©2015 mfmer | slide-1 introduction to immuno-oncology keith l. knutson, ph.d. professor of...
TRANSCRIPT
©2015 MFMER | slide-1
Introduction to Immuno-Oncology
Keith L. Knutson, Ph.D.Professor of ImmunologyCommunity Oncology Conference 2.0April 23-24, 2015
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Cells of the immune system
All cellular elements of the blood are derived from a single pluripotent hematopoietic stem cell
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Phagocytes
MonocytesDCP
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Polymorpho-nuclear
leukocytes
All (except maybe mast cells) are derived from the common myeloid precursor
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Natural Killer Cells
INNATE
Both are derived from the common lymphoid precursor
Lymphocytes
Antigen-Specific
LymphocytesADAPTIVE
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Antigens are recognized by the immune response while epitopes are sites within antigens
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Antibody dependent cellular cytotoxicity
Antibodies have multiple functions
Antibody mediated opsonizationSignal interferenceBlockade of uptake
Shuttle
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Oncogenesis
proto-oncogenes
tumorsuppressorgenes
oncogenes
Carcinogenresults in mutation
dysfunctional tumor suppressorgenes
inheriteddefect
increased GF
increased GF receptors
exaggerated response to GF
loss of ability torepair damaged cells or induceapoptosis
Increased growth
Virus introduces oncogenes
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Tumor Antigen Classifications
• Tumor-specific antigens– Ras– p53– BCR-Abl– Viral antigens– Mis-splice variants
• Cancer-Testis antigen– MAGE (1st cloned tumor
antigen)– NY-ESO
• Differentiation antigens– Tyrosinase– MART-1
• Overexpressed antigens– HER-2/neu– hTERT
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Paradoxical roles of the immune system in cancer
development1. The key functions of the mammalian immune system:
(1) Protect from infectious pathogens(2) Monitor tissue homeostasis => Eliminate damaged
cells (e.g. tumor cells) and induce wound healing.
2. Mechanisms against cancer development: (1) Cellular immunity- T, NK, & Other innate immune cells(2) Humoral immunity- Cytokines, Abs, etc.
3. Mechanisms promoting cancer development: (1) Inflammation => Angiogenesis & Tissue remodeling(2) Enhance survival pathways (NF-kB activation)(3) Suppression of anti-tumor immune responses
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The complex relationship between the immune system
and cancers1. Adaptive and innate immune cells regulate tissue
homeostasis and efficient wound healing
2. Altered interactions between adaptive and innate immune cells can lead to “chronic inflammatory disorders”.
3. Chronic inflammatory conditions enhance a predisposition to cancer development.
4. In cancers, an abundance of infiltrating innate immune cells (e.g. macrophages, mast cells, and neutrophils) correlates with increased angiogenesis and/or poor prognosis.
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Inflammation elevates cytokines that activate transcription factors which promote tumor formation and
progression.
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Inflammation induces immune suppressive cells which prevent
adaptive cellular immunity
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Science 2013;339:286-291
Malignant cells foster development of wound healing responses
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Preventing Tumor-inducing Inflammation
• Life style changes: lose weight, quit smoking, quit drinking.
• Non-steroidal anti-inflammatories: colorectal, bladder, ovarian.
• Vaccination: HBV, MUC1
• Phytochemicals: Variety of inhibitors (Natural Cox and Stat3 inhibitors).
Gut 2010;59:1670-1679
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Science 2013;339:286-291
Reversing Tumor-Associated Chronic
Inflammation
• Adoptive Therapies• T cells• Cytokines
• Vaccines• Combination
approaches
• Viruses to induce acute inflammation
• Checkpoint blockade
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• Reconstituting humoral immunity
• Humanization of mouse monoclonals
• Mechanisms of action• ADCC• Complement• Signal enhancer/inhibitor• Enhances acute immunity
Monoclonal antibody therapy
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Mocellin et al, Cochrane Database of Systemic Reviews 2013;DOI10.1002/14651858
Meta-analysis of interferon impact on overall survival
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MAb Name Trade Name Used to Treat: Target
Rituximab Rituxan Non-Hodgkinlymphoma CD20
Trastuzumab Herceptin Breast cancer HER-2/neu
Gemtuzumab ozogamicin* Mylotarg
AcuteMyelogenousleukemia (AML)
CD33
Alemtuzumab CampathChronicLymphocyticleukemia (CLL)
CD52
Ibritumomab tiuxetan* Zevalin Non-Hodgkin
lymphoma CD20
Tositumomab* Bexxar Non-Hodgkinlymphoma CD20
Cetuximab Erbitux Colorectal cancer EGFR
Bevacizumab Avastin Colorectal cancer VEGF
FDA-Approved antibodies
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HER2+ Breast Cancer Management
1st-line: chemo + trastuzumab
Metastatic Disease• Response 50-80%• Time to disease
progression ~ 11-14 mo
Adjuvant Setting• ~50% reduction in relapse• Best if used concurrently
with chemo.
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Current Opinion in Immunology
Tumor regression following T cell infusion
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Current Opinion in Immunology
Survival of Patients Treated with TIL and IL-2
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• Target suppressive molecules: anti-IL-10 antibodies
• Block key immune regulatory loops• Anti-CTLA-4 (checkpoint blockade)
• Block systemic and infiltrating regulatory T cells
• IL-2 immunotoxin• Anti-CD25 antibody
Blocking immune suppression
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Anti-CTLA-4 causes regressions of melanoma metastases
Klein O et al. Clin Cancer Res 2009;15:2507-2513
Lung met
Lymph node met
Chest wall met
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Anti-PD-1 causes regressions of melanoma metastases
New England Journal of Medicine