Tumor Tumor immunotherapyimmunotherapy

张沛张沛 张书铭张书铭

张黎明张黎明 赵宸赵宸 赵世刚赵世刚

Tumour Immunotherapy: Tumour Immunotherapy: questionsquestions

• 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=DeathTumor=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

NKMØ

Conjugated to toxin / isotope

N.o 1 N.o 1 ‘Passive’ immunotherapy ‘Passive’ immunotherapy

STRESSES

HSPs protect the delicate functions of the cell.

N.o 2 Heat Shock Proteins for TherapyN.o 2 Heat Shock Proteins for Therapy

Heat Shock Proteins(HSP70)

NH4COOH

ATPase peptide-binding domain

tumour peptide sequence

APC

TAP systemTransporter Associated with Peptide processingCD91

Hsp70 or gp96 / peptide complex

endocytosisreceptor

CTL

NK

tumour peptides presented to CTL / NK cells via HLA Class I

How is the anti-tumour effect produced?How is the anti-tumour effect produced?

Vaccination using HSP complexesVaccination using HSP complexes

Peripheral blood from CML patient

Isolate HSP complexes from

tumour cellsAPC

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)

NH4COOH

ATPase peptide-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 therapyN.o 3 Dendritic cell therapy

DC-based therapyDC-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

CirculatingMyeloid 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 HSP—peptide complex vaccine Dendritic cells vaccine Dendritic cells vaccine ------Active immunotherapy ------Active immunotherapy

N.o4 N.o4 Adoptive immunotherapyAdoptive immunotherapy

Definition: Definition: Induce, activate or multiply the anti-Induce, activate or multiply the anti-

tumor effective cells tumor effective cells inin vitrovitro.Then .Then transfuse the cells to thetransfuse the cells to the patients to patients to cause anti-tumor function .cause anti-tumor function .

Common anti-tumor effective cellsCommon anti-tumor effective cells

LAK (lymphokine-activated killers)LAK (lymphokine-activated killers)TIL (tumor infiltrating lymphocytes) :TIL (tumor infiltrating lymphocytes) :higherhigher

specificityspecificityCD3AK (CD3 antibodty activated killers)CD3AK (CD3 antibodty activated killers)CTL cellCTL 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 therapyN.o 5 Cytokine therapy

The mechanism of cytokine therapy for The mechanism of cytokine therapy for tumor is that after being injected into body tumor is that after being injected into body , the cytokine can regulate and , the cytokine can regulate and increase the activity of immune cells ,and increase the activity of immune cells ,and have enhance anti-tumor effect. have enhance anti-tumor effect.

So far, So far, IL-2IL-2,IFN-r,TNF-a and CSF have been ,IFN-r,TNF-a and CSF have been used for tumor treatmentused for tumor treatment . .

N.o 6 N.o 6 Gene therapyGene therapy

Tumor cells may lose some genes or Tumor cells may lose some genes or express abnormal genes . express abnormal genes . Transduce Transduce target genetarget gene to body and restore the to body and restore the function of tumor cells help them to function of tumor cells help them to express normal products.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 ‡ Tumor ‡ DeathDeath

Thank you!

See you!See you!

Common anti-tumor effective cellsCommon anti-tumor effective cells

LAK (lymphokine-activated killers)LAK (lymphokine-activated killers)TIL (tumor infiltrating lymphocytes) :TIL (tumor infiltrating lymphocytes) :higherhigher

specificityspecificityCD3AK (CD3 antibodty activated killers)CD3AK (CD3 antibodty activated killers)CTL cellCTL cell