IL、IFN、TNF） • Tumor Ag gene • MHC gene • Co-stimulatory molecule gene（B7） • Tumor suicide gene • anti-oncogene

29. Tumor ‡ Death

30. Thank you! See you!

31. Common anti-tumor effective cells • LAK (lymphokine-activated killers) • TIL (tumor infiltrating lymphocytes) :higherspecificity • CD3AK (CD3 antibodty activated killers) • CTL cell