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Immuno-Oncology (I-O): Seeking to Transform the Treatment of Cancer
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Presentation Overview
This presentation focuses on developing an understanding of I-O and the critical role of the immune system in cancer This presentation provides an overview of I-O pathways and approaches that target the immune system but does not focus on any particular product At the end of the program there will be time for questions specific to its content but not specific to any products Speaker Notes: Notes to speaker: You may answer a question regarding a specific product if asked; however, you should make sure to redirect to the topic at hand and remind the audience that questions should be kept on unbranded topics At the beginning of your presentation(s), you must disclose your relationship to BMS, including the fact that you are receiving compensation for the presentation Present information from slide I-O, immuno-oncology.
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Presentation Objectives
Review the current unmet need for improved survival in cancer treatment Present an overview of the immune system and its role in cancer Describe the regulation of the immune system through immune pathways Examine the types of safety considerations associated with different I-O therapy approaches Discuss potential clinical response patterns with I-O therapy approaches Provide an overview of I-O research in various tumor types Speaker Notes: Present information from slide I-O, immuno-oncology.
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Improved Survival Remains a Challenge in Some Advanced Cancers
5-year Survival in Advanced Cancers (%)1 Lung 4.0 Colorectal 12.9 Kidney and Renal Pelvis 12.1 1. SEER Lung/p3; SEER Colon and Rectum/p3; SEER Kidney and Renal Pelvis/p3; SEER Melanoma/p3; SEER Bladder/p3 5-year survival remains poor for many patients with advanced metastatic solid tumors1 In the United States, it is estimated that2: A total of 589,430 deaths due to cancer will occur in 2015 1. SEER Lung/p3; SEER Colon and Rectum/p3; SEER Kidney and Renal Pelvis/p3; SEER Melanoma/p3; SEER Bladder/p3 Siegel/p11/c2/¶4; p12/c1/¶1; p23/c2/¶2 Rosenberg/p1/c1/¶2/¶3/ c2/¶1 Bladder 5.5 Melanoma 16.1 Speaker Notes: The 5-year survival rates for patients with metastatic disease are below 20% for several common cancers1 New treatments and therapeutic modalities for patients with advanced cancer are needed2 In this presentation, we will discuss immuno-oncology, or I-O, a treatment modality with potential in oncology There is an ongoing need for new treatments and therapeutic modalities for patients with advanced cancers3 1. SEER Lung/p3; SEER Colon and Rectum/p3; SEER Kidney and Renal Pelvis/p3; SEER Melanoma/p3; SEER Bladder/p3 2. Rosenberg/p1/c1/¶2/ ¶3/c2/¶1 Surveillance, Epidemiology and End Results (SEER) Program. Available at: Accessed March 26, 2015. Siegel RL et al. CA Cancer J Clin. 2015;65(1):5-29. Rosenberg SA. Sci Transl Med. 2012;4(127ps8):1-5. References: Surveillance, Epidemiology and End Results (SEER) Program. Cancer Stat Fact Sheets. Available at Accessed January 18, 2015. Rosenberg SA. Raising the bar: the curative potential of human cancer immunotherapy. Sci Transl Med. 2012;4(127ps8):1-5.
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Goal of Current Cancer Research
Slide Builds Research Goals1-3: Long-term survival in most patients 1. FDA Guidance for Industry/p5/¶1 2. Goldstein/p4/c2/¶3 3. Dickman/p104/c1/¶1 Survival Rates* Speaker Notes: This slide depicts a hypothetical survival curve not based on clinical trials but is meant to be used for illustration purposes only Global mortality remains high for many patients with advanced tumors The goal of Immuno-Oncology, or I-O, research is to improve long-term survival in most patients with advanced cancers1-3 Years 1. FDA Guidance for Industry/p5/¶1 2. Goldstein/p4/c2/¶3 3. Dickman/p104/c1/¶1 * This is a hypothetical survival curve not based on clinical trials and is to be used for illustration purposes only. 1. United States Food and Drug Administration (FDA). Guidances/ucm pdf. Accessed January 16, 2015. Goldstein I et al. Trends Mol Med. 2012;18(6): Dickman PW, Adami HO. J Intern Med. 2006;260(2): References: United States Food and Drug Administration (FDA). Guidances/ucm pdf. Accessed January 16, 2015. Goldstein I, Madar S, Rotter V. Cancer research, a field on the verge of a paradigm shift? Trends Mol Med. 2012;18(6): Dickman PW, Adami HO. Interpreting trends in cancer patient survival. J Intern Med. 2006;260(2):
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I-O Is an Evolving Cancer Treatment Modality
I-O is a fundamentally different approach to fighting cancer that harnesses the body’s own immune system1 1. Murphy/p68/c1/¶1 2. Kirkwood/p309/¶1 Chemotherapy/ Targeted therapy Radiation Murphy/p68/c1/¶1 Kirkwood/p327/c2/¶2 Borghaei/p42/c1/¶2 Surgery Immuno-Oncology Speaker Notes: Current cancer treatment modalities include radiation, surgery, and chemotherapy/targeted therapies, all of which are intended to target the tumor. Immuno-Oncology (I-O) is a therapeutic modality that uses the natural capability of the patient’s own immune system to fight the cancer1-3 I-O therapies are being actively investigated in an attempt to fulfill the unmet need for improving clinical outcomes in advanced cancer4 There are over 900 oncology clinical trials of immunotherapy in various phases of development Through I-O research, therapies are being investigated in an attempt to utilize the body's own immune system to fight cancer1-3 Murphy/p67/abstract; p68/c1/¶1 Kirkwood/p309/¶1 Borghaei/p42/c1/¶2 Clinicaltrials.gov. Search terms: "immunotherapy" and "cancer,” excluding unknown: 943 results I-O, immuno-oncology. Murphy JF. Oncology. 2010;4:67-80. Kirkwood JM et al. CA Cancer J Clin. 2012;62(5): Borghaei H et al. Eur J Pharmacol. 2009;625(1-3):41-54. References: Murphy JF. Trends in cancer immunotherapy. Oncology. 2010;4:67-80. Kirkwood JM, Butterfield LH, Tarhini AA, et al. Immunotherapy of cancer in CA Cancer J Clin. 2012;62: Borghaei H, Smith MR, Campbell KS. Immunotherapy of cancer. Eur J Pharmacol. 2009;625:41-45. Clinicaltrials.gov. Search terms: "immunotherapy" AND "cancer,” excluding unknown: 943 results. Accessed January 18, 2015.
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Case Study of Initial Increase in Tumor Volume
Screening Week 12: Increase in tumor volume Week 16: Responding Week 20: Response Week 108: Complete remission* May be used to answer questions such as: “What patterns of response have been observed with ipilimumab?” Read as stated. Patient from study CA *Courtesy of Dr Kaan Harmankaya. This case study represents an example of treatment outcome with ipilimumab, which varies across patients. Harmankaya K et al. Presented at: 33rd ESMO Congress; September 12-16, 2008; Stockholm, Sweden. 7 BMS Confidential – Do Not Distribute or Duplicate 7
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The Immune System’s Role in Cancer
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Immune Surveillance: Identification and Elimination of Cancer Cells by the Immune System1-5
Antibody production 1. Abbas/p270/Figure 12‐1 2. Mellman/p481/Figure 1/c2/¶2; p482/c1/¶1 3. Boudreau/p841/ c1/¶2/ c2/¶1 4. Janeway/p2/¶1/¶3/¶4 5. Pardoll/Nat Rev Cancer/p252/¶1 Priming/ T-cell activation Priming APC activation NK cell trafficking & tumor killing Antigen release Activated T-cell migration to tumor and tumor killing Speaker Notes: The human body is constantly subject to external threats, such as microbes and toxins, and internal threats, such as cancer The immune system is made up of multiple mechanisms that act to protect the human body and generate an immune response1 Cells of the immune system can be generally grouped into the innate and adaptive arms1: The innate immune system is the first line of defense against external threats The adaptive immune system requires proliferation of antigen‐specific T cells as well as antibody‐producing B cells The immune response to cancer is characterized by a balance between continuous activation and suppression2,3 Tumor cells APC, antigen-presenting cell; NK, natural killer. Abbas AK et al. Cellular and Molecular Immunology. 7th ed. Philadelphia, PA: Elsevier Saunders;2012. Mellman I et al. Nature. 2011;480: Boudreau JE et al. Mol Ther. 2011;19(5): Janeway CA Jr et al. Immunobiology: The Immune System in Health and Disease. 5th ed. New York, NY: Garland Science; 2001. Pardoll DM. Nat Rev Cancer. 2012;12: Dranoff /Nat Rev Cancer 2004; p12/c1/ ¶1/l1‐18 Vesely/p237/c1/¶1 Mellman/p481/Figure 1/c2/¶2; p482/c1/¶1 References: Dranoff G. Cytokines in cancer pathogenesis and cancer therapy. Nat Rev Cancer Jan;4(1):11-22. Vesely MD, Kershaw MH, Schreiber RD, Smyth MJ. Natural innate and adaptive immunity to cancer. Annu Rev Immunol. 2011;29: Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480(7378):
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B Cell–Mediated Cytotoxicity
Slide Builds Activated B cells B cells1 Immune cells that bind free-floating antigens in the blood or lymph through B-cell receptors Once activated, B cells differentiate to become plasma cells, which can secrete large quantities of antibodies against a specific antigen1 1. Janeway/p2/¶1/¶3/¶4 Mature B cell Janeway/p2/¶4 Vesely/p237/c1/¶1 Natural Killer cells1,2 Cytotoxic lymphocytes that attack infected or malignant cells based on recognition of antibodies on a cell surface Tumor-associated antigens Speaker Notes: Tumor cells release specific proteins called tumor-associated antigens that are recognized and responded to by the immune system1 On click: B-cell activation2-4 B-cell response to cancer begins when B cells capture tumor antigens and become activated in the presence of T-helper cells Activated B cells can also differentiate to become memory B cells, which are used to mount a rapid immune response to subsequent introductions of the antigen Activated B cells secrete antibodies that seek out and bind to tumor antigens on tumor cells, marking them for destruction via antibody-dependent, T-cell–mediated cytotoxicity and complement-dependent cytotoxicity through other immune cells such as NK cells. NK cells are among the body's first line of defense in recognizing and eliminating tumor cells by various activating, inhibitory, adhesion, and cytokine receptors while sparing normal cells5-12 Vesely/p237/c1/¶1 Abbas/p244/Figure 11; p270/Figure 12‐1 Mellman/p481/Figure 1/c2/¶2; p482/c1/¶1 Boudreau/p841/c1/¶2/ c2/¶1 Tumor cells NK cells Cheng/p233/c2¶1 Long/p232/c1¶1; p228/c1¶1, c3/¶2 Vivier/p240/c2/¶2 Bryceson/p2664/c2/¶3 Montel/p243/c2/¶2 Takeda/p98/c2/¶2-3 Frohn/p662/c1/¶2 Carbone/p257/c2/¶3 Apoptotic tumor cell NK, natural killer. Janeway CA Jr et al. Immunobiology: The Immune System in Health and Disease. 5th ed. New York, NY: Garland Science; 2001. Vesely MD et al. Annu Rev Immunol. 2011;29: References: Vesely MD, Kershaw MH, Schreiber RD, Smyth MJ. Natural innate and adaptive immunity to cancer. Annu Rev Immunol. 2011;29: Abbas AK, Lichtman AH, Pillai S. Cellular and Molecular Immunology. 7th ed. Philadelphia, PA: Elsevier Saunders; 2012. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480(7378): Boudreau JE, Bonehill A, Thielemans K, Wan Y. Engineering dendritic cells to enhance cancer immunotherapy. Mol Ther. 2011;19(5): Cheng M, Chen Y, Xiao W, et al. NK cell-based immunotherapy for malignant diseases. Cell Molec Immunol. 2013;10: Long EO, Kim HS, Liu D, et al. Controlling natural killer cell responses: integration of signals for activation and inhibition. Annu Rev Immunol. 2013;31: Vivier E, Ugolini S, Blaise D, et al. Targeting natural killer cells and natural killer T cells in cancer. Nat Rev Immunol. 2012;12: Bryceson YT, Ljunggren HG, Long EO, et al. Minimal requirement for induction of natural cytotoxicity and intersection of activation signals by inhibitory receptors. Blood. 2009;114: Montel AH, Bochan MR, Hobbs JA, et al. Fas involvement in cytotoxicity mediated by human NK cells. Cell Immunol. 1995;166: Takeda K, Hayakawa Y, Smyth MJ, et al. Involvement of tumor necrosis factor-related apoptosis-inducing ligand in surveillance of tumor metastasis by liver natural killer cells. Nat Med. 2001;7: Frohn C, Höppner M, Schlenke P, et al. Anti-myeloma activity of natural killer lymphocytes. Br J Haematol. 2002;199: Carbone E, Neri P, Mesuraca M, et al. HLA class I, NKG2D, and natural cytotoxicity receptors regulate multiple myeloma cell recognition by natural killer cells. Blood. 2005;105:
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T Cell–Mediated Cytotoxicity
Slide Builds T cells1,2 APCs present antigens to naïve T cells, which can recognize tumor-associated antigens Antigen-presenting cells1,2 Take up antigens from infected or malignant cells and process them into shorter peptide segments Inactive T cell Mellman/p481/Figure 1/c2/¶2; p482/c1/¶1 Boudreau/p841/c1/¶2/ c2/¶1 APC Together with a second, positive co-stimulation signal, T cells become activated… Activated T cells Tumor-associated antigens Speaker Notes: T-cell response to cancer begins when the antigen-presenting cell (APC) captures tumor antigens released by the tumor; after antigen capture, APCs undergo maturation to become activated APCs that can interact with T cells1,2 After antigen presentation to a T cell, a second co-stimulatory signal is transmitted from the APC to the T cell1,2 Co-stimulation results in T-cell activation and proliferation to initiate a cytotoxic T- cell response1,2 Cytotoxic T cells migrate to the tumor, where they can recognize expressed tumor antigen and destroy tumor cells1,2 A subset of activated T cells becomes memory T cells to generate a rapid response in the future1,2 Tumor cells …and play a major role in killing infected or malignant cells when activated Apoptotic tumor cell Mellman/p481/Figure 1/c2/¶2; p482/c1/¶1 Boudreau/p841/c1/¶2/ c2/¶1 APC, antigen-presenting cell. Mellman I et al. Nature. 2011;480(7378): Boudreau JE et al. Mol Ther. 2011;19(5): References: Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480(7378): Boudreau JE, Bonehill A, Thielemans K, Wan Y. Engineering dendritic cells to enhance cancer immunotherapy. Mol Ther. 2011;19(5):
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Immune Evasion in the Tumor Microenvironment
The tumor microenvironment, a network of cells and structures that surround a tumor, creates conditions that may foster tumor growth and immune evasion1,2 Immune cell activity is regulated by multiple activation and inhibition pathways that modulate the duration and level of the immune response2 Tumors may target these pathways to alter the immune system’s response to cancer cells, resulting in tumor evasion of the immune system3 Gajewski/p1015/c2/¶1 Pardoll/p252/abstract/ c1/¶1; p254/Figure 1 Vesely/p253/c1/¶2/¶3 APC Active T cell Tumor-associated antigens Speaker Notes: To prevent damage to normal tissues, T-cell immune checkpoint pathways are used to regulate the level of response by cytotoxic T cells1 One way cancer cells escape immune system detection or elimination is by interfering with the regulation of the immune response within the tumor microenvironment2 By evading the immune system, cancer cells are free to grow into clinically apparent disease3 In fact, many tumor types have been observed to modulate the immune system to prevent an immune response against cancer cells4 The goal of I-O therapy is to aid the immune response in tumor cell destruction5 Tumor cells Pardoll/p252/abstract/ c1/¶1 Kirkwood/p318/c2/¶4 Whiteside/p3/¶4; p4/¶1 Vesely/p251/c2/¶1; p252/c1/¶1 Finn/pviii7/c1/¶4 APC, antigen-presenting cell. Gajewski TF et al. Nat Immunol. 2013;14(10): Pardoll DM. Nat Rev Cancer. 2012;12(4): Vesely MD et al. Annu Rev Immunol. 2011;29: Inactive T cell References: Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4): Kirkwood JM, Butterfield LH, Tarhini AA, Zarour H, Kalinski P, Ferrone S. Immunotherapy of cancer in CA Cancer J Clin. 2012;62(5): Whiteside TL. The tumor microenvironment and its role in promoting tumor growth. Oncogene. 2008;27(45): Vesely MD, Kershaw MH, Schreiber RD, Smyth MJ. Natural innate and adaptive immunity to cancer. Annu Rev Immunol. 2011;29: Finn OJ. Immuno-oncology: understanding the function and dysfunction of the immune system in cancer. Ann Oncol. 2012;23(suppl 8):viii6-viii9.
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Immune-Based Therapeutic Approaches
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Immunotherapies Encompass a Wide Variety of Classes
Immunotherapy1,2 1. Finn/pviii8/c1/¶3 Passive (Designed to act on the tumor) Active (Designed to act on the immune system itself) Finn/pviii8/c1/¶3 Mellman/p480/c1/¶3/ box 1/¶3; p481/c1/¶1; p482/c2/¶3; p483/c1/¶3; p486/c1/¶1 1. Finn/pviii8/c1/¶3 2. Mellman/p480/c1/¶1 Antitumor mAbs Adoptive Cytokines Therapeutic cancer vaccines I-O therapies Tumor-directed mAbs Cell therapies Interleukins Interferons Cell-based Single antigen/ peptide-based Immune effector cell modulators Checkpoint inhibitors Co-stimulatory agonists Speaker Notes: Agents that work with the immune system are called immunotherapies and encompass a wide variety of classes1,2 This table is a quick overview of classes of immunotherapies There are 5 different classes of immunotherapies, with a variety of examples in each class Tumor-directed monoclonal antibodies and cell therapy are examples of passive immunotherapies. Passive immunotherapies act on the tumor, in some cases, using immune-based mechanisms to fight cancer. Vaccines, cytokines, and mediators of T cell activation are active immunotherapies. Active immunotherapies act directly on the body’s own immune system to elicit an immune response to fight cancer I-O therapies are a class of active immunotherapy that directly modulate the activity of immune cells Let’s take a look at the various classes of immunotherapies, focusing on immune checkpoint inhibitors and co-stimulatory pathway agonists Finn/pviii8/c1/¶3 Mellman/p480/c1/¶1/¶3/box 1/¶3; p481/c1/¶1; p482/c2/¶3; p483/c1/¶3; p486/c1/¶1 I-O, immuno-oncology; mAb, monoclonal antibody. Finn OJ. Ann Oncol. 2012;23(suppl 8 ):viii6-viii9. Mellman I et al. Nature. 2011;480: References: Finn OJ. Immuno-oncology: understanding the function and dysfunction of the immune system in cancer. Ann Oncol. 2012;23(suppl 8):viii6-viii9. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480:
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Passive Immunotherapy
Passive immunotherapies act on the tumor, in some cases, using immune-based mechanisms to fight cancer, but they do not require the patient’s own immune system to initiate a response1-3 Finn/pviii8/c1/¶3 Rescigno/p113/c1/¶2 Mellman/p480/c1/¶1 2. Rescigno/p113/c1/¶2 3. Mellman/p480/box 1/¶1 Cell therapies4 Autologous immune cells are removed from the cancer-bearing patient, then activated and expanded in culture away from the immunosuppressive tumor environment 4. Rosenberg/p4/Figure 1 Activated T cell 2. Rescigno/p113/c1/¶2 NK cell Tumor-directed mAbs2-3 Speaker Notes: Passive immunotherapies act on the tumor1-3 In some cases, passive immunotherapies act through immune-based mechanisms Passive immunotherapies do not require the patient’s immune system to initiate a response Examples of passive immunotherapies are tumor-directed monoclonal antibodies and cell therapies2-4 Monoclonal antibodies (mAbs) can be produced with an affinity to a specific tumor-associated antigen (TAA). mAbs may mark tumor cells for destruction, interfere with receptor signaling, promote receptor degradation, and/or deliver anti-cancer agents directly to tumor cells, minimizing exposure of normal tissues5-9 Cell therapies facilitate removal of T cells from the immunosuppressive tumor microenvironment within the patient’s body10-13 Patient T cells are manipulated and allowed to multiply ex vivo to enhance antitumor activity and are then reinfused into the patient; in some cases, the T cells are genetically engineered In vitro modification and expansion TAA-reactive monoclonal antibodies are isolated and injected into a patient Finn/pviii8/c1/¶3 Rescigno/p113/c1/¶2 Mellman/p480/c1/¶1 Tumor cell death 2. Rescigno/p113/c1/¶2 3. Mellman/p480/box 1/¶1 4. Rosenberg/p4/Figure 1 5. Hudis/p40/legend; p41/Fig 1C-F 6. Lundin/p768/c1/¶1/ l13‐17 7. Coiffier/p1094/c1/¶3, c2/¶1 8. Verma/p1784/c1/¶2 9. Bodet‐Milin/ p2/ c1/¶2 mAbs, monoclonal antibodies; NK, natural killer; TAA, tumor-associated antigen. Finn OJ. Ann Oncol. 2012;23(suppl 8):viii6-viii9. Rescigno M et al. Biochim Biophys Acta. 2007;1776: Mellman I et al. Nature. 2011;480: Rosenberg SA. Sci Transl Med. 2012;4(127ps8):1-5. 10. Amos/p499/c2/¶3 11. West/p787/c1/¶3; c2/¶1 12. Chacon/p1/c1/¶1; p2/c1/ ¶2 13. Rosenberg/p2/c3/¶2; p3/c1/¶2 References: Finn OJ. Immuno-oncology: understanding the function and dysfunction of the immune system in cancer. Ann Oncol. 2012;23(suppl 8): viii6-viii9. Rescigno M, Avogadri F, Curigliano G. Challenges and prospects of immunotherapy as cancer treatment. Biochim Biophys Acta. 2007;1776: Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480: Rosenberg SA. Raising the bar: the curative potential of human cancer immunotherapy. Sci Transl Med. 2012;4(127ps8):1-5. Hudis CA. Trastuzumab--mechanism of action and use in clinical practice. N Engl J Med. 2007;357:39-51. Lundin J, Kimby E, Björkholm M, et al. Phase II trial of subcutaneous anti-CD52 monoclonal antibody alemtuzumab (Campath-1H) as first-line treatment for patients with B-cell chronic lymphocytic leukemia (B-CLL). Blood. 2002;100: Coiffier B, Lepretre S, Pedersen LM, et al. Safety and efficacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: a phase 1-2 study. Blood. 2008;111: Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med ;367: Bodet-Milin C, Ferrer L, Pallardy A, et al. Radioimmunotherapy of B-cell Non-Hodgkin's lymphoma. Front Oncol. 2013;3:177. Amos SM, Duong CP, Westwood JA, et al. Autoimmunity associated with immunotherapy of cancer. Blood. 2011;118: West EJ, Scott KJ, Jennings VA, et al. Immune activation by combination human lymphokine-activated killer and dendritic cell therapy. Br J Cancer. 2011;105: Chacon JA, Wu RC, Sukhumalchandra P, et al. Co-stimulation through 4-1BB/CD137 improves the expansion and function of CD8(+) melanoma tumor-infiltrating lymphocytes for adoptive T-cell therapy. PloS One. 2013;8:e60031.
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Therapeutic cancer vaccines2-4
Active Immunotherapy Active immunotherapies act directly on the body’s own immune system to elicit an immune response to fight cancer1-2 Finn/pviii8/c1/¶3 Rescigno/p113/c2/¶2 Activated B cell 2. Rescigno/p113/c2/¶2 3. Lizee/p73/c2/¶1 4. Mellman/p481/c2/¶2 List/p29/Intro/¶1-2 Therapeutic cancer vaccines2-4 Activated T cell Cytokines5 Therapeutic cancer vaccines may prime the immune system to attack existing cancer cells in the body by introducing immune cells to one or more tumor-associated antigens NK cell Cytokines are small proteins that boost the effector functions of immune cells, thereby strengthening the antitumor response Speaker Notes: Active immunotherapies act directly on the body’s own immune system to elicit an immune response to fight cancer.1-2 Therapeutic cancer vaccines are an example of an active immunotherapy2-4 A vaccine may prompt an immune response to the tumor by directly inducing T‐cell and antibody activation against one or more tumor antigens The immune response may be generated by vaccinating the patient with peptides, proteins, recombinant viruses or other microorganisms, killed tumor cells, or peptide‐activated dendritic cells5 Cytokines are another example of active immunity, which acts by facilitating T-cell, B-cell, and NK cell activation and proliferation6 Antigen release Finn/pviii8/c1/¶3 Rescigno/p113/c2/¶2 Lizee/p73/c2/¶1 Mellman/p481/c2/¶2 Tumor cell death NK, natural killer. Finn OJ. Ann Oncol. 2012;23(suppl 8):viii6-viii9. Rescigno M et al. Biochim Biophys Acta. 2007;1776: Lizee G et al. Annu Rev Med. 2013;64:71-90. Mellman I et al. Nature. 2011;480: List T, Neri D. Clin Pharmacol. 2013;5(suppl):29-45. Schlom/p599/c1/¶2, c2/¶1; p600/Table 1 List/p29/¶1-2 References: Finn OJ. Immuno-oncology: understanding the function and dysfunction of the immune system in cancer. Ann Oncol. 2012;23(suppl 8):viii6-viii9. Rescigno M, Avogadri F, Curigliano G. Challenges and prospects of immunotherapy as cancer treatment. Biochim Biophys Acta ;1776: Lizee G, Overwijk WW, Radvanyi L, et al. Harnessing the power of the immune system to target cancer. Annu Rev Med. 2013;64:71-90. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480: Schlom J. Therapeutic cancer vaccines: current status and moving forward. J Natl Cancer Inst ;104: List T, Neri D. Immunocytokines: a review of molecules in clinical development for cancer therapy. Clin Pharmacol Aug 20;5:29-45.
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Immuno-Oncology: Mediators of Immune Cell Activation
APC Mediators of immune cell activation are monoclonal antibodies that have been engineered to either agonize or antagonize specific immune pathways thought to be manipulated by cancer cells to impede the antitumor response. They can also target proteins to both activate and engage natural killer cells. In doing so, they may be able to strengthen the antitumor response1-2 Pardoll/p 252/c1/¶1; p 253/c1/¶1/c2/ ¶1; p 262/c1/¶2/c2/¶1 Hsi/p2276/c1/¶1; p2783/c2/¶1 Active T cell NK cell Tumor cells Speaker Notes: Mediators of immune cell activation are monoclonal antibodies that have been engineered to either agonize or antagonize specific immune pathways thought to be manipulated by cancer to impede the antitumor response1,2 They can also target proteins to both activate and engage natural killer cells, which may also strengthen the antitumor response Interfering with immune checkpoints can disrupt immune homeostasis and lead to a greater number of self-reactive T cells3 These T cells can attack healthy tissues and potentially cause adverse effects Pardoll/p 252/c1/¶1; p 253/c1/¶1/c2/ ¶1; p 262/c1/¶2/c2/¶1 Hsi/p2276/c1/¶1; p2783/c2/¶1 APC, antigen-presenting cell; NK, natural killer. Pardoll DM. Nat Rev Cancer. 2012;12(4): Hsi ED et al. Clin Cancer Res. 2008;14: Amos/p505/c1/¶2/c2/ ¶1/Figure 2 References: Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4): Hsi ED, Steinle R, Balasa B, et al. CS1, a potential new therapeutic antibody target for the treatment of multiple myeloma. Clin Cancer Res ;14: Amos SM, Duong CPM, Westwood JA, et al. Autoimmunity associated with immunotherapy of cancer. Blood. 2011;118(3):
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Immuno-Oncology: Immune System Activating Pathways
Natural Killer Cell T Cell CD40L CD137 CD137 Long/p231/c2/¶1; p234/c1/¶1 Benson/p2013/c1/¶2/ ¶3/Figure 1 Pardoll/p254/Figure 1 Kirkwood/p320/c2/¶3; p321/c1/¶4/c2/¶1/¶3; p322/c1/¶1 SLAMF7 CD28 OX40 Speaker Notes: Immune responses are regulated by a balance of co-stimulatory and co-inhibitory signals1 Co-stimulatory pathways may enhance the immune response by either promoting APC activation and antigen presentation, enhancing T cell proliferation and survival, or activating natural killer cell activity1-4 [Present information on slide] Activating pathways enable cytotoxic activity by binding to receptors or ligands on APCs; they can also be expressed or preferentially upregulated by tumor cells1-4 Several activating receptors are thought to be involved in regulating NK Cell activity, including CD137 and SLAMF71,2 T-cell activity may be regulated by pathways, including CD40, CD137, CD28, and OX403,4 Long/p231/c2/¶1; p234/c1/¶1 Benson/p2013/c1/¶2/¶3/ Figure 1 Pardoll/p254/Figure 1 Kirkwood/p320/c2/¶3; p321/c1/¶4/c2/¶1/¶3; p322/c1/¶1 APC, antigen-presenting cell; NK, natural killer. 1. Long EO et al. Annu Rev Immunol. 2013;13:227– Benson DM Jr et al. J Clin Oncol. 2012;30: Pardoll DM. Nat Rev Cancer. 2012;12(4): Kirkwood JM, et al. CA Cancer J Clin. 2012;62(5): APC, antigen-presenting cell. References: Long EO, Kim HS, Liu D, et al. Controlling natural killer cell responses: integration of signals for activation and inhibition. Annu Rev Immunol ;31: Benson DM Jr, Byrd JC. CS1-directed monoclonal antibody therapy for multiple myeloma. J Clin Oncol. 2012;30: Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4): Kirkwood JM, Butterfield LH, Tarhini AA, Zarour H, Kalinski P, Ferrone S. Immunotherapy of cancer in CA Cancer J Clin. 2012;62(5):
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Immuno-Oncology: Immune System Inhibitory Pathways
Natural Killer Cell T Cell LAG-3 Long/p244/c2/¶1 Pardoll/p254/Figure 1; p262/c1/¶2 Kirkwood/p319/c1/¶1; p320/c1/¶1 KIR CTLA-4 B7-H3 receptor* PD-1 Speaker Notes: Co-inhibitory pathways suppress the immune response by limiting immune cell effector functions1-3 Under normal physiological conditions, some of these co-inhibitory pathways are involved in the maintenance of self-tolerance1-3 [Present information on slide] Tumors may enhance inhibitory pathways to block NK cell and T-cell activation1-3 Several inhibitory receptors are thought to be involved in regulating NK cell activity, including inhibitory KIRs2,3 T-cell activity may be negatively regulated by pathways including LAG-3, CTLA-4, B7-H3, and PD-12 Long/p244/c2/¶1 Pardoll/p254/Figure 1; p262/c1/¶2 Kirkwood/p319/c1/¶1; p320/c1/¶1 *Defined receptors are not yet known and precise mechanism of T-cell inhibition by B7-H3 is currently unknown. KIR, killer-cell immunoglobulin-like receptor; NK, natural killer. Long EO et al. Annu Rev Immunol. 2013;31: Pardoll DM. Nat Rev Cancer. 2012;12(4): Kirkwood JM et al. CA Cancer J Clin. 2012;62(5): References: Long EO, Kim HS, Liu D, et al. Controlling natural killer cell responses: integration of signals for activation and inhibition. Annu Rev Immunol ;31: Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4): Kirkwood JM, Butterfield LH, Tarhini AA, Zarour H, Kalinski P, Ferrone S. Immunotherapy of cancer in CA Cancer J Clin. 2012;62(5):
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Potential Clinical Implications and Response Patterns Associated With T-Cell Modulating I-O Therapy
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Response to I-O Therapy Is a Multistep Process That May Impact Response Kinetics
Slide Builds The response to I‐O therapies that modulate T-cell activity may be characterized as a multistep process1 Hoos/p335/c2/¶4; 336/c1/¶1-2 Hoos/p1388/c1/¶3; p1389/Table 1 Start Initial I-O therapy administration2 Days to Weeks Immune cell activation and proliferation2 Weeks to Months Effect on tumor2 Several Months Effect on survival2 Speaker Notes: [First timeline build appears automatically] The response to I‐O therapies may be characterized as a multistep process1 [On click] After the initial administration, there may be a lag period of days to weeks as the immune system becomes activated and immune cells proliferate [On click] T cells infiltrate the tumor site [On click] Clinically measurable antitumor effects mediated by the activated immune cells may occur over subsequent weeks to months [On click] Potential survival effects may be seen several months after the initial administration of I‐O therapy Hoos/p335/c2/¶4; 336/c1/¶1-2 Hoos/p1388/c1/¶3; p1389/Table 1 I-O, immuno-oncology. Hoos A, Britten CM. OncoImmunology. 2012;1: Hoos A et al. J Natl Cancer Inst. 2010;102: References: Hoos A, Britten CM. The immuno-oncology framework: enabling a new era of cancer therapy. OncoImmunology. 2012;1: Hoos A, Eggermont AM, Janetzki S, et al. Improved endpoints for cancer immunotherapy trials. J Natl Cancer Inst. 2010;102:
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Potential Patterns of Response to I-O Therapy
Therapies that affect the immune system may not induce a measurable impact on tumor growth immediately after administration. Potential effects may be seen weeks to months after initial administration. The potential patterns of response to I-O therapies that modulate T-cell activity are1,2: Hoos/p335/c2/¶4; p336/ c1/¶1/¶2 Aarntzen/p2249/c1/¶3 Immediate response3 Wolchok/p7414/c1/¶3/ c2/¶1 Ribas/p7117/Figure 1 Lack of tumor shrinkage but a slowing of tumor progression3 Early but clinically insignificant progression3 Tumor regression after early radiographical progression that may be caused by T cells infiltrating the tumor site or appearance of new lesions upon imaging3,4 Speaker Notes: Therapies that affect the immune system may not induce a measurable impact on tumor growth immediately after administration. Potential effects may be seen weeks to months after initial administration.1,2 The continuum of biological events is thought to be as follows3: After the initial administration, there may be a lag period of days to weeks as the immune system becomes activated and immune cells proliferate Clinically measurable antitumor effects mediated by the activated immune cells may occur over subsequent weeks These responses may be an immediate reduction in the tumor A lack of tumor shrinkage but a slowing of tumor progression Early but clinically insignificant progression A nonconventional response pattern of tumor regression after early radiographical progression may also occur, the clinical manifestation of which may not be what clinicians are generally accustomed to. This response may be caused by T cells infiltrating the tumor site or appearance of new lesions upon imaging. There is also the potential that patients may not respond to therapy.3,4 Hoos/p335/c2/¶4; p336/ c1/¶1/¶2 Aarntzen/p2249/c1/¶3 There is also the potential that patients may not respond to therapy. I-O, immuno-oncology. 1. Hoos A et al. OncoImmunol. 2012;1: Aarntzen EHJG et al. Cell Mol Life Sci. 2013;70: Wolchok JD et al. Clin Cancer Res. 2009;15: Ribas A et al. Clin Cancer Res. 2009;15: 22 Wolchok/p7414/c1/¶3/ c2/¶1 Ribas/p7117/Figure 1 References: Hoos A, Britten CM. The immuno-oncology framework: enabling a new era of cancer therapy. OncoImmunol. 2012;1: Aarntzen EHJG, Srinivas M, Radu CG, et al. In vivo imaging of therapy-induced anti-cancer immune responses in humans. Cell Mol Life Sci. 2013;70: Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009;15: Ribas A, Chmielowski B, Glaspy JA. Do we need a different set of response assessment criteria for tumor immunotherapy? Clin Cancer Res ;15:
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Non-Conventional Response and I-O Therapy
Slide Builds Apparent progression upon radiographic imaging after initial I-O therapy can actually be a sign of non-conventional response to I-O therapy. This response may occur when T cells infiltrate the tumor site and cause tumors to flare or appearance of new lesions upon imaging.1,2 Wolchok/p7417/c1/¶2/ c2/¶1 Ribas/p7117/Figure 1 I-O therapy T cells infiltrating the tumor site Speaker Notes: Apparent progression upon radiographic imaging after initial I-O therapy can actually be a sign of non-conventional response to I-O therapy.1,2 This response may occur when T cells infiltrate the tumor site and cause tumors to flare or appearance of new lesions upon imaging Tumor cells Wolchok/p7417/c1/¶2/ c2/¶1 Ribas/p7117/Figure 1 Appearance of new lesions upon imaging I-O, immuno-oncology. Wolchok JD et al. Clin Cancer Res. 2009;15: Ribas A et al. Clin Cancer Res. 2009;15: References: Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009;15: Ribas A, Chmielowski B, Glaspy JA. Do we need a different set of response assessment criteria for tumor immunotherapy? Clin Cancer Res ;15:
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Differentiating Disease Progression From Non-Conventional Response With I-O Therapy
T-cell infiltration can cause tumors to flare or new lesions may appear upon imaging1 Considerations that may indicate disease progression vs. non-conventional response include1,2: Wolchok/p7417/c2/¶1 Disease Progression Non-Conventional Response Performance status Deterioration of performance Remains stable or improves Systemic symptoms Worsen May or may not improve Symptoms of tumor enlargement Present May or may not be present Tumor burden Baseline New lesions Increase Appear and increase in size Increase followed by response Appear then remain stable and/or subsequently respond Biopsy may reveal Evidence of tumor growth Evidence of T-cell infiltration Wolchok/p7414/c1/¶3/ c2/¶1; p7417/c2/¶1; p7418/Figure 4/c1/¶1 Eisenhauer/p233/c1/ ¶1 Speaker Notes: Non-conventional kinetics are apparent with pseudo-progression1,2 Non-conventional responses with I-O therapy are thought to occur when T cells infiltrate the tumor site In some cases, this gives the impression that tumor burden is increasing due to radiographic evidence of flare or appearance of new lesions Clinicians should be aware that it may be possible to distinguish pseudo- progression from progression, as this chart demonstrates Differences can be observed in the patient’s well-being or performance status, changes in systemic symptoms, symptoms accompanying tumor enlargement, changes in tumor burden from baseline, the appearance of new lesions, and finally, results of a biopsy Since progression may lead to discontinuation of therapy, it is critical that clinicians identify patients displaying non-conventional response Wolchok/p7414/c1/¶3/ c2/¶1; p7417/c2/¶1; p7418/Figure 4/c1/¶1 Eisenhauer/p233/c1/ ¶1 I-O, immuno-oncology. Wolchok JD et al. Clin Cancer Res. 2009;15(23): Eisenhauer EA et al. Eur J Cancer. 2009;45(2): References: Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009;15(23): Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):
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Immune-Mediated Adverse Reactions
Immune-mediated adverse reactions related to T-cell modulation may affect certain organ systems1 Nervous system2 Respiratory system1,2 Eyes1,3 Skin1,2,4 Liver2,4 Hematopoietic cells5 Endocrine system2,4 Gastrointestinal tract1-4 Amos/p499/c1/¶2; p502/Table 2 Chow/pe282/c1/¶3; pe283/c1/¶1, 4 Robinson/p478/c2/¶1-2; p479/c2/¶3 Phan/p8373/Table1 Lin/p4502/c1/¶4, c2/¶1; p4503/c1/¶2-3 Speaker Notes: Not all normal tissues are adversely affected by I-O therapies However, some are more affected than others, as shown in this slide It should be noted, however, that not all I-O therapies affect all of the listed organ systems For example, AEs have been reported in the following organ systems in association with various I-O therapies: Nervous system, eyes, skin, respiratory system, liver, endocrine system, gastrointestinal tract, and hematopoietic cells Of course, each therapy is different and clinicians should be knowledgeable and remain vigilant regarding immune-mediated side effects that occur with each compound or drug Amos/p499/c1/¶2; p502/Table 2 Chow/pe282/c1/¶3; pe283/c1/¶1, 4 Robinson/p478/c2/¶1-2; p479/c2/¶3 Phan/p8373/Table1 Lin/p4502/c1/¶4, c2/¶1; p4503/c1/¶2-3 Amos SM et al. Blood. 2011;118(3): Chow LQ. Am Soc Clin Oncol Educ Book. 2013: Robinson MR et al. J Immunother. 2004;27(6): Phan GQ et al. Proc Natl Acad Sci U S A. 2003;100(14): Lin TS et al. J Clin Oncol. 2010;28(29): References: Amos SM, Duong CP, Westwood JA, et al. Autoimmunity associated with immunotherapy of cancer. Blood. 2011;118(3): Chow LQ. Exploring novel immune-related toxicities and endpoints with immune- checkpoint inhibitors in non-small cell lung cancer. American Society of Clinical Oncology Educational Book. 2013: Robinson MR, Chan CC, Yang JC, et al. Cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma: a new cause of uveitis. J Immunother. 2004;27(6): Phan GQ, Yang JC, Sherry RM, et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci U S A. 2003;100(14): Lin TS, Donohue KA, Byrd JC, et al. Consolidation therapy with subcutaneous alemtuzumab after fludarabine and rituximab induction therapy for previously untreated chronic lymphocytic leukemia: final analysis of CALGB J Clin Oncol. 2010;28(29):
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Clinical Implications of Immune-Mediated ARs
Since I-O can increase immune system activity, the potential exists for toxicity against healthy tissues in addition to cancer cells1 ARs can be serious and potentially fatal2,3 An AR is any unfavorable medical occurrence temporally associated with the use of a medical treatment2 Serious ARs are defined as any AR that requires hospitalization, is life-threatening, results in death, or otherwise causes persistent or significant incapacity3 Remain vigilant throughout and after treatment4 Educate and encourage patients to monitor for and report symptoms of immune-mediated ARs Amos/p500/Figure 1; p505/c1/¶2/c2/¶1 NCI/p2/¶3 FDA/p1/¶1/¶2/¶3/¶4 Gelao/p923/¶3; p925/¶5; p926/¶1 Not all immune-mediated ARs will require permanent cessation of therapy. Providing optimal care for your patients includes following management algorithms for certain immune-mediated ARs.4 Speaker Notes: Since I-O can increase immune system activity, the potential exists for toxicity against healthy tissues in addition to cancer cells1 Adverse reactions (ARs) can be serious and potentially fatal2,3 An AE is any unfavorable medical occurrence temporally associated with the use of a medical treatment Serious adverse reactions are defined as any AR that requires hospitalization, is life-threatening, results in death, or otherwise causes persistent or significant incapacity Remain vigilant throughout and after treatment4 Educate and encourage patients to monitor for and report symptoms of immune- mediated ARs (imARs) The management of imARs is based upon the severity of the observed toxicity and typically involves the early detection of toxicity, interruption of therapy, close clinical monitoring and early symptomatic relief. Not all imARs will require permanent cessation of therapy.4 Following management algorithms for certain imARs helps provide optimal care for your patients.4 AR, adverse reaction; I-O, immuno-oncology. Amos SM et al. Blood. 2011;118(3): NCI. Radiation therapy for cancer. V4.0. US Department of Health and Human Services FDA. What is a serious adverse event? Accessed January 28, 2015. Gelao L et al. Toxins. 2014;6: Amos/p500/Figure 1; p505/c1/¶2/c2/¶1 NCI/p2/¶3 FDA/p1/¶1/¶2/¶3/¶4 Gelao/p923/¶3; p925/¶5; p926/¶1 References: Amos SM, Duong CPM, Westwood JA, et al. Autoimmunity associated with immunotherapy of cancer. Blood. 2011;118(3): National Cancer Institute. Radiation therapy for cancer. V4.0. Bethesda, MD: US Department of Health and Human Services; 2010. U.S. Food and Drug Administration. What is a serious adverse event? Accessed January 28, 2015. Gelao L, Criscitiello C, Esposito A, Goldhirsch A, Curigliano G. Immune checkpoint blockade in cancer treatment: a double-edged sword cross-targeting the host as an “innocent bystander”. Toxins. 2014;6:
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The Potential of I-O
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The Potential Applicability for I-O
Sharma/p3967c1/¶1; p3970/c2/¶2; p3971/c1/ ¶1/c2/¶2 Winerdal/p1675/c3/¶4; p1677/c1/¶3/ c2/¶1 Inman/p1504/c1/¶1 Zhang/p204/c1/¶2; p205/ c1/¶5/c2/¶1; p208/c2/¶2 Liyanage/p2757/c1/¶2 Pardoll/p258/c1/¶1; p259/c1/¶1; p260/c1/¶3; p261/c2/¶2 Rody/p6/c2/¶3/¶4 Pages/p2664/c2/¶2; p2665/c2/¶1 Salama/p186/c1/¶1; p189/c2/¶2 Kono/p1064/c2/¶2/¶3/¶4; p1069/c2/¶1 Ichihara/p4405/c1/¶1; p4406/c2/¶4 Badoual/p466/c1/¶2; p467/c2/¶1; p470/c1/¶8 Schaefer/p918/c2/¶2; p919/c1/¶3 Gao/p971/c2/¶1; p974/c2/¶2; p975/c2/¶4; p976/c1/¶1/ c2/¶2 Mellman/p484/c1/¶7/c2/¶1; p486/c1/¶1 Karube/p82/c1/¶1; p84/c1/¶4 Dieu-Nosjean/p4414/c1/ ¶2; p4415/c1/¶1 Hiraoka/p277/c1/¶2; p278/c1/¶3 Woo/p4274/c1/¶3/c2/¶1 Taylor/p872/c1/¶2/c2/¶2 Chapon/p1305/c2/¶3 Carbone/pg 257; c1; ¶2 von Lilienfeld-Toal/pg 831; c2; ¶4/pg 837; c2; ¶3/pg 838; c1; ¶1/pg 836; c1; ¶2. Nielsen/pg 343; c1; ¶2/pg 345; c1; ¶2 Jurisic/pg 315; c2; ¶1 Hamanishi/p3363/c1/¶3/ c2/¶1/¶2 Karja/p4436/c2/¶3 Thompson/p1757/c1/¶1; p1760/c2/¶1 Bladder 1-3 Breast 4-7,11 Colorectal 1,4,6,8-10 Esophageal 1,4,11 Gastric 10,11 Head and Neck 12,13 Tumor-mediated inhibition of the immune system has been observed in multiple tumor types Hepatocellular 14,15 Leukemia 16 Lung 6,10,11,17-19 Lymphoma 6 Melanoma 4,6,10,15,20,21 Myeloma 22-25 Speaker Notes: This table gives an overview of a wide range of tumor types for which I-O therapies may have applicability based on evidence of1-28: Presence of tumor-infiltrating lymphocytes, indicative of immunogenic potential Tumor-associated immunosuppression, supporting potential immune evasive mechanisms Tumor-immune system interactions known to be correlated with clinical prognosis Ovarian1,4,6,10,11,15,20,21,26 Sharma/p3967c1/¶1; p3970/c2/¶2; p3971/c1/ ¶1/c2/¶2 Winerdal/p1675/c3/¶4; p1677/c1/¶3/ c2/¶1 Inman/p1504/c1/¶1 Zhang/p204/c1/¶2; p205/ c1/¶5/c2/¶1; p208/c2/¶2 Liyanage/p2757/c1/¶2 Pardoll/p258/c1/¶1; p259/c1/¶1; p260/c1/¶3; p261/c2/¶2 Rody/p6/c2/¶3/¶4 Pages/p2664/c2/¶2; p2665/c2/¶1 Salama/p186/c1/¶1; p189/c2/¶2 Kono/p1064/c2/¶2/¶3/¶4; p1069/c2/¶1 Ichihara/p4405/c1/¶1; p4406/c2/¶4 Badoual/p466/c1/¶2; p467/c2/¶1; p470/c1/¶8 Schaefer/p918/c2/¶2; p919/c1/¶3 Gao/p971/c2/¶1; p974/c2/¶2; p975/c2/¶4; p976/c1/¶1/ c2/¶2 Mellman/p484/c1/¶7/c2/¶1; p486/c1/¶1 Karube/p82/c1/¶1; p84/c1/¶4 Dieu-Nosjean/p4414/c1/ ¶2; p4415/c1/¶1 Hiraoka/p277/c1/¶2; p278/c1/¶3 Woo/p4274/c1/¶3/c2/¶1 Taylor/p872/c1/¶2/c2/¶2 Chapon/p1305/c2/¶3 Carbone/pg 257; c1; ¶2 von Lilienfeld-Toal/pg 831; c2; ¶4/pg 837; c2; ¶3/pg 838; c1; ¶1/pg 836; c1; ¶2. Nielsen/pg 343; c1; ¶2/pg 345; c1; ¶2 Jurisic/pg 315; c2; ¶1 Hamanishi/p3363/c1/¶3/ c2/¶1/¶2 Karja/p4436/c2/¶3 Thompson/p1757/c1/¶1; p1760/c2/¶1 I-O, immuno-oncology. 1. Sharma P et al. Proc Natl Acad Sci U S A. 2007;104(10): Winerdal ME et al. BJU Int. 2011;108(10): Inman BA et al. Cancer. 2007;109(8): Zhang L et al. N Engl J Med. 2003;348(3): Liyanage UK et al. J Immunol. 2002;169(5): Pardoll DM. Nat Rev Cancer. 2012;12(4): Rody A et al. Breast Cancer Res. 2009;11(2): Pages F et al. N Engl J Med. 2005;353(25): Salama P et al. J Clin Oncol. 2009;27(2): Kono K et al. Cancer Immunol Immunother. 2006;55(9): Ichihara F et al. Clin Cancer Res. 2003;9(12): Badoual C et al. Clin Cancer Res. 2006;12(2): Schaefer C et al. Br J Cancer. 2005;92(5): Gao Q et al. Clin Cancer Res. 2009;15(3): Mellman I et al. Nature. 2011;480(7378): Karube K et al. Br J Haematol. 2004;126(1): Dieu-Nosjean MC et al. J Clin Oncol. 2008;26(27): Hiraoka K et al. Br J Cancer. 2006;94(2): Woo EY et al. J Immunol. 2002;168(9); Taylor RC et al. J Clin Oncol. 2007;25(7): Chapon M et al. J Invest Dermatol. 2011;131(6): Carbone E et al. Blood. 2005;105(1): von Lilienfeld-Toal M et al. Cancer Immunol Immunother. 2010;59(6): Nielsen H et al. APMIS Apr;99(4): Jurisic V et al. Med Oncol. 2007;24(3): Hamanishi J et al. PNAS. 2007;104(9): Kärjä V et al. Anticancer Res. 2005;25(6C): Thompson RH et al. Clin Cancer Res. 2007;13(6): Pancreatic 5,10 Prostate 4,27 Renal Cell Carcinoma1,4,6,15,28 References: Sharma P, Shen Y, Wen S, et al. CD8 tumor-infiltrating lymphocytes are predictive of survival in muscle-invasive urothelial carcinoma. Proc Natl Acad Sci U S A. 2007;104(10): Winerdal ME, Marits P, Winerdal M, et al. FOXP3 and survival in urinary bladder cancer. BJU Int. 2011;108(10): Inman BA, Sebo TJ, Frigola X, et al. PD-L1 (B7-H1) expression by urothelial carcinoma of the bladder and BCG-induced granulomata: associations with localized stage progression. Cancer. 2007;109(8): Zhang L, Conejo-Garcia JR, Katsaros D, et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med. 2003;348(3): Liyanage UK, Moore TT, Joo HG, et al. Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol ;169(5): Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4): Rody A, Holtrich U, Pusztai L, et al. T-cell metagene predicts a favorable prognosis in estrogen receptor-negative and HER2-positive breast cancers. Breast Cancer Res. 2009;11(2):1-13. Pages F, Berger A, Camus M, et al. Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med. 2005;353(25): Salama P, Phillips M, Grieu F, et al. Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol. 2009;27(2): Kono K, Kawaida H, Takahashi A, et al. CD4(+)CD25high regulatory T cells increase with tumor stage in patients with gastric and esophageal cancers. Cancer Immunol Immunother ;55(9): Ichihara F, Kono K, Takahashi A, Kawaida H, Sugai H, Fujii H. Increased populations of regulatory T cells in peripheral blood and tumor-infiltrating lymphocytes in patients with gastric and esophageal cancers. Clin Cancer Res. 2003;9(12): Badoual C, Hans S, Rodriguez J, et al. Prognostic value of tumor-infiltrating CD4+ T-cell subpopulations in head and neck cancers. Clin Cancer Res. 2006;12(2): Schaefer C, Kim GG, Albers A, Hoermann K, Myers EN, Whiteside TL. Characteristics of CD4+CD25+ regulatory T cells in the peripheral circulation of patients with head and neck cancer. Br J Cancer ;92(5): Gao Q, Wang XY, Qiu SJ, et al. Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clin Cancer Res. 2009;15(3): Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480(7378): Karube K, Ohshima K, Tsuchiya T, et al. Expression of FoxP3, a key molecule in CD4+CD25+ regulatory T cells, in adult T-cell leukaemia/lymphoma cells. Br J Haematol. 2004;126(1):81-84. Dieu-Nosjean MC, Antoine M, Danel C, et al. Long-term survival for patients with non–small-cell lung cancer with intratumoral lymphoid structures. J Clin Oncol. 2008;26(27): Hiraoka K, Miyamoto M, Cho Y, et al. Concurrent infiltration by CD8+ T cells and CD4+ T cells is a favourable prognostic factor in non-small-cell lung carcinoma. Br J Cancer. 2006;94(2): Woo EY, Yeh H, Chu CS, et al. Cutting edge: regulatory T cells from lung cancer patients directly inhibit autologous T cell proliferation. J Immunol. 2002;168(9); Taylor RC, Patel A, Panageas KS, Busam KJ, Brady MS. Tumor-infiltrating lymphocytes predict sentinel lymph node positivity in patients with cutaneous melanoma. J Clin Oncol. 2007;25(7): Chapon M, Randriamampita C, Maubec E, et al. Progressive upregulation of PD-1 in primary and metastatic melanomas associated with blunted TCR signaling in infiltrating T lymphocytes. J Invest Dermatol. 2011;131(6): 22. Carbone E, Neri P, Mesuraca M, et al. HLA class I, NKG2D, and natural cytotoxicity receptors regulate multiple myeloma cell recognition by natural killer cells. Blood Jan 1;105(1): 23. von Lilienfeld-Toal M, Frank S, Leyendecker C, et al. Reduced immune effector cell NKG2D expression and increased levels of soluble NKG2D ligands in multiple myeloma may not be causally linked. Cancer Immunol Immunother Jun;59(6): 24. Nielsen H, Nielsen HJ, Tvede N, et al. Immune dysfunction in multiple myeloma. Reduced natural killer cell activity and increased levels of soluble interleukin-2 receptors. APMIS Apr;99(4): 25. Jurisic V, Srdic T, Konjevic G, et al. Clinical stage-depending decrease of NK cell activity in multiple myeloma patients. Med Oncol. 2007;24(3): Hamanishi J, Mandai M, Iwasaki M, et al. Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci U S A ;104(9): Kärjä V, Aaltomaa S, Lipponen P, Isotalo T, Talja M, Mokka R. Tumour-infiltrating lymphocytes: a prognostic factor of PSA-free survival in patients with local prostate carcinoma treated by radical prostatectomy. Anticancer Res. 2005;25(6C): Thompson RH, Dong H, Lohse CM, et al. PD-1 is expressed by tumor-infiltrating immune cells and is associated with poor outcome for patients with renal cell carcinoma. Clin Cancer Res. 2007;13(6):
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I-O Therapies Have the Potential To Be Used As Monotherapy or Part of Combination Regimens
I-O research and development will continue to inform future strategies, including new targets and rationales for combinations and sequencing1 By understanding multiple barriers that tumor cells use to evade the anti-tumor immune response, combination and sequencing strategies can help to empower the immune system in the fight against cancer1,2 Drake/pviii41/c1/¶1/c2/ ¶2; pviii43/c2/¶1; pviii44/c1/¶1/c2/¶1/¶2; pviii45/c1/¶2 Ribas/p291/c2/¶1 Natural Killer Cell3-5 T Cell3-5 Pardoll/p254/Figure 1; p262/c1/¶2 Benson/p2013/c1/¶2/ ¶3/Figure 1 Mellman/p485/c2/Fig3 legend; p486/c2/¶4 Inhibitory receptors Inhibitory receptors Speaker Notes: I-O research and development will continue to inform future strategies, including new targets and rationales for combinations and sequencing1 For example, by identifying different immune pathways that may work together, such as blocking inhibitory pathways in addition to stimulating activating pathways, I-O therapies can be potentially combined to enhance the antitumor activity of NK cells and T cells.3 By understanding multiple barriers that tumor cells use to evade the anti-tumor immune response, combination and sequencing strategies can help to empower the immune system in the fight against cancer1,2 Activating receptors Activating receptors Drake/pviii41/c1/¶1/c2/ ¶2; pviii43/c2/¶1; pviii44/c1/¶1/c2/¶1/¶2; pviii45/c1/¶2 Ribas/p291/c2/¶1 Mellman/p486/c2/¶4 I-O, immuno-oncology. Drake CG. Ann Oncol. 2012;23(suppl 8):viii41–viii46. Ribas A et al. Curr Opin Immunol. 2013:25(2):291–296. Pardoll DM. Nat Rev Cancer. 2012;12(4): Benson DM, Byrd JC. J Clin Oncol. 2012;30: Mellman I et al. Nature. 2011;480(7378): References: Drake CG. Combination immunotherapy approaches. Ann Oncol. 2012;23 (suppl 8):viii41-viii46. Ribas A, Wolchok JD. Combining cancer immunotherapy and targeted therapy. Curr Opin Immunol. 2013;25(2): Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480(7378):
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Summary I-O research goals aim to address the unmet need for improved survival As response to I-O therapies that modulate T-cell activity is a multistep process, they may not induce a measureable impact on tumor growth immediately after I-O treatment I-O therapies that modulate T-cell activity may also target normal tissues and can be associated with immune-mediated ARs; understanding how to recognize and manage immune-mediated ARs is critical By understanding multiple barriers that tumor cells use to evade the anti- tumor immune response, I-O therapy combination and sequencing strategies can help to empower the immune system in the fight against cancer Speaker Notes: In summary, Immuno-Oncology (I-O) research goals aim to address the unmet need for improved survival As response to I-O therapies is a multistep process, they may not induce a measureable impact on tumor growth immediately after I-O treatment I-O therapies may also target normal tissues and can be associated with immune- mediated adverse reactions (imARs); understanding how to recognize and manage imARs is critical By understanding multiple barriers that tumor cells use to evade the anti-tumor immune response, I-O therapy combination and sequencing strategies can help to empower the immune system in the fight against cancer AR, adverse reaction; I-O, immuno-oncology.
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Q & A REMINDER: Speaker may not prompt questions about any commercialized or investigational products If an audience member does ask a question about a product, you may answer briefly, but then remind the audience that this presentation was not about a particular product You should only answer questions about I-O–related content
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