©2015 MFMER | slide-1 Introduction to Immuno-Oncology Keith L. Knutson, Ph.D. Professor of Immunology Community Oncology Conference 2.0 April 23-24, 2015
©2015 MFMER | slide-2 Cells of the immune system All cellular elements of the blood are derived from a single pluripotent hematopoietic stem cell
©2015 MFMER | slide-3 Phagocytes Monocytes DCP
©2015 MFMER | slide-4 Polymorpho- nuclear leukocytes All (except maybe mast cells) are derived from the common myeloid precursor
©2015 MFMER | slide-5 Natural Killer Cells INNATE Both are derived from the common lymphoid precursor Lymphocytes Antigen-Specific Lymphocytes ADAPTIVE
©2015 MFMER | slide-6 Schematic Structure of Antigen Receptors
©2015 MFMER | slide-7 Antigens are recognized by the immune response while epitopes are sites within antigens
©2015 MFMER | slide-8 Antibodies and T cell receptors recognize antigen by different mechanisms
©2015 MFMER | slide-9 Antibody dependent cellular cytotoxicity
©2015 MFMER | slide-10
©2015 MFMER | slide-11 Oncogenesis proto-oncogenes tumor suppressor genes oncogenes Carcinogen results in mutation dysfunctional tumor suppressor genes inherited defect increased GF increased GF receptors exaggerated response to GF loss of ability to repair damaged cells or induce apoptosis Increased growth Virus introduces oncogenes
©2015 MFMER | slide-12 Tumor Antigen Classifications Tumor-specific antigens –Ras –p53 –BCR-Abl –Viral antigens –Mis-splice variants Cancer-Testis antigen –MAGE (1 st cloned tumor antigen) –NY-ESO Differentiation antigens –Tyrosinase –MART-1 Overexpressed antigens –HER-2/neu –hTERT
©2015 MFMER | slide-13 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
©2015 MFMER | slide-14 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.
©2015 MFMER | slide-15 Association of inflammation with cancers
©2015 MFMER | slide-16 Acute vs. Chronic Inflammation: Role in Cancer Pathology
©2015 MFMER | slide-17 Inflammation causes genomic damage through reactive oxygen and nitrogen
©2015 MFMER | slide-18 Inflammation elevates cytokines that activate transcription factors which promote tumor formation and progression.
©2015 MFMER | slide-19 Inflammation induces immune suppressive cells which prevent adaptive cellular immunity
©2015 MFMER | slide-20 Science 2013;339: Malignant cells foster development of wound healing responses
©2015 MFMER | slide-21 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:
©2015 MFMER | slide-22 Science 2013;339: Converting chronic to acute inflammation
©2015 MFMER | slide-23 Science 2013;339: Reversing Tumor-Associated Chronic Inflammation Adoptive Therapies T cells Cytokines Vaccines Combination approaches Viruses to induce acute inflammation Checkpoint blockade
©2015 MFMER | slide-24 Reconstituting humoral immunity Humanization of mouse monoclonals Mechanisms of action ADCC Complement Signal enhancer/inhibitor Enhances acute immunity Monoclonal antibody therapy
©2015 MFMER | slide-25 Mocellin et al, Cochrane Database of Systemic Reviews 2013;DOI / Meta-analysis of interferon impact on overall survival
©2015 MFMER | slide-26 Humanizing monoclonal antibodies Monoclonal antibody therapy
©2015 MFMER | slide-27 MAb NameTrade NameUsed to Treat:Target RituximabRituxan Non-Hodgkin lymphoma CD20 TrastuzumabHerceptinBreast cancerHER-2/neu Gemtuzumab ozogamicin* Mylotarg Acute Myelogenous leukemia (AML) CD33 AlemtuzumabCampath Chronic Lymphocytic leukemia (CLL) CD52 Ibritumomab tiuxetan* Zevalin Non-Hodgkin lymphoma CD20 Tositumomab*Bexxar Non-Hodgkin lymphoma CD20 CetuximabErbituxColorectal cancerEGFR BevacizumabAvastinColorectal cancerVEGF FDA-Approved antibodies
©2015 MFMER | slide-28 HER2+ Breast Cancer Management 1 st -line: chemo + trastuzumab Metastatic Disease Response 50-80% Time to disease progression ~ mo Adjuvant Setting ~50% reduction in relapse Best if used concurrently with chemo.
©2015 MFMER | slide-29 Therapeutic Efficacy of Herceptin New England Journal of Medicine
©2015 MFMER | slide-30 TIL Therapy
©2015 MFMER | slide-31 Current Opinion in Immunology Tumor regression following T cell infusion
©2015 MFMER | slide-32 Current Opinion in Immunology Survival of Patients Treated with TIL and IL-2
©2015 MFMER | slide-33 Uveitis Vitiligo Autoimmunity Following Cell therapy
©2015 MFMER | slide-34 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
©2015 MFMER | slide-35 Checkpoint Blockade
©2015 MFMER | slide-36
©2015 MFMER | slide-37 Anti-CTLA-4 causes regressions of melanoma metastases Klein O et al. Clin Cancer Res 2009;15: Lung met Lymph node met Chest wall met
©2015 MFMER | slide-38 Anti-PD-1 causes regressions of melanoma metastases New England Journal of Medicine
©2015 MFMER | slide-39 Chimeric Antigen Receptor T cell Therapy