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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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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

Antibodies have multiple functions

Antibody mediated opsonizationSignal interferenceBlockade of uptake

Shuttle

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There are a variety of T cell subsets

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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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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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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

Converting chronic to

acute inflammatio

n

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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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Humanizing monoclonal antibodiesMonoclonal antibody therapy

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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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Therapeutic Efficacy of Herceptin

New England Journal of Medicine

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TIL Therapy

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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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UveitisVitiligo

Autoimmunity Following Cell therapy

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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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Checkpoint Blockade

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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

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Chimeric Antigen Receptor T cell Therapy