Beruflich Dokumente
Kultur Dokumente
Immunotherapy
---- The battle between immune system and cancers
Dr Kevin Sun
Department of Molecular Medicine &
Pathology
What is Cancer?
How does cancer occur?
How many types of cancers?
Current therapeutic strategies for cancers
Definitions of Cancer
Cancer consists of single clones or several
clones of cells that are capable of
independent growth in the host.
host
C
Cancer cells
ll arise
i from
f
host
h
cells
ll via
i
neoplastic transformation or carcinogenesis.
Physical,
y
, chemical and biological
g
agents
g
may cause cancer. -- carcinogens
Carcinogens
g
Radiation: Ultraviolet light,
g sunshine; X-rays,
y
radioactive elements induce DNA damage and
chromosome brakes.
Chemical: smoke and tar, countless chemicals
that damage DNA (mutagens).
Oncogenic viruses: insert DNA or cDNA copies
of viral oncogens into the genome of host target
cells.
Hereditary:
Hereditar certain oncogenes are inheritable
inheritable.
Neoplastic Transformation
-- Carcinogenesis
Activate growth regulatory genes: Growth factor
receptors (erbA, -B, fims, neu); molecules of signal
transduction (src, abl, ras); transcription factors (jun,
fos ,myc)- referred to as oncogenes.
Genes that inhibit growth: (p53 controls DNA repair
and
d cellll proliferation;
lif ti
Rb)
Rb)-suppressor oncogenes.
Genes
G
that
th t regulate
l t apoptosis:
t i bcl-2,
b l2 B
Bax, Bid
Bid.
Classification of cancer
Carcinoma: epithelial origin involving the skin
skin,
mucous membranes, epithelial cells in glands
Sarcoma: cancer of connective tissue
tissue, ii.e.
e
liposarcoma, fibrosarcoma
Lymphoma: T-cell,
T cell B
B-cell,
cell Hodgkins
Hodgkin s, Burkitts
Burkitt s
lymphomas; - solid tumors
Leukemia: disseminated tumors - lymphoid,
lymphoid
myeloid, acute and chronic
Mechanics
M
h i
Physics
Chemistry
Biology
-----
surgery,1600BC
1600BC
radiotherapy,1896
chemotherapy,1942
immunotherapy 1976
immunotherapy,1976
Advantages of Immunotherapy
for cancer
Cancer Immunology
gy and
Immunotherapy
Cancer Immunosurveilance
Th
The hypothesis
h
th i was first
fi t proposed
db
by Eh
Ehrlich
li h iin
1909, and modified by Thomas and Burnet in
1957.
Immunosurveilance: the immunological
resistance of the host against
g
the development of
cancer.
Now referred to cancer immunoediting
encompassing 3 phases: elimination
elimination, equilibrium
and escape.
Marrow
Mast cell
Eosinophil
Erythrocytes
Basophil
Monocyte
Bone
Megakaryocyte
Hematopoietic
stem cell
Multipotential
stem cell
Myeloid
progenitor Neutrophil
cell
Pl t l t
Platelets
D d iti cell
Dendritic
ll
B lymphocyte
Cancer cell
Helper T cell
cytokine
chemokine
NK cell
Dendritic cell
Cytotoxic T cell
Helper T cells
CD4+ T cells: reacting to class II MHCpeptide
p
p
complex,
p , they
y secret cytokines.
y
cytotoxic T cell response (Th1 helper T cells)
antibody response (Th2 helper T cells)
Logistics force
Dendritic Cells
The professional antigen-presenting cells In the
fi l common pathway
final
th
ffor activating
ti ti nave
T
cells.
Dendritic
cell
T cell
-- Early
E l Warning
W
i Aircraft
Ai
ft
Other cells
NK cells: after activation
activation, directly killing tumor cell
NKT cells: TRAIL/perforin- tumor cell lysis;
IFN-angiogenesis
Macrophages: antigen presenting
NK cell
NKT cell
M
Macrophage
h
Cytokines
Regulating the innate immune system: NK cells,
macrophages and neutrophils; and the adaptive immune
macrophages,
system: T and B cells
IFN
IFN-
-- upregulating MHC class II, tumor antigens
antigens, and
adhesion molecules; promoting activity of B and T cells,
macrophages, and dendritic cells.
IL-2 -- T cell growth factor that binds to a specific tripartite
receptor on T cells.
IL-12
IL 12 promoting NK and T cell activity
activity, and a growth factor
for B cells
G
GM-CSF
CS (G
Granulocyte-monocyte
a u ocyte o ocyte co
colony
o y st
stimulating
u at g factor
acto ) -reconstituting antigen-presenting cells.
-- missile
Tumor elimination
Single
cancer cell
progress?
Escape
Advanced cancer
Cancer
I
Immunology/Immunotherapy
l
/I
th
How does the immune system eliminate cancer cells?
How do cancer cells escape from Immunosurveilance?
How can we help to win the battle between immune
system
t
and
d cancers?
? Cancer
C
iimmunotherapy
th
Examples
(2) Down
Down--regulation, mutation or loss of
tumor antigens
Tumor antigens (TA)
Tumor associated antigen (TAA)
Complete loss
Down-modulation
Tumor Antigens
g
Altered self: K-ras, products of normally unexpressed
genes (MAGE,
(MAGE BAGE,
BAGE GAGE)
GAGE), proteins of alternative
reading frame, - of post-translational modification, glycosylation
y
y
((mucin-CA125, MUC1).
)
different orders of g
Viral antigens: EBNA, E-6,E-7, papilloma virus antigens
of cervical carcinomas.
Oncofetal antigens: alpha-fetoprotein (AFP),
Carcinoembryonic antigen (CEA)
Autoantigens: overexpression - c-myc
c myc in lymphomas
lymphomas,
leukemias; HER-2/neu epidermal growth factor receptorbreast cancer (Herceptin).
(
p )
B7 family
T cell Activation
No Activation
T cell
T cell
CD28
B7.1
TCR CD28
Peptide/
MHC
B7.2
APC
Co-stimulation
CD28
TCR CD28
Peptide/
p
MHC
APC
L
Loss
off costimulation
ti l ti
(5) Immunosuppressive
cytokines
a number of immunosuppressive cytokines.
cytokines
IL-10 inhibits antigen presentation and IL-12
production.
production
TGF-beta induces overproduction of IL-10.
VEGF (vascular endothelial growth factor),
avoid immune recognition, inhibit the
effector function, prevent T cell activation,
cytokine production.
(6) Induction of
Immunosuppressive cells
Regulatory T Cells
T cells compete
f same antigen
for
ti
Cytotoxic
T cell
Mature
dendritic
cell
Regulatory
T cell
Regulatory
T cells
Proliferation
Potential
sources for
regulatory
T cells
Tumor
u o mass
ss
Vessel
Lymphocyte
Apoptotic lymphocyte
Effect on DCs
VEGF
TGF-beta
Gangliosides
IL 6
IL-6
differentiation
IL-10
differentiation,CD80/CD86/CD40
expression,IL-12 production
Prostanoids,prostaglandins
differentiation
PgE2
generation
NO
induction of apoptosis
Summary
How do tumors progress?
Cytokines
Tumor
T cell
Activation >
suppression
Suppression
> activation
NK cell
DC
Tumor
Progression
Antigen/MHC loss
T-cell dysfunction
Suppressive cytokine
Suppressive T cells
Overweighing effector cells
Balance
Cancer
I
Immunology/Immunotherapy
l
/I
th
How does the immune system eliminate cancer cells?
How do cancer cells escape from Immunosurveilance?
How can we help to win the battle between immune
system
t
and
d cancers?
? Cancer
C
iimmunotherapy
th
Examples
Tumor Immunotherapy
Strategies to improve the tumorassociated immune response by
either boosting components of the
immune system that produce an
effective immune response or by
inhibiting components that suppress
p
the immune response.
Tumor Progression
T cells
Dendritic Cells
DC vaccination
TAA
Effector cytokines
IL-2, IL-12
dysfunctional DCs
Suppressive cytokines
Suppressive factors
Main Mechanisms of
Immunotherapy
Stimulating the antitumor response, either by increasing
the number of effector cells or by producing soluble
mediators.
Decreasing suppressor mechanisms.
Altering tumor cells to increase their immunogenicity and
make them more susceptible to immunologic defences.
Improving
p
g tolerance to cytotoxic
y
drugs
g or radiotherapy,
py,
such as stimulating bone marrow function with GM-CSF.
Current Immunotherapeutic
strategies in clinic or clinical trials
Antibody Therapy
Cytokine Therapy
Adoptive Therapy
Vaccination
Combinational therapy
Examples
p
Antibody
y Therapy
py
Rituximab: The first approved antibody by FDA in clinical trial.
Targeting CD20. low-grade non-Hodgkin lymphoma
Cytokine therapy
-- IL
IL--2
Event
Author
Discovery of IL-2
Morgan et al.(1976)
Grimm et al.(1982)
Bubenk et al.(1983)
(
)
Systemic
y
administration of IL-2 inhibits g
growth of metastatic
experimental tumours
Rosenberg
g et al.(1985a)
(
)
Rosenberg et al
al.(1985b)
(1985b)
Bubenk et al.(1988)
Anderson ((1992);
);
Foa et al. (1992)
Local and regional IL-2 administration in cancer patients selected examples from the early trials
Interleukin-2
Dose
( it / ti t)
(units/patient)
Tumour
Response (%)
Complete/partial
C
l t /
ti l
Reference
gibbon lymphoid
1.5 x 10-2 4.0 x 10-3
human recombinant 1.0 x 10-4 2.8 x 10-4
30/ 30
0/ 82
Pizza (1984)
Yasumoto (1987)
human recombinant
human lymphoid
human lymphoid
human lymphoid
malignant gliomas
squamous cell carcinomas
squamous cell carcinomas
urinary bladder carcinomas
13/ 13
29/ 29
30/ 30
20/ n.v.
Yoshida (1988)
Forni (1988)
Cortesina (1988)
Huland and Huland
(1989)
Adoptive immunotherapy
Stimulating immune cells by exposing
them to tumour cells or antigens in the
laboratory and then injecting expanded
populations of the treated cells into
patients.
Patient is both donor and recipient
recipient.
(1)
Tumor cells that produce TGF that exert inhibitory effects on the immune system. Specific CTL can be genetically
modified to become resistant to the TGF inhibitory effect through transgene expression of a mutant dominantnegative
ti TGF type
t
II receptor
t (DNR).
(DNR)
(2)
Specific T cells genetically modified to produce IL-12 can overcome IL-10 inhibitory effect.
(3)
Tumors express FasL and induce apoptosis of effector T cells. Small interfering RNA (siRNA) can be used to
knock-down Fas receptor in specific CTL, allowing a significant reduction of their susceptibility to Fas/FasLmediated apoptosis.
Adoptive immunotherapy
The Journal of Clinical Investigation Vol 113 Number 11 June 2004 pp 1515
Antitumor Vaccines
Administration of some form
of antigen to induce a specific
antitumour
tit
immune
i
response.
Antitumor Vaccines
Antitumor Vaccines
The Journal of Clinical Investigation Vol 113 ( 11) June 2004 pp 1515
Complex binds
to dendritic cell
precursor
Tumor antigen
Tumor
antigen is
linked to a
cytokine
T cell
Complex is
taken in by
dendritic cell
precursor
Cancer cell
Combinational Therapy
py
-- a three
three--stranded cord is not easily broken
Sun X
X, et al
al. Gene Therapy 2001; 8: 638
638-645
645
AS-HIF
B7 1
B7.1
Activates
A
i
NK cells
Tumor
cell
Apoptosis
Glycolysis
Necrosis
Tumor
cell
Tumor
cell
v
v
v
APC
B7 1
B7.1
Anti-angiogenesis
hsp70- tumor
+ hsp70
Antigen
TumorC
cell
B7.1
MHCI
MHCI
CD28
CD28
T cell
MHCII
MHCII
Heat-shock
di
driven
antii
tumor
immunity
Cell vitality
T cell
Proliferation
& CTLmediated
killing
Tumor
Cell
Apoptosis
Immune suppressive
pp
elements
IgV-like
IgC-like
Cytoplasmic
Transmembrance
Signal peptide
MLRGWGGPSVGVCVRTALGVLCLCLTGAVEVQVSEDPVVALVDTDATLRC
IgV-like
g
domain
SFSPEPGFSLAQLNLIWQLTDTKQLVHSFTEGRDQGSAYSNRTALFPDLLVQ
GNASLRLQRVRVTDEGSYTCFVSIQDFDSAAVSLQVAAPYSKPSMTLEPNK
IgC-like domain
DLRPGNMVTITCSSYQGYPEAEVFWKDGQGVPLTGNVTTSQMANERGLFD
VHSVLRVVLGANGTYSCLVRNPVLQQDAHGSVTITGQPLTFPPEALWVTVG
Transmembrane
Cytoplasmic
LSVCLVVLLVALAFVCWRKIKQSCEDENAGAEDQDGDGEGSKTALRPLKPS
ENKEDDGQEIA
Sun X,
X et al.
al Gene Therapy 2003; 101728-1734
101728-1734.
Flag-B7H3
Flag-B7H3
Tubulin
B7H3+As2O3
B7H3
As2O3
pcDNA3.1
PBS
Tumor Size
e (cm)
2.4
2
16
1.6
1.2
0.8
04
0.4
0
3
4 5
6
7
Weeks After Therapy
12
20
500
400
Sera
300
200
100
Level of IFN
N- (ng/ml)
Level of IFN
N- (pg/ml)
60
50
40
30
20
10
0
Supernatants
6
4
2
0
*
*
60
E:T Ratio
20:1
100:1
Cytotoxicity
y (%)
Cytotoxicity (%)
10
50
40
30
**
PBS
CD4+
CD8+
NK
20
10
0
B7H3+As2O3
B7H3
PBS
Tum
mor Size(cm,diam
meter)
0.6
Tumor-1,treated
0.5
Tumor-2,untreated
Tumor 3 untreated
Tumor-3,untreated
04
0.4
Tumor-4,untreated
0.3
Tumor-5,untreated
0.2
0.1
0
0
Conclusion
Immunotherapy
py may
y be the next g
great hope
p for
cancer treatment.
While antibodies, cytokines, and vaccines have
individually shown some promise, it is likely that
the best strategy to combat cancer will be to
attack on all fronts.
The effect of immunotherapy in combination with
traditional cancer therapies is another avenue.
Introduction
Controversial
Unclear
Not reported
Shortcomings
Further investigation
Hypothesis
Materials and Methods
Experiments
Results
Discussion
Conclusion
Discussion
Combined
Si ifi
Significance
Future Investigation
g
DR Kevin Sun
Department of Molecular Medicine & Pathology
Rm 4231
Tel:3737599-85935
Email:k.sun@auckland.ac.nz