Lecture 15 Cancer and the Immune System PDF

Lecture 15 Cancer and the immune system  Objectives  Explain the fundamental principles of cancer biology and the immune system.  Examine how the immune system can both suppress and facilitate tumor development, including the concept of tumor immunosurveillance and immune ev...

Lecture 15 Cancer and the immune system  Objectives  Explain the fundamental principles of cancer biology and the immune system.  Examine how the immune system can both suppress and facilitate tumor development, including the concept of tumor immunosurveillance and immune evasion by cancer cells.  Provide an overview of current immunotherapy approaches in cancer treatment, such as checkpoint inhibitors, CAR T-cell therapy, and cancer vaccines, including their mechanisms of action and clinical applications.  Explore the interaction between cancer cells and immune cells in the tumor microenvironment.  Discuss the role of genetic mutations and epigenetic modifications in shaping immune response against tumors and their implications in personalized medicine 2 © Macmillan Learning 2023  Cancer Development and Key Characteristics ▪ Most mature cells in the body have a finite life span. ▪ Occasionally, a cell arises that does not respond to normal growth control mechanisms, leading to cancer. ▪ Cells that expand in an uncontrolled manner will produce a tumor or neoplasm. ▪ Benign tumors are incapable of indefinite growth and do not invade surrounding healthy tissue. ▪ Malignant tumors continue to grow and become progressively more invasive and spread (metastasize) to other tissues. © Macmillan Learning 2023  Mechanisms of Cancer Development ▪ Mutations in genes regulating cell division can lead to unregulated cell growth. ▪ Cells can be transformed by various chemicals (i.e., pesticides), physical agents (i.e., asbestos), ionizing radiation, or viral infections which can lead to DNA mutations. ▪ Agents that induce DNA mutations and lead to unregulated cell proliferation are carcinogens. © Macmillan Learning 2023  Cancer-Associated Genes ▪ Genes that have been associated with cancer control cell proliferation and survival. ▪ Oncogenes encourage growth and proliferation; they promote cancer when their activity is increased. ▪ Tumor-suppressor genes inhibit proliferation or mediate DNA repair; their failure allows cancer cell survival. ▪ Apoptosis genes enforce or inhibit cell death signals, thereby controlling programmed cell death. © Macmillan Learning 2023  Cancer Hallmarks Six original defining characteristics, known as cancer hallmarks, focus on essential cellular processes that distinguish cancerous and non- transformed somatic cells. Four enabling characteristics were added to describe microenvironmental influences. Fig. 20-2 © Macmillan Learning 2023  The Immune Response to Cancer ▪ Three proposed pathways for how the immune system controls or inhibits cancer: ▪ Destroying viruses that are known to transform cells ▪ Eliminating all pathogens and downregulating inflammation ▪ Identifying and eliminating pre-cancerous and transformed cells – immunosurveillance © Macmillan Learning 2023  Immunoediting ▪ The modern view is nuanced – the immune system can have tumor-inhibiting and tumor-enhancing effects. ▪ Immunoediting describes how white blood cells have pro- and anti-tumor effects that shape the tumor cell population over time. ▪ The antitumor immune responses select for the toughest cells. ▪ Three sequential phases are proposed: ▪ Elimination – identifying and attacking the cells that can be targeted ▪ Equilibrium – a state of balance between the destruction of some tumor cells, and the survival of the “best” tumor cells ▪ Escape – the most aggressive and least immunogenic cells thrive and spread © Macmillan Learning 2023  Phases of Immunoediting © Macmillan Learning 2023 Fig. 20-4  The Role of Cytokines in Cancer Immunity ▪ Cytokines play an important role in cancer immunity. ▪ IFN-γ ▪ All interferon types enhance tumor-cell removal activities of immune cells. ▪ IL-12 ▪ Encourages DCs to activate strong TH1 and CTL responses. ▪ IL-12 deficiency results in more papillomas in animals. ▪ Administration of IL-12 protects mice from chemically induced tumors. ▪ TNF-α may promote or inhibit anticancer effects; its role in cancer immunity is complex. © Macmillan Learning 2023  Evasion of Immune Recognition Some tumor cells evade immune recognition and activation. ▪ One way is via reduced MHC expression in tumor cells. ▪ Tumor cells with mutations in genes for MHC class I expression make poor CTL targets. ▪ Decreased expression of NK-activating receptor ligands makes cells with low MHC class I expression poor targets for NK cells. ▪ Expression of immune inhibitory proteins (like CD80/86 and PD-L1/L2) © Macmillan Learning 2023  Immunosuppression in the Tumor Microenvironment ▪ Active immunosuppression in tumor microenvironments ▪ Soluble factors (e.g., TGF-β, IL-10, and IDO) can suppress immunity to form a tumor (immune) microenvironment (TME or TIME). ▪ Immunosuppressive cell types like TREG cells can also be found in tumor areas. ▪ Suppression prevents antitumor activities of immune cells creating a tumor-protective microenvironment. © Macmillan Learning 2023  Microenvironment during the escape phase of immunoediting Pro-Tumor Down- regulation of MHC class I and/or Expression of immune inhibitory proteins (like CD80/86 and PD-L1/L2) Immunosuppressive Secreting anti-inflammatory cytokines and other compounds (e.g., TGF-β, IL-10, and IDO) Microenvironment anti-inflammatory/tumor-protective. Fig. 20-5 © Macmillan Learning 2023  Tumor-Cell Resistance to Apoptosis Some tumor cells evade immune recognition and activation. ▪ Tumor-cell resistance to apoptosis can occur by: ▪ expression of mutated or absent death receptors, for example, Fas and TRAILR ▪ upregulation of anti-apoptotic mediators ▪ downregulation of pro-apoptotic mediators © Macmillan Learning 2023  Co-inhibitory and Immunosuppressive Tumor Signals Some tumor cells evade immune recognition and activation. ▪ Tumor cells provide poor costimulatory signals. ▪ There may be mutations in or downregulation of second signal molecules. CD80/86 (B7) on APCs CD28 on T cells ▪ Lack of a proper second signal may lead to clonal anergy in T cells and immune tolerance to cancer cells. Some recently approved therapies are aimed at enhancing costimulation to antitumor T cells. © Macmillan Learning 2023  Cancer Therapies ▪ Surgical removal (resection) and radiation are commonly used for solid tumors. ▪ Drug therapies generally fall into four loosely organized categories: ▪ Chemotherapies – aimed at blocking DNA synthesis and cell division ▪ Adjuvant cancer therapy adds drugs or small molecule inhibitors. ▪ Neoadjuvant cancer therapy starts with drugs and follows with surgery. ▪ Hormonal therapies – interfere with tumor-cell growth ▪ targeted therapies – small molecule inhibitors for tumors that are sensitive to the drugs ▪ immunotherapies – induce or enhance the antitumor immune response © Macmillan Learning 2023  Cancer Immunotherapies Fig. 20-7 © Macmillan Learning 2023  Monoclonal Antibodies ▪ Monoclonal antibodies (mAbs) can be targeted to tumor cells. ▪ Initially intended to deliver toxin or activate immune pathways (e.g., complement, ADCC, ADCP) ▪ Names are complicated, but include the suffix –mab. ▪ Successes include: ▪ Treatment of terminal B-cell lymphoma with anti-idiotype mAb ▪ mAb against CD20 B-cell marker for non-Hodgkin’s lymphoma and chronic lymphocytic leukemia (CLL) ▪ Antibody-drug conjugates that couple toxic molecules with mAb ▪ can include immunotoxins (e.g., diphtheria toxin) ▪ mAb against receptors example cetuximab against EGFR © Macmillan Learning 2023  Bispecific T-Cell Engagers (BiTEs) ▪ Bispecific T-cell engagers (BiTEs) ▪ recognize two target epitopes ▪ activate T cells ▪ are made by combining light- and heavy-chain variable regions of two antibodies into a single chain Fig. 20-8 © Macmillan Learning 2023  Monoclonal Antibodies Approved by the FDA for Cancer Treatment First mAb name Trade name Target Used to treat approved Rituximab RITUXAN® CD20 Non-Hodgkin’s lymphoma 1997 Chronic lymphocytic leukemia (CLL) Trastuzumab Herceptin® HER2 Breast and stomach cancer 1998 and 2010 Gemtuzumab Mylotarg™ CD33 Acute myelogenous leukemia (AML) 2000† ozogamicin* Alemtuzumab Campath® CD52 CLL 2001 Ibritumomab tiuxetan* Zevalin® CD20 Non-Hodgkin’s lymphoma 2002 131 I-Tositumomab* BEXXAR® CD20 Non-Hodgkin’s lymphoma 2003 Bevacizumab Avastin® VEGF Colorectal, non–small cell lung, 2004 breast, glioblastoma, and kidney cancer Table 20-4 © Macmillan Learning 2023  Monoclonal Antibodies Approved by the FDA for Cancer Treatment, Continued mAb name Trade name Target Used to treat First approved Panitumumab Vectibix® EGFR Colorectal cancer 2006 Ofatumumab Arzerra® CD20 CLL 2009 Denosumab XGEVA® RANK ligand Bone metastases 2010 Ipilimumab YERVOY® CTLA-4 Melanoma 2011 Brentuximab vedotin* ADCETRIS® CD30 Hodgkin’s lymphoma and 2011 one type of non–Hodgkin’s lymphoma Pembrolizumab KEYTRUDA® PD-1 Melanoma, non–small cell 2014 lung, and kidney cancers, as well as Hodgkin’s lymphoma‡ Atezolizumab TECENTRIQ® PD-L1 Bladder, non–small cell lung, 2016 Merkel cell carcinoma, and triple-negative breast cancers Table 20-4 © Macmillan Learning 2023  Immune Checkpoint Blockades ▪ Ipilimumab is a monoclonal antibody against CTLA-4. ▪ It is an immune checkpoint inhibitor (ICI) that employs immune checkpoint blockage (ICB). ▪ Originally licensed for use against malignant melanoma. Fig. 20-9 © Macmillan Learning 2023  Adoptive Cell Transfers ▪ Tumor-specific T cells can be expanded and reintroduced into patients. ▪ In 1998, tumor-infiltrating lymphocytes (TILs) were obtained from patients with metastatic melanoma. ▪ Immune cell-transfer therapies now use peripheral cells and are called adoptive cell transfers. © Macmillan Learning 2023  CAR T Therapies ▪ The newest T-cell therapy for cancer are chimeric antigen-receptor (CAR) T cells or CARs; ▪ They are part immunoglobulin and part TCR. Box 20-2 Figure 1 © Macmillan Learning 2023  CAR T Therapies ▪ CAR T cells can be modified with specific accessory molecules. © Macmillan Learning 2023 Box 20-2 Figure 2  Cancer Vaccines ▪ Vaccines are commonly prophylactic and designed to initiate an immune response before the onset of disease or an antigen encounter. ▪ New therapeutic vaccines may enhance the antitumor immune response. ▪ Are intended to enhance or redirect the immune response after disease has occurred. ▪ Antigens in prophylactic vaccines do not always work in a therapeutic approach (e.g., the vaccine against HPV). Fig. 20-10 © Macmillan Learning 2023  The NeoVax Cancer Vaccine Platform ▪ Scientists at Dana Farber Cancer Institute have been using the NeoVax system to produce personalized, neoantigen-based vaccines based on unique mutations from the patient’s own cancer cells. Fig. 20-11 © Macmillan Learning 2023  Oncolytic Viruses ▪ Oncolytic viruses (OVs) can infect healthy and cancerous cells. ▪ They are only cytolytic in cancerous cells. ▪ Cancer cells are more susceptible to viral infection. ▪ Several viruses are being investigated to manipulate tumor cells. ▪ T-VEC (Imlygic™) was the first OV approved to treat chemotherapy- resistant melanoma. Fig. 20-11 © Macmillan Learning 2023  Thank you PRESENTATION TITLE 29