Transcript Introduction to Immuno

Introduction to Immuno-Oncology
Keith L. Knutson, Ph.D.
Professor of Immunology
Community Oncology Conference 2.0
April 23-24, 2015
©2015 MFMER | slide-1
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
Monocytes
DCP
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Polymorphonuclear
leukocytes
All (except maybe mast cells)
are derived from the
common myeloid precursor
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Lymphocytes
Antigen-Specific
Lymphocytes
ADAPTIVE
Natural Killer
Cells
INNATE
Both are derived from the common lymphoid precursor
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Schematic Structure of Antigen
Receptors
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Antigens are
recognized by
the immune
response while
epitopes are
sites within
antigens
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Antibodies and T cell
receptors recognize antigen
by different mechanisms
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Antibody dependent cellular cytotoxicity
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Oncogenesis
Carcinogen
Virus introduces
results in mutation
oncogenes
increased GF
Increased growth
proto-oncogenes
oncogenes
increased GF receptors
exaggerated
response to GF
tumor
suppressor
genes
inherited
defect
dysfunctional
tumor suppressor
genes
loss of ability to
repair damaged
cells or induce
apoptosis
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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 development
1.
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 cancers
1. 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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Association of inflammation with cancers
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Acute vs. Chronic Inflammation: Role
in Cancer Pathology
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Inflammation causes genomic damage
through reactive oxygen and nitrogen
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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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Malignant cells foster development of
wound healing responses
Science 2013;339:286-291
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Preventing Tumor-inducing Inflammation
• Life style changes: lose
weight, quit smoking, quit
drinking.
• Non-steroidal antiinflammatories:
colorectal, bladder,
ovarian.
• Vaccination: HBV, MUC1
• Phytochemicals: Variety
of inhibitors (Natural Cox
and Stat3 inhibitors).
Gut 2010;59:1670-1679
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Converting
chronic to
acute
inflammation
Science 2013;339:286-291
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Reversing Tumor-Associated
Chronic Inflammation
•
Adoptive Therapies
• T cells
• Cytokines
•
•
Vaccines
Combination
approaches
•
Viruses to induce acute
inflammation
•
Checkpoint blockade
Science 2013;339:286-291
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Monoclonal antibody therapy
• Reconstituting humoral immunity
• Humanization of mouse monoclonals
• Mechanisms of action
• ADCC
• Complement
• Signal enhancer/inhibitor
• Enhances acute immunity
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Meta-analysis of interferon impact on
overall survival
Mocellin et al, Cochrane Database of Systemic Reviews 2013;DOI10.1002/14651858
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Monoclonal antibody therapy
Humanizing monoclonal antibodies
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FDA-Approved antibodies
MAb Name
Trade Name
Rituximab
Rituxan
Non-Hodgkin
lymphoma
CD20
Trastuzumab
Herceptin
Breast cancer
HER-2/neu
Mylotarg
Acute
Myelogenous
leukemia (AML)
CD33
Alemtuzumab
Campath
Chronic
Lymphocytic
leukemia (CLL)
CD52
Ibritumomab
tiuxetan*
Zevalin
Non-Hodgkin
lymphoma
CD20
Tositumomab*
Bexxar
Non-Hodgkin
lymphoma
CD20
Cetuximab
Erbitux
Colorectal cancer
EGFR
Bevacizumab
Avastin
Colorectal cancer
VEGF
Gemtuzumab
ozogamicin*
Used to Treat:
Target
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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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Therapeutic Efficacy of
Herceptin
New England Journal of Medicine
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TIL Therapy
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Tumor regression following T cell infusion
Current Opinion in Immunology
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Survival of Patients Treated with TIL and
IL-2
Current Opinion in Immunology
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Autoimmunity
Following Cell therapy
Vitiligo
Uveitis
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Blocking immune suppression
• 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
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Checkpoint Blockade
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Anti-CTLA-4 causes regressions of melanoma
metastases
Lung met
Lymph node met
Chest wall met
Klein O et al. Clin Cancer Res 2009;15:2507-2513
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Anti-PD-1 causes regressions of melanoma
metastases
New England Journal of Medicine
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Chimeric Antigen Receptor T cell
Therapy
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