Tumor Immunology (Cancer) Robert Beatty MCB150 Tumors arise from accumulated genetic mutations.
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Transcript of Tumor Immunology (Cancer) Robert Beatty MCB150 Tumors arise from accumulated genetic mutations.
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Tumor Immunology(Cancer)
Robert Beatty
MCB150
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Tumors arise from accumulated genetic mutations
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MutationsUsually have >6 mutations in both activation/growth factors
and tumor suppressor genes.
Mutations lead to changes in tissue growth and further progression can result in tumors.
*APC- adenomatous polyposis coli gene. Tumor suppressor.
*
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Types of genes that control cancer
Oncogenes
Mutations
Oncogenes can be receptors or activation/signaling proteins.
Viral infection
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Types of genes that control cancer
Tumor suppressor genes – cancer arises when the tumor suppressor genes stop
working, lack of growth inhibitory signals. – These genes are part of normal control of cell cycle,
usually inhibiting growth-promoting factors and cell division.
Cell Death Proteins– The cell death proteins are either activating or
inhibiting cell death, apoptosis.
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Inherited predisposition to cancer
Most inherited cancer genes are mutated tumor suppressor genes.
These inherited genes can result in early onset of cancer (higher predisposition).
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Immunological Surveillance(Burnet, Thomas)
Hypothesis: Tumors are constantly arising. A major role of the immune system is to eliminate this constant threat. Tumors get through when immune system fails.
Evidence: Pro: Incidence of cancer is higher in conditions of
immunosuppression, ie. Transplant recipients, AIDS.
Con: Those tumors seem to be largely of viral origin, so findings are no different than for any infectious agent.
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New Theory Adaptive immune response can kill tumors BUT
tumor cells evade host immune response
Mechanisms of Tumor Escape Antigen lossLoss of MHC or TAPProduction of inhibitory cytokines (TGFb)Expression of FasL
Tumor Seen as SelfDo not initiate inflammationInduction of tolerance
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Immune Response to Tumors
Cell Mediated – Cytokines from activated CD4+ T cells.
TNF- and LT- (TNF-) directly toxic to some tumor cells.
– CD8+ CTL, NK cells, and macrophages activated by IFN-g from CD4+ T cells.
Antibody Response– ADCC and Complement lysis possible.
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What is the Anti-Tumor Immune Response?
Tumor infiltrating lymphocytes including CTLS and NK cells were isolated from tumors.
These CTLS were specific for tumor antigens.
What are these tumor antigens?
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I. Identification of Tumor AntigensUsing T cell clones from patient Biochemical identification:
Purify MHC from tumor cells, elute peptides.Isolate peptides by HPLC and determine sequence
Use T cell clones to screen tumor cell cDNA library. Confirm with synthetic peptide of predicted sequence
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Sources of Antigens that StimulateAnti-tumor Immune Reponses
Fundamentally related to the neoplastic process
– Mutated oncogenes, suppressor genes (ras, p53)
– New antigens generated by translocation (bcr/abl fusion protein)
– Antigens derived from oncogenic virus (EBV, HPV) Coincidental antigens
– Overexpressed normal differentiation antigen
– Re-expressed oncofetal antigen
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II. Types of Tumor Antigens
Rexpressed embryonic antigens. Self antigens. (oncofetal proteins).
Differentiation antigens. Overexpressed normal proteins such as melanocyte regulation proteins expressed in melanomas can become antigens.
Viral antigens. Oncogenic viruses.
Mutated self proteins. Point mutations of normal cellular genes (unique tumor antigens).
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Shared Tumor Antigens
Embryonic antigens e.g. MAGE-1---MAGE-12,
Overexpressed melanocyte proteins
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Shared Tumor Antigens
Differentiation antigens
Overexpressed proteins found in tumors from unique cell type.
Immune system was probably not tolerized in thymus to these antigens. – Examples: Melanoma tumor antigens which are
proteins used in melanin production. MART-1, tyrosinase.
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Cancer Therapies
Most preventive agents can be effective at different stages along the progression towards cancer.
Janne and Mayer NEJM 342:1960. 2000
I. Prevention
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II. Older Cancer Treatments
SLASH/BURN/POISON
Slash SurgeryBurn RadiationPoison Chemotherapy
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Cancer Therapy
III. New Targeted Cancer Treatments•Receptor antagonists. •Protein Kinase inhibitors. •Enzyme Inhibitors. •Antisense oligonucleotides.•Anti-angiogenic factors
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New Targeted Cancer Therapies
Enhance immune response to tumors
CK therapyIL-2, IFN-g, TNF-a given in IV doses.
Adoptive transfer of anti-tumor immune cellslymphokine-activated killer (LAK) cells, tumor infiltrating lymphocytes (TILs)
Cancer vaccines– Irradiate tumor cells inject back into patient.– Shared tumor antigens as vaccines.
Manipulate costimulation – Add B7. Block CTLA4
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Peptide/MHC
CD28TCR
B7
Two Signals Required for T cell Activation
No Proliferation(Anergy?)
T Cell
Proliferation
APCAPC
T Cell
IL-2
Epithelial CellsTumor Cells
Dendritic CellsMacrophagesAct. B cells
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B7 Transfected tumor cells are rejected
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Peptide/MHC
CTLA-4CD28TCR
B7 B7
APC
UnrestrainedProliferation
AttenuatedProliferation
APC
Tumor
CTLA-4 BlockadeEnhances Tumor-Specific Immune Responses
GM-CSF VaccinePeptide-pulsed DCs
AND/ORIrradiation
Chemotherapy
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104 live B16-BL6s.c., day -12, -8, -4 or 0
Anti-CTLA4/GMCSF-VaccineCombination Immunotherapy
106 irradiated GM-CSF producing B16-BL6s.c, days 0, 3, 6
Anti-CTLA-4i.p., days 3, 6, 9
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Pre-established B16-BL-6 melanoma tumors can be eradicated using anti-CTLA-4 and a GM-CSF producing cellular vaccine
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Skin and hair depigmentation as a result of treatment of B16 tumors with anti-CTLA-4 and
GM-CSF producing vaccines
challenge
vaccination
rejected B16-F10 lung metastases
rejected day 8 tumor
CD4 depleted
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Strategies Based on Knowledge of Antigenic Peptides
Active Immunization:
– Peptide: With adjuvant, linked to helper peptide, pulsed on APC
– Peptide followed by immunostimulatory cytokines
– Recombinant virus: Epitope together with genes encoding cytokines, costimulatory molecules, or other immunomodulatory agents
Passive Immunotherapy:
– Adoptive transfer of anti-tumor lymphocytes expanded in culture by stimulation with antigenic peptides
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Antibody-based therapy
Tumor-specific therapies: Not very successful due to lack of true tumor specific antigens, some problems with delivery
Anti-CD20 (Rituximab), anti-Her2/Neu (Herceptin)Immunotoxins: Antibody specific to tumor used to
deliver toxic molecule to lyse tumor cells.
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Oncolytic Viruses
Viruses naturally selected or lab engineered to grow in and specifically kill tumor cells.– Example: Engineer measles virus to interact with
specific receptor that is overexpressed on tumor cells. – Example: Vesicular stomatitis virus (VSV) can
replicate in tumor cells deficient in IFN pathway. Tumor cells with mutations in their interferon response can be rapidly killed by VSV.
Advantages of oncolytic viruses– Can elicit host immune response against tumor– Limited resistance developed