Sessions 69 and 70
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- Hallmarks of Cancer
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-provide own growth signals
-ignore growth-inhibitory signals
-avoid cell death
-replicate w/o limits
-sustain angiogenesis
-invade tissues through basement membrane and capillary walls
-avoidance of immunosurviellance - Extrinsic hallmark of cancer
- avoidance of immunosurveillance
- Cancer Immunosurveillance
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phsyiologic function of immune system
recognize and destory clones of transformed cells before they grow into tumors
eradicate tumors after they have formed - CD8+ CTL Function
- Lysis of tumor stromal fibroblasts, tumor cells, and tumor stromal endothelial cells
- CD4+ T Helper Function
- Prevent angiogenesis of tumor stromal fibroblasts, promote M2 Macrophages
- IKDC Function
- Promote tumor cell lysis, cross-presentation of tumor antigens, and prevent angiogenesis
- NK Cell Function
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Activated by BCR-ABL, IL-4 and IL-13, KIT inhibitors
Interact with inhibitory receptor on tumor cell - NKT Cell Function
- Prevent angiogenesis, promote lysis of tumor cells
- Gamma-delta Function
- Promote lysis
- Tumor-specific antibody function
- Lysis, complement-mediated lysis, antibody-dependent cytotoxicity
- Mechanisms of Escape from Immunosurveillance
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Immune selection for non-immunogenic tumors
Myeloid suppressor cells (Tregs) - Immune selection
- Immune selection develops at equilibrium for cells with decreased MHC Class I molecules and decreased IFNgamma response
- Tregs
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Inhibit CD8+ proliferation
Promote CD4+ apoptosis
Suppressive mechanisms lead to T-cell arrest, anergy, apoptosis or APC apoptosis/dysfunction - TH2 shift
- Suppression of tumor cell lysis
- iDC and Tregs
- Cause anergy of T cells
- Tumor Dependent Factor
- Promotes apoptosis
- TGF-Beta
- Promotes apoptosis and antigen uptake
- Cancer Vaccines
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Whole Tumor Cells
Plasmid DNA
Defined tumor antigens
Recombinant viral vectors
Provide anti-tumor immunity (antigen specific)
Can cause auto-immune damage to normal tissues - Adaptive Cell Therapy
- Tumor excision --> cultures with IL-2 --> test for IFNgamma production --> rapid clonal expansion with IL-2 and CD3 Antibody --> adaptive transfer of anti-tumor lymphocytes
- Gene Therapy:
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technique for introducing genetic material of a gene into cells or patient
reverese genetic cause of cancer or progress of carcinogenic process - Viruses Used in Gene Therapy
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Retrovirus
Adenovirus
Lentivirus
Adeno-associated virus - Retrovirus
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-activates proto-oncogene by insertional mutagenesis
-contaminated wild-type retrovirues cause lymphoma transgene inactivation in vivo
-easily inactivated
-must incubate target cells with producer cells for high transduction - Adenovirus
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-episomal
-transient
-highly immunogenic
-causes inflammation, anaphylaxis - Adeno-associated Virus
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-non-pathogenic
-chromosomal integration
-long-term expression
-safe - Ex Vivo Gene Therapy
- Cells removed from body --> transgene delivered --> cells cultured --> cells returned to body
- In Vivo Gene Therapy
- Transgene delivered directly into host
- rAAV Advantages
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Safe
Activation of CTLs and Antibody responses
Ease of inserting foreign genes
At least 6 months, up to 2 years - Somatic Gene Therapy
- Corrects cell populations or tissues
- Germinal Gene Therapy
- Whole "transgenic" organisms
- Gene Vaccines
- Mobilize normal human defenses against some tumor products
- Non-viral Vectors
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liposomes
coat DNA with proteins
biodegradable polymers
gene gun
chemical/physical methods