Tumor immunotherapy 张沛张书铭 张黎明 赵宸 赵世刚

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? ……???

Tumor=Death ?

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

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

Heat Shock Proteins (HSP70) NH 4 COOH ATPasepeptide-binding domain tumour peptide sequence

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

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

Heat Shock Proteins (HSP70) NH 4 COOH ATPasepeptide-binding domain tumour peptide sequence

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 (  )

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

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

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

 HSP—peptide complex vaccine Dendritic cells vaccine Active immunotherapy

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

Common anti-tumor effective cells LAK (lymphokine-activated killers) LAK (lymphokine-activated killers) TIL (tumor infiltrating lymphocytes) :higher specificity TIL (tumor infiltrating lymphocytes) :higher specificity CD3AK (CD3 antibodty activated killers) CD3AK (CD3 antibodty activated killers) CTL cell CTL cell

手术 复发免疫治疗 肿瘤消失另一侧新生肿瘤

肿瘤组织减少

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.

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.

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

Tumor ‡ Death

Thank you! See you!

Common anti-tumor effective cells LAK (lymphokine-activated killers) LAK (lymphokine-activated killers) TIL (tumor infiltrating lymphocytes) :higher specificity TIL (tumor infiltrating lymphocytes) :higher specificity CD3AK (CD3 antibodty activated killers) CD3AK (CD3 antibodty activated killers) CTL cell CTL cell