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Cancer Immunology andCancer Immunology andCancer Immunology and Cancer Immunology and ImmunotherapyImmunotherapyImmunotherapyImmunotherapy
-------- The battle between immune system and cancersThe battle between immune system and cancers
Dr Kevin Sun
Department of Molecular Medicine & Department of Molecular Medicine & PathologyPathology
Basic knowledge of cancerBasic knowledge of cancerBasic knowledge of cancerBasic knowledge of cancer
• What is Cancer?• How does cancer occur?• How many types of cancers?• How many types of cancers?• Current therapeutic strategies for cancers
Definitions of CancerDefinitions of Cancer
• Cancer consists of single clones or several• Cancer consists of single clones or several clones of cells that are capable of independent growth in the hostindependent growth in the host.
C ll i f h ll i• Cancer cells arise from host cells via neoplastic transformation or carcinogenesis.
• Physical, chemical and biological agents y , g gmay cause cancer. -- carcinogens
CarcinogensCarcinogensgg• Radiation: Ultraviolet light, sunshine; X-rays, g y
radioactive elements induce DNA damage and chromosome brakes.
• Chemical: smoke and tar, countless chemicals that damage DNA (mutagens).that damage DNA (mutagens).
• Oncogenic viruses: insert DNA or cDNA copies of viral oncogens into the genome of host targetof viral oncogens into the genome of host target cells.Hereditar certain oncogenes are inheritable• Hereditary: certain oncogenes are inheritable.
Neoplastic TransformationNeoplastic Transformation---- CarcinogenesisCarcinogenesis
• 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 d ll lif ti Rb)and cell proliferation; Rb)-suppressor oncogenes.
G th t l t t i b l 2 B Bid• Genes that regulate apoptosis: bcl-2, Bax, Bid.
Classification of cancerClassification of cancerClassification of cancerClassification of cancer• Carcinoma: epithelial origin involving the skin• Carcinoma: epithelial origin involving the skin,
mucous membranes, epithelial cells in glands• Sarcoma: cancer of connective tissue i e• Sarcoma: cancer of connective tissue, i.e.
liposarcoma, fibrosarcoma• Lymphoma: T cell B cell Hodgkin’s Burkitt’s• Lymphoma: T-cell, B-cell, Hodgkin s, Burkitt s
lymphomas; - solid tumors• Leukemia: disseminated tumors - lymphoid• Leukemia: disseminated tumors - lymphoid,
myeloid, acute and chronic
Current strategies to combatCurrent strategies to combatCurrent strategies to combat Current strategies to combat cancerscancers
M h i 1600BC• Mechanics -- surgery,1600BC• Physics -- radiotherapy,1896• Chemistry -- chemotherapy,1942• Biology -- immunotherapy 1976Biology immunotherapy,1976
Advantages of ImmunotherapyAdvantages of ImmunotherapyAdvantages of Immunotherapy Advantages of Immunotherapy for cancerfor cancer
• Cancer cells are immunogenicg• Single cell kill• Migrate to tissue• Migrate to tissue• Memory• Specific• Life-long protectionLife long protection
Cancer Immunology and Cancer Immunology and gygyImmunotherapyImmunotherapy
• How does the immune system eliminate cancer cells?
• How do cancer cells escape from Immunosurveilance?• How do cancer cells escape from Immunosurveilance?
• How can we help to win the battle between immune t d ? C i thsystem and cancers? – Cancer immunotherapy
• Examples
Cancer ImmunosurveilanceCancer ImmunosurveilanceCancer ImmunosurveilanceCancer ImmunosurveilanceTh h th i fi t d b Eh li h i• The hypothesis was first proposed by Ehrlich in 1909, and modified by Thomas and Burnet in 1957.1957.
• Immunosurveilance: the immunological resistance of the host against the development of gcancer.
• Now referred to “cancer immunoediting” encompassing 3 phases: elimination equilibriumencompassing 3 phases: elimination, equilibrium and escape.
Cells of the Immune System Bone graft
Macrophage
ErythrocytesEosinophil
Mast cell
Erythrocytes
Megakaryocyte
Basophil
Monocyte
Marrow
Hematopoieticstem cell
MegakaryocyteMonocyteBone
Multipotentialstem cell
Pl t l t
NeutrophilMyeloid
progenitor cell
Platelets
D d iti ll
Lymphoid progenitor cell
T lymphocyte Dendritic cell
Natural killer cellB lymphocyte
Army of the host to fight cancersArmy of the host to fight cancers
Antibody
Macrophage
Cancer cellHelper T cell
cytokine
chemokineNK cell
Cytotoxic T cellDendritic cell
Cytotoxic T cells (CTLs)Cytotoxic T cells (CTLs)Cytotoxic T cells (CTLs)Cytotoxic T cells (CTLs)CD8+ T cells: attaching to class I MHC -gpeptide complex, they destroy cancer cells by perforating the membrane withby perforating the membrane with enzymes or by triggering an apoptotic pathwaypathway.
Surface contact
Release of enzymes
Helper T cellsHelper T cellsHelper T cellsHelper T cells
CD4+ T cells: reacting to class II MHC-peptide complex, they secret cytokines.p p p , y y
cytotoxic T cell response (Th1 helper T cells) antibody response (Th2 helper T cells)antibody response (Th2 helper T cells)
Logistics force
Dendritic CellsDendritic CellsDendritic CellsDendritic CellsThe professional antigen-presenting cells In the fi l th f ti ti ï Tfinal common pathway for activating naïve T cells.
Dendritic cell
E l W i Ai ft
T cell
-- Early Warning Aircraft
A novel subset of dendritic cells [IFN-producing killer DC] (IKDC): TRAIL& perforin- tumor cell lysis; via T cell; IFNγ-angiogenesisp y ; ; γ g g
Other cellsOther cellsNK cells: after activation directly killing tumor cellNK cells: after activation, directly killing tumor cell
NKT cells: TRAIL/perforin- tumor cell lysis;
IFNγ-angiogenesis
Macrophages: antigen presentingMacrophages: antigen presenting
NK cell NKT cellM hMacrophage
CytokinesCytokinesCytokinesCytokines• Regulating the innate immune system: NK cells,
macrophages and neutrophils; and the adaptive immunemacrophages, and neutrophils; and the adaptive immune system: T and B cells
• IFN-α -- upregulating MHC class I tumor antigens andIFN α upregulating MHC class I, tumor 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 promoting NK and T cell activity and a growth factor• IL-12 – promoting NK and T cell activity, and a growth factor for B cells
• GM-CSF (Granulocyte-monocyte colony stimulating factor) --G CS (G a u ocyte o ocyte co o y st u at g acto )reconstituting antigen-presenting cells.
Antibody Antibody -- produced by B cellsproduced by B cellsyy• Direct attack: blocking growth factor receptors, arresting
proliferation of tumor cells, or inducing apoptosis. -- is not usually sufficient to completely protect the body.
• Indirect attack: -- major protective efforts(1) ADCC (antibody-dependent cell mediated cytotoxicity ) ( ) ( y p y y )-- recruiting cells that have cytotoxicity, such as monocytes and macrophages.
(2) CDC (complement dependent cytotoxicity)(2) CDC (complement dependent cytotoxicity) -- binding to receptor, initiating the complement system, 'complement cascade’, resulting in a membrane attack complex causing cell lysis and deathcomplex, causing cell lysis and death.
Heavy chain
Light chain
Antigen-bindingregion
Light chain
-- missileAssembled antibody molecule
Constant region
Tumor elimination
How does cancer SingleHow does cancer
progress?Single cancer cell
progress?
Escape
Advanced cancer
Cancer Cancer I l /I thI l /I thImmunology/ImmunotherapyImmunology/Immunotherapy
• How does the immune system eliminate cancer cells?
• How do cancer cells escape from Immunosurveilance?• How do cancer cells escape from Immunosurveilance?
• How can we help to win the battle between immune t d ? C i thsystem and cancers? – Cancer immunotherapy
• Examples
Mechanisms of cancer escape from the Immunosurveilance
1 Alt i Th i Ch t i ti
the Immunosurveilance
1. Altering Their Characteristics : Loss/downregulation of MHC class I Down-regulation mutation or loss of tumor antigensDown regulation, mutation, or loss of tumor antigens Loss of costimulation
2. Suppressing the Immune Response : ineffective signals to CTLAlteration in cell death receptor signalingI i t kiImmunosuppressive cytokine
3. Outpacing the Immune Response: Tumour cells can simply proliferate so quickly that the immune p y p q yresponse is not fast enough to keep their growth in check
How cancer cells avoid How cancer cells avoid immunosurveillanceimmunosurveillance
1. Weapons from tumors
2 Defects of imm ne s stem2. Defects of immune system
(1) Loss/down(1) Loss/down--regulation of HLA regulation of HLA class I (MHC I)class I (MHC I)
• Total loss: β2 microglobulin mutation, alteration in antigen processing machinery
• Haplotype loss: LOH in chromosome 6• HLA allelic loss: mutations of HLA class I genesHLA allelic loss: mutations of HLA class I genes • HLA-A, B, C locus down-regulation: alteration of
transcriptional factorstranscriptional factors• Compound phenotype: 2 or more independent
h imechanisms
(2) Down(2) Down--regulation, mutation or loss of regulation, mutation or loss of tumor antigenstumor antigens
Tumor antigens (TA)Tumor associated antigen (TAA)
• Complete loss• Down-modulation
Tumor AntigensTumor Antigensgg• Altered self: K-ras, products of normally unexpressed
genes (MAGE BAGE GAGE) proteins of alternativegenes (MAGE, BAGE, GAGE), proteins of alternative reading frame, - of post-translational modification, -different orders of glycosylation (mucin-CA125, MUC1).g y y ( , )
• 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 in lymphomas• Autoantigens: overexpression - c-myc in lymphomas, leukemias; HER-2/neu epidermal growth factor receptor-breast cancer (Herceptin).( p )
(3) Loss of costimulation(3) Loss of costimulation(3) Loss of costimulation(3) Loss of costimulationCostimulatory molecules recognized:
B7 1(CD80)
Costimulatory molecules recognized:
B7.1(CD80)B7.2(CD86)CD40 L
B7 familyCD40 LCD27, CD30 4-1BB4-1BBOX40ICAM-1ICAM-1
T cell Activation No Activation
T cell T cell
TCRCD28 CD28 TCRCD28 CD28
Peptide/B7.1 B7.2 Peptide/
APC
Peptide/MHC
APC
pMHC
L f ti l tiCo-stimulation Loss of costimulation
The initiation of T cell responses requires two p qdistinct signals
X
(4) Alterations in cell death(4) Alterations in cell death(4) Alterations in cell death (4) Alterations in cell death receptor signallingreceptor signalling
• Defects in Fas/FasL signaling system:Defects in Fas/FasL signaling system:resistance to apoptosis
• Apoptosis resistance: overexpression of Bcl-2
(5) Immunosuppressive (5) Immunosuppressive cytokinescytokines
• a number of immunosuppressive cytokines• a number of immunosuppressive cytokines.• IL-10 inhibits antigen presentation and IL-12
productionproduction.• 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 (6) Induction of Immunosuppressive cellsImmunosuppressive cells
• CD4+CD25+ T cells (constitute 5-10% of CD4+ T cells): immunological tolerance to self-antigens, inhibition of T cell
lif tiproliferation.
• Gr1+CD11b+ myeloid cells: -- Expressing the granulocyte-monocyte markers Gr1+CD11b+, accumulate in spleens, lymph nodes and blood of tumor-bearing mice.
I hibiti tib d d ti CTL ti T ll-- Inhibiting antibody production, CTL generation, T cell function, lymphocytic proliferation, CD3 ζ chain expression.
Regulatory T CellsRegulatory T CellsT cells compete for
t ki i lT cells competef ti cytokine signalsfor same antigen
CytotoxicT cell
Mature dendriticdendritic
cell
Regulatory T cellsRegulatory
T cell
Proliferation
PotentialPotential sources for regulatory T cellsT cells
Possible suppressive mechanisms regulatory T cells
(7) Production of other (7) Production of other ( )( )suppressive factorssuppressive factors
• IDO (Indoleamine 2, 3-dioxygenase): expressed in most human tumour tissuesexpressed in most human tumour tissues and splenic DC subsets, leading to blockage of proliferation of T cellsblockage of proliferation of T cells
• ganglioside (sialic acid containing gl cosphingolipids)glycosphingolipids)
• Prostaglandins
Summary: Main defences of the Summary: Main defences of the tumors against immunitytumors against immunity
1) Alteration of MHC class I and tumor antigen expression1) Alteration of MHC class I and tumor antigen expression
2) Dysregulated expression of adhesion / costimulatory molecules by tumor and/or antigen-presenting cellsmolecules by tumor and/or antigen-presenting cells
3) Changes in T-cell signal transduction molecules, i.e. cell death receptor signallingreceptor signalling
4) Induction of immune suppressive cytokines
5) Induction of immunosuppressive cells
6) S i f i f6) Secretion of suppressive factors
1. Weapons from the tumors
2. Defects of immune system
• Immune defects in T cells
• Malfunction of dendritic cell systemy
Immune defects in T cells in cancerImmune defects in T cells in cancerImmune defects in T cells in cancerImmune defects in T cells in cancer
• Alterations in the expression of signal transduction molecules in immune cells.
• Loss of CD 3ζ chain. TCR-CD3 complex. It functions as a single transducer upon antigen binding.
• Receptor-mediated apoptosis of T cells contributes to T cell dysfunction.
Tumor massu o ss
Vessel
Lymphocyte
FasL+ tumor cell
Apoptotic lymphocyte
Receptor-mediated apoptosis of lymphocytes
Malfunction of dendritic cell systemMalfunction of dendritic cell systemMalfunction of dendritic cell systemMalfunction of dendritic cell system
– Tumor-mediated inhibition of DC generation, differentiation and maturationdifferentiation and maturation
– Functional impairment of DCs: lack of expression of costimulatory moleculesexpression of costimulatory molecules
– Induction of DC apoptosis by tumors
TumorTumor--derived factors with DC inhibitory propertiesderived factors with DC inhibitory properties
Tumor-derived factors Effect on DCs
VEGF tumor infiltration and generation
TGF-beta CD80 and CD86 expression
Gangliosides inhibition of dendropoiesis from hematopoietic precursor cells
IL 6 differentiationIL-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?
Activation versus suppression of immunity during tumor progression
Tumor Regression
Cytokines
immunity during tumor progression
g
Activation >suppressionT cellTumor
Suppression> activation
Tumor Progression
DCNK cell
The fortune of tumor cellsThe fortune of tumor cells depends on the battle between p
immune system and tumor cells
The defense of tumor overweighs the anti-t i ittumor immunity
Cytotoxic CD8 cellsDendritic cellsMacrophagesC t ki
Antigen/MHC lossCytokinesAntibodies
T-cell dysfunctionSuppressive cytokineSuppressive T cellsOverweighing effector cells
Balance
Cancer Cancer I l /I thI l /I thImmunology/ImmunotherapyImmunology/Immunotherapy
• How does the immune system eliminate cancer cells?
• How do cancer cells escape from Immunosurveilance?• How do cancer cells escape from Immunosurveilance?
• How can we help to win the battle between immune t d ? C i thsystem and cancers? – Cancer immunotherapy
• Examples
Tumor ImmunotherapyTumor ImmunotherapyTumor ImmunotherapyTumor Immunotherapy
Strategies to improve the tumor-associated immune response byassociated immune response by either boosting components of the immune system that produce animmune system that produce an effective immune response or by inhibiting components that suppress the immune response.p
Immunotherapy Immunotherapy ------ Reverse Reverse the imbalancethe imbalance
Tumor Immunotherapy
Tumor Progression
StrategiStrategiees to supplement the missing or s to supplement the missing or insufficient immune elementsinsufficient immune elements
Immune elements Enhancing ‘the enhancer’
T cells Injection of cytotoxic T cells
Dendritic Cells DC vaccinationDendritic Cells DC vaccination
Natural killer cells Injection of activated NK cells
TAA Peptide, TAA-vector vaccination
Effector cytokines IL-2, IL-12
Strategies to block the suppreStrategies to block the suppresssive sive mechanismsmechanisms
Suppressive elements Inhibiting ‘the inhibitors’Regulatory T cells Blocking their function
dysfunctional DCs Blocking the pathway
Suppressive cytokines Blocking potential common t ki i llicytokine signalling
Suppressive factors Blocking their functionSuppressive factors Blocking their function
Main Mechanisms of Main Mechanisms of ImmunotherapyImmunotherapy
• Stimulating the antitumor response, either by increasingStimulating 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.make them more susceptible to immunologic defences.
• Improving tolerance to cytotoxic drugs or radiotherapy, p g y g py,such as stimulating bone marrow function with GM-CSF.
History: NonHistory: Non--specific approachspecific approachHistory: NonHistory: Non--specific approachspecific approach
1892 WB C l b d t i• 1892 - WB Coley observed tumour regression after bacterial infections
• BCG vaccine to treat bladder carcinoma• 1970-80’s – cytokines y
– includes interferons, interleukins and tumor necrosis factor (TNF)necrosis factor (TNF)
– Limited success
Current Immunotherapeutic Current Immunotherapeutic strategies in clinic or clinical trialsstrategies in clinic or clinical trials
• Antibody Therapy• Cytokine Therapy• Adoptive Therapy• Adoptive Therapy• Vaccination• Combinational therapy
ExamplesExamplespp
Antibody TherapyAntibody Therapyy pyy pyRituximab: The first approved antibody by FDA in clinical trial. Targeting CD20. low-grade non-Hodgkin lymphoma
Cytokine therapyCytokine therapyILIL 22---- ILIL--22
Event Author
Discovery of IL-2 Morgan et al.(1976)
Mitogenic IL-2 signal and long-term cultures of tumor-specific CTL Gillis and Smith (1977)
Activating IL-2 signal (LAK cells) Grimm et al.(1982)
Local administration of IL-2 inhibits tumour growth in preclinical models Bubeník et al.(1983)p ( )
Local administration of IL-2 inhibits growth of human tumors Pizza et al. (1984)
Systemic administration of IL-2 inhibits growth of metastatic Rosenberg et al.(1985a)y g g ( )experimental tumours
Utilization of recombinant IL-2 for clinical trials in patientswith generalized tumours Rosenberg et al (1985b)with generalized tumours Rosenberg et al.(1985b)
Local IL-2 gene therapy inhibits tumour growth in preclinical models Bubeník et al.(1988)
Utilization of TIL or tumour cells carrying an inserted IL-2 gene Anderson (1992);Utilization of TIL or tumour cells carrying an inserted IL 2 gene for the first clinical trials
( );Foa et al. (1992)
Local and regional IL-2 administration in cancer patients -selected examples from the early trials
Interleukin-2 Dose Tumour Response (%) Reference ( it / ti t) C l t / ti l(units/patient) Complete/partial
gibbon lymphoid 1.5 x 10-2 – 4.0 x 10-3 urinary bladder carcinomas 30/ 30 Pizza (1984)human recombinant 1.0 x 10-4 – 2.8 x 10-4 lung carcinomas 0/ 82 Yasumoto (1987)
human recombinant 8.0 x 10-2 – 5.4 x 10-3 malignant gliomas 13/ 13 Yoshida (1988)human lymphoid 2.0 x 10-3 squamous cell carcinomas 29/ 29 Forni (1988) human lymphoid 2.0 x 10-3 squamous cell carcinomas 30/ 30 Cortesina (1988)human lymphoid continuous perfusion urinary bladder carcinomas 20/ n.v. Huland and Huland
1.5 x 10-6/week (1989)
n.v., not verified because of incomplete transurethral resection
Adoptive immunotherapyAdoptive immunotherapyAdoptive immunotherapyAdoptive immunotherapy
• Stimulating immune cells by exposing them to tumour cells or antigens in thethem to tumour cells or antigens in the laboratory and then injecting expanded populations of the treated cells intopopulations of the treated cells into patients.
• Patient is both donor and recipient• Patient is both donor and recipient.
Tumor escape mechanism and T-cell adoptive immunotherapy after genetic manipulation
(1) Tumor cells that produce TGFß that exert inhibitory effects on the immune system. Specific CTL can be genetically modified to become resistant to the TGFβ inhibitory effect through transgene expression of a mutant dominant-
ti TGFß t II t (DNR)negative TGFß type II receptor (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/FasL-mediated apoptosis.mediated apoptosis.
Adoptive immunotherapyAdoptive immunotherapyThe Journal of Clinical Investigation Vol 113 Number 11 June 2004 pp 1515The Journal of Clinical Investigation Vol 113 Number 11 June 2004 pp 1515
Generation of dendritic cell vaccines from peripheral blood monocytes:p p y1) Monocytes cultures with GM-CSF +IL-4 to produce DCs2) Matured with CD40 ligand3) Pulsed with peptide or tumour lysate4) Re-injected as vaccine to induce T-cell immune response against tumour
Antitumor VaccinesAntitumor Vaccines
Administration of some formAdministration of some formAdministration of some form Administration of some form of antigen to induce a specific of antigen to induce a specific
tit itit iantitumour immune response.antitumour immune response.
Antitumor VaccinesAntitumor Vaccines
Antitumor VaccinesAntitumor Vaccines
Approaches to antitumor vaccinationApproaches to antitumor vaccination
The Journal of Clinical Investigation Vol 113 ( 11) June 2004 pp 1515
APC – antigen presenting cell TAA – tumour associated antigenDC – dendritic cell MHC – major histocompatibility complex
Dendritic Cells That Attack CancerDendritic cell
Complex binds to dendritic cell precursor
matures and is infused back into patient
T cell
Tumor antigen
TumorTumor antigen is linked to a cytokine
Complex is taken in by dendritic celldendritic cell precursor
Cancer cell
T cells attack cancer cell
Combinational Combinational TTherapyherapypypy---- a threea three--stranded cord is not easily brokenstranded cord is not easily broken
• Combination of different immunotherapies pACT+IL-2 + costimulation
• Combining immunotherapy with other therapeutic strategies
Examples from my research workExamples from my research workExamples from my research workExamples from my research work
The immune system can be harnessedas a potent weapon to combat canceras a potent weapon to combat cancer,but only if immunotherapy is combinedwith treatment strategies that target atumour’s weapons of survival, defence,p , ,and attack. If cancer cells are preventedfrom growing they will be unable tofrom growing they will be unable togenerate immune escape variants.
Gene transfer of antisense hypoxia inducible factorGene transfer of antisense hypoxia inducible factor--1α1αGene transfer of antisense hypoxia inducible factorGene transfer of antisense hypoxia inducible factor 1α 1α
enhances the therapeutic efficacy of cancer immunotherapyenhances the therapeutic efficacy of cancer immunotherapy
Sun X et al Gene Therapy 2001; 8: 638 645Sun X, et al. Gene Therapy 2001; 8: 638-645
Potential mechanisms for synergy displayed by combined blocking hypoxia pathway and B7.1-mediated immunotherapy
B7.1+AS-HIFB7 1
AS-HIFNK A iB7.1Tumor
cellApoptosis Necrosis
Tumor
NK
Glycolysis
Activates NK cells
v
Tumorcell Tumor
cell
+ hsp70- tumor
Anti-angiogenesis
vv
B7 1APCMHCI
CTumorcell
B7.1
+ hsp70 tumorAntigen
Heat-shockd i i
Cell vitalityB7.1 MHCI
MHCIICD28
MHCI
CD28
T cell
MHCII
T cell
driven anti-tumorimmunity
Immune suppressive Proliferation
& CTL-mediated
killing
ppelements
TumorCell
Apoptosis
B7H3-meidated Cancer Immunotherapyy
Arsenic trioxide synergizes with B7H3-mediated immunotherapy to eradicate hepatocellular carcinomas
International Journal of Cancer 2006; 118:1823-1830.
C l t di ti f h t ll l i b bi dComplete eradication of hepatocellular carcinomas by combined vasostatin gene therapy and B7H3-mediated immunotherapy. Journal of Hepatology 2007;46: 98-106Journal of Hepatology 2007;46: 98 106
Novel co-stimulatory molecule- B7H3
Molecular StructureSS IgV-like IgC-like Cytoplasmic
Signal peptideMLRGWGGPSVGVCVRTALGVLCLCLTGAVEVQVSEDPVVALVDTDATLRC
IgV-like domain
Transmembrance
gSFSPEPGFSLAQLNLIWQLTDTKQLVHSFTEGRDQGSAYSNRTALFPDLLVQ
GNASLRLQRVRVTDEGSYTCFVSIQDFDSAAVSLQVAAPYSKPSMTLEPNKIgC-like domain
DLRPGNMVTITCSSYQGYPEAEVFWKDGQGVPLTGNVTTSQMANERGLFDDLRPGNMVTITCSSYQGYPEAEVFWKDGQGVPLTGNVTTSQMANERGLFD
VHSVLRVVLGANGTYSCLVRNPVLQQDAHGSVTITGQPLTFPPEALWVTVGTransmembrane Cytoplasmic
LSVCLVVLLVALAFVCWRKIKQSCEDENAGAEDQDGDGEGSKTALRPLKPS
ENKEDDGQEIA
Sun X et al Gene Therapy 2003; 10:1728-1734Sun X, et al. Gene Therapy 2003; 10:1728-1734.
Gene transfer results in expression of B7H3 on the surface of tumor cells
pcDNA3.1 Flag-B7H3
the surface of tumor cells
Flag-B7H3
Tubulin
Combinational therapy led to eradication of large tumorsCombinational therapy led to eradication of large tumors and generation of memorized anti-tumor immunity
1 6
2
2.4e
(cm
)B7H3+As2O3B7H3As2O3pcDNA3.1PBS
0 4
0.8
1.2
1.6
Tum
or S
ize
0
0.4
0 1 2 3 4 5 6 7 9 12Weeks After Therapy
20
Production of anti-tumor cytokine and CTLs by immunotherapy
300
400
500
N-γ
(pg/
ml)
* *Sera
6
8
10
N-γ
(ng/
ml)
* *Supernatants
100
200
300
Leve
l of I
FN
2
4
6
Leve
l of I
FN
0 0
405060
ity (%
)
20:1 E:T Ratio* *
y (%
) PBSCD4+CD8+40
5060
10203040
Cyt
otox
ic 100:1* *
Cyt
otox
icity
CD8+NK
10203040
* * * *
0B7H3+As2O3 B7H3 PBS
010
Treatment of single tumor eradicates multiple distant tumors
0.6
0 4
0.5
met
er) Tumor-1,treated
Tumor-2,untreated
Tumor 3 untreated
0.3
0.4cm
,dia
m Tumor-3,untreated
Tumor-4,untreated
Tumor-5,untreated
0.1
0.2
mor
Siz
e(
0
0 1 2 3 4
Tum
Weeks after therapy
ConclusionConclusionConclusion Conclusion • Immunotherapy may be the next great hope for py y g p
cancer treatment. • While antibodies, cytokines, and vaccines haveWhile antibodies, cytokines, and vaccines have
individually shown some promise, it is likely that the best strategy to combat cancer will be tothe best strategy to combat cancer will be to attack on all fronts.
• The effect of immunotherapy in combination with• The effect of immunotherapy in combination with traditional cancer therapies is another avenue.
Background – mini review
Unclear
Controversial Not reported
Further investigation
ShortcomingsIntroduction
Hypothesis
ExperimentsMaterials and Methods
ResultsDiscussion
Conclusion
Si ifiDiscussion Combined
Future Investigation
Significance
g
DR Kevin Sun Department of Molecular Medicine & PathologyDepartment of Molecular Medicine & PathologyRm 4231Tel:3737599-85935Email:[email protected]:[email protected]