* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Introduction to Immuno-Oncology
Survey
Document related concepts
Lymphopoiesis wikipedia , lookup
Immunocontraception wikipedia , lookup
DNA vaccination wikipedia , lookup
Molecular mimicry wikipedia , lookup
Inflammation wikipedia , lookup
Sjögren syndrome wikipedia , lookup
Hygiene hypothesis wikipedia , lookup
Immune system wikipedia , lookup
Monoclonal antibody wikipedia , lookup
Adaptive immune system wikipedia , lookup
Polyclonal B cell response wikipedia , lookup
Innate immune system wikipedia , lookup
Adoptive cell transfer wikipedia , lookup
Immunosuppressive drug wikipedia , lookup
Transcript
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 ©2015 MFMER | slide-2 Phagocytes Monocytes DCP ©2015 MFMER | slide-3 Polymorphonuclear leukocytes All (except maybe mast cells) are derived from the common myeloid precursor ©2015 MFMER | slide-4 Lymphocytes Antigen-Specific Lymphocytes ADAPTIVE Natural Killer Cells INNATE Both are derived from the common lymphoid precursor ©2015 MFMER | slide-5 Schematic Structure of Antigen Receptors ©2015 MFMER | slide-6 Antigens are recognized by the immune response while epitopes are sites within antigens ©2015 MFMER | slide-7 Antibodies and T cell receptors recognize antigen by different mechanisms ©2015 MFMER | slide-8 Antibody dependent cellular cytotoxicity ©2015 MFMER | slide-9 ©2015 MFMER | slide-10 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 ©2015 MFMER | slide-11 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 ©2015 MFMER | slide-12 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-13 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-14 Association of inflammation with cancers ©2015 MFMER | slide-15 Acute vs. Chronic Inflammation: Role in Cancer Pathology ©2015 MFMER | slide-16 Inflammation causes genomic damage through reactive oxygen and nitrogen ©2015 MFMER | slide-17 Inflammation elevates cytokines that activate transcription factors which promote tumor formation and progression. ©2015 MFMER | slide-18 Inflammation induces immune suppressive cells which prevent adaptive cellular immunity ©2015 MFMER | slide-19 Malignant cells foster development of wound healing responses Science 2013;339:286-291 ©2015 MFMER | slide-20 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 ©2015 MFMER | slide-21 Converting chronic to acute inflammation Science 2013;339:286-291 ©2015 MFMER | slide-22 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 ©2015 MFMER | slide-23 Monoclonal antibody therapy • Reconstituting humoral immunity • Humanization of mouse monoclonals • Mechanisms of action • ADCC • Complement • Signal enhancer/inhibitor • Enhances acute immunity ©2015 MFMER | slide-24 Meta-analysis of interferon impact on overall survival Mocellin et al, Cochrane Database of Systemic Reviews 2013;DOI10.1002/14651858 ©2015 MFMER | slide-25 Monoclonal antibody therapy Humanizing monoclonal antibodies ©2015 MFMER | slide-26 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 ©2015 MFMER | slide-27 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. ©2015 MFMER | slide-28 Therapeutic Efficacy of Herceptin New England Journal of Medicine ©2015 MFMER | slide-29 TIL Therapy ©2015 MFMER | slide-30 Tumor regression following T cell infusion Current Opinion in Immunology ©2015 MFMER | slide-31 Survival of Patients Treated with TIL and IL-2 Current Opinion in Immunology ©2015 MFMER | slide-32 Autoimmunity Following Cell therapy Vitiligo Uveitis ©2015 MFMER | slide-33 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 ©2015 MFMER | slide-34 Checkpoint Blockade ©2015 MFMER | slide-35 ©2015 MFMER | slide-36 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 ©2015 MFMER | slide-37 Anti-PD-1 causes regressions of melanoma metastases New England Journal of Medicine ©2015 MFMER | slide-38 Chimeric Antigen Receptor T cell Therapy ©2015 MFMER | slide-39