Trivedi_Immunology and immunotherapy in cancer-1_2024.pdf

Introduction to Cancer Immunology and Immunotherapy Meghana V. Trivedi, Pharm.D., Ph.D., BCOP University of Houston, College of Pharmacy [email protected] Integrated Hematology/Oncology Module PHAR 5367 Jan 17, 2024 Learning Objectives 1. 2. Classify different types of cancer, terminology,...

Introduction to Cancer Immunology and Immunotherapy Meghana V. Trivedi, Pharm.D., Ph.D., BCOP University of Houston, College of Pharmacy [email protected] Integrated Hematology/Oncology Module PHAR 5367 Jan 17, 2024 Learning Objectives 1. 2. Classify different types of cancer, terminology, and nomenclature. Differentiate between various cancer pathophysiology and common cancer hypotheses. 3. 4. Classify different roles of immune system in prevention of cancer Identify mechanism of action for monoclonal antibodies, cytokines, cell-based therapies, checkpoint inhibitors, and other immunologic therapies in the treatment of cancer. 2 Cancer: A system-level problem Food 3 Cancer: A system-level problem Proliferation HOMEOSTASIS Normal cell Apoptosis Diseased microenvironment Out of balance Cancer cell Healthy & Diverse Microenvironment (normal stromal & immune cells) 4 Cancer is a result of failure in regulation of cellular and local microenvironment function. Immune system Foreign (Infection) Domestic (Cancer) 5 Cancer and Immune system Relative risk of various cancers in immunocompromised individuals Type of immune deficiency Kaposi’s sarcoma Non-hodgkin’s lymphoma Cutaneous squamous cell cancer Anogenital cancer Organ allograft recipients 150 – 200 20 – 120 18 – 65 100 >10,000 >100 5.4 4 – 6.8 Case reports 100 Not reported Not reported AIDS Congenital immune deficiency 6 Adapted from Gates and Kaplan, Oncology, 2012. Cancer and immune system 7 Shankaran et al., Nature, 2001. Hallmarks of Cancer 8 https://www.cell.com/fulltext/S0092-8674(11)00127-9 Cancer cell recognition by immune system • Antigen recognition is a process used by the immune system to recognize a “foreign” cell or material. • Cancer is not “foreign” but “altered self”. • Our immune system can recognize “altered” self as well as something foreign 9 Tumor antigens • When normal cells turn into cancer cells, some antigens on their surface change. • Tumor cells constantly shed bits of protein from their surface into the circulatory system. Often, tumor antigens are among the shed proteins. • The tumor antigens prompt action from immune cells such as cytotoxic T cells, natural killer cells, and macrophages. • Some immune cells provide continuous body-wide surveillance – catching and eliminating abnormal cells. • Tumor develops when this immune surveillance breaks down or is overwhelmed. 10 Tumor antigens Tumor-specific antigens (TSAs) Tumor-associated antigens (TAAs) 11 Tumor-specific antigens (TSAs) • Specific to only tumor cells not normal cells • Can be membrane-bound or short peptides derived from cytosolic proteins that are presented with class I MHC molecules • Virus-specific TSAs are shared by all tumors induced by the same virus • Are often indicators of neoplastic transformation • Can be targeted using vaccines (for prevention of cancer) 12 Tumor-associated antigens (TAAs) • Expressed during specific developmental stage- called oncofetal antigens • Alphafetoprotein (AFP)- in most liver cancers • Carcinoembryonic antigen (CEA)- most colorectal cancer (CRCs) • Expressed in human germ line only- ectopic • Cancer/testis antigens (CTA)- some CRCs, melanoma, bladder, lung, liver cancers • Expressed at very low levels in normal tissue- but overexpressed or mutated in cancer • Human epidermal growth factor receptor (HER)- breast, lung cancers • Prostate surface antigen (PSA)- prostate cancer 13 https://www-nejm-org.ezproxy.lib.uh.edu/doi/full/10.1056/NEJMra072739 Question Tumor-specific antigens (TSAs) are only expressed on cancer cells and not on any other human cells; whereas, tumorassociated antigens (TAAs) can be expressed on other human cells in addition to cancer cells. A. True B. False 14 Immune response to cancer • Activated macrophage can kill many tumor cells more efficiently than they can kill normal cells. • Macrophages also express tumor antigens on the surface and act as antigen-presenting cells to activate Helper T cells to release anti-tumor cytokines and to activate cytotoxic T cells. • Cytotoxic T cells also target IgG antibody-coated tumor cells by Fc receptors (FcgRIII or CD16) and kill them. • NK cells kill many types of tumor cells, especially those with reduced class I MHC (NK cells) expression and escape killing by T cells. • The principal mechanism of tumor immunity is killing of tumor cells by CD8+ cytotoxic T cells. http://www.cancer.gov/cancertopics/understandingcancer/immunesystem/AllPages 15 Immune response to cancer • Immune response to cancer is necessary if the intrinsic mechanisms within the cell itself and locally within a tissue fail to eradicate a “transformed” cell. • 3 immune mechanisms for tumor destruction 1) Destroy viruses that transform cells 2) Reduce pro-tumor inflammation 3) Identify and eliminate cancerous cells (immunosurveillance) • Immune system checks for abnormal activity of cells within a tissue and goes out for inspection if some anomaly is detected. • Our immune system is also charged with eliminating any abnormal cell before they form a group. 16 Cancer immunoediting 17 Schreiber et al., Science, 2011. Cancer immunoediting Cancer immunoediting is the process whereby the immune system can both constrain and promote tumor development. Tumor cell death B cells and antibodies T cells, Treg cells, NK cells Elimination Equilibrium Escape Cancer-free Restricted growth Cancer Good Bad Ugly 18 Question In which phase, immunogenicity of a tumor is edited such that it stays in check without being removed by the immune system? A. B. C. D. Entrance Elimination Equilibrium Escape 19 Immune pathways in tumor eradication • NK cells • Activated macrophages • Eosinophils • Cytotoxic T cells • B cells • Cytokines DC= Dendritic cells 20 Hallmarks of Cancer 21 https://www.cell.com/fulltext/S0092-8674(11)00127-9 Inflammation & cancer • In 1863, Virchow hypothesized that the origin of cancer was at sites of chronic inflammation. • Hypothesis: Some classes of irritants, together with the tissue injury and ensuing inflammation they cause, enhance cell proliferation • During tissue injury associated with wounding, cell proliferation is enhanced while the tissue regenerates. • Proliferation and inflammation subside after the assaulting agent is removed or the repair completed. • In contrast, proliferating cells that sustain DNA damage and/or mutagenic assault continue to proliferate in microenvironments rich in inflammatory cells and growth/survival factors that support their growth. • In a sense, tumors act as wounds that fail to heal 22 Inflammation & cancer • Chronic inflammation creates pro-tumor microenvironment. • Genotoxic stress (increased mutation rates) • Proliferative cytokines • Pro-angiogenic • Anti-tumor antibodies • May bind to TSAs and mask antigens from Cytotoxic T-cells • Active immunosuppression in tumor microenvironment by soluble factors • TGF-β • IL-10 23 Types of cancer immunotherapy Monoclonal antibodies Treatment of cancer with Treatment bacterial of bladder products (“Coley’s toxin”) cancer with BCG Immune checkpoint inhibitors Vaccines Adoptive cell therapy FDA approves rituximab for NHL HPV vaccination in VIN FDA approval of anti-CTLA4 (ipilumimab) for melanoma FDA approval of CAR-T therapy 1863 1898 1957 1976 1983 1985 1991, 4 1997 2002 2009 2010 2011 2014, 16 Description of immune infiltrates in tumors by Virchow Cancer immunosurveillance hypothesis (Burnet, Thomas) IL-2 therapy for cancer Cytokines Discovery of human tumor antigens (Boon, others) Adoptive T cell therapy FDA approval of sipuleucelT (DC vaccine) in prostate cancer Cellular immunotherapy FDA approval of anti-PD1, anti-PD-L1 in melanoma and/or lung cancer 24 Antibodies • Produced by B-lymphocytes • Confer adaptive immunity • Antibody structure is conserved except for the Fab • IgG isotype provides the majority of antibody-based immunity against invading pathogen • Monoclonal antibodies (mAbs) derived from a single B lymphocyte or its clone are used for cancer therapeutics. • Fc region of mAbs is important for recognition by the immune cells. 25 mAbs in cancer (Trastuzumab) http://www.cancer.gov/cancertopics/understandingcancer/immunesystem/AllPages 26 FDA-approved mAbs for cancer Target MAB Trade name Origin Uses CD20 Rituximab Rituxan Chimeric NHL, CLL CD20 Ofatumumab Arzerra Human CLL CD20 Obinutuzumab Gazyva Humanized CLL, Folicular lymphoma EGFR Cetuximab Erbitux Chimeric CRC, Head & neck EGFR Panitumumab Vectibix Human CRC HER2/neu Trastuzumab Herceptin Humanized HER2+ Breast HER2/neu Pertuzumab Perjeta Humanized HER2+ Breast cancer VEGF Bevacizumab Avastin Humanized Colon, NSCLC, RCC, Glioblastoma VEGFR Ramucirumab Cyramza Human Gastric, NSCLC, CRC, HC Blincyto Murine ALL Bispecific T-cell engager (BiTE) CD19/CD3 Blinatumomab Abbreviations: CD- cluster of differentiation, CLL- chronic lymphocytic leukemia, CRC- colorectal cancer, EGFR, epidermal growth factor receptor, HC- hepatocellular carcinoma, HER2- human epidermal growth factor receptor-2, NHL- non-hodgkin’s lymphoma, NSCLC- non-small cell lung27 cancer, RCC- renal cell carcinoma, VEGF(R)- vascular endothelial growth factor (receptor) FDA-approved FDA-approved conjugatedmAbs mAbsfor cancer FDA-approved conjugated mAb-conjugates Target MAB Conjugate Trade name Origin Uses MABs conjugated with radioisotope (radio-immunotherapy) CD20 Ibritumomab tiuxetan Y-90 Zevalin Murine NHL CD20 Tositumomab I-131 Bexxar Murine NHL Humanized ALL MABs conjugated with cytotoxic chemotherapeutic drug CD22 Inotuzumab ozogamicin Ozogamicin CD30 Brentuximab vedotin Vedotin (MMAE) Adcetris Chimeric HL, SALCL CD33 Gemtuzumab ozogamicin Ozogamicin Mylotarg Humanized AML HER2 Trastuzumab emtansine Mertansine (T-DM1) (DM1) Kadcyla Humanized Breast cancer HER2 Trastuzumab deruxtecan Enhertu Humanized Breast cancer Deruxtecan Besponsa Abbreviations: ALL- acute lymphocytic leukemia, AML- acute myelogenous leukemia, CD- cluster of differentiation, MMAE- monomethyl auristatin E, NHL- non-hodgkin’s lymphoma, SALCL- Systemic 28 anaplastic large cell lymphoma Annual Price of Treatment (US $) Cost of monoclonal antibodies treatment 29 MOA of mABs Monoclonal antibodies Cytotoxicity Neutralization Inactivation of growth factors Inactivation of growth factor receptors ADCC CDC Apoptosis ADCC= antibody-dependent cell-mediated cytotoxicity CDC= complement-dependent cytotoxicity 30 mAB: neutralization Inactivate growth factor e.g. VEGF • Bevacizumab Antagonism e.g. EGFR • Cetuximab • Panitumumab HER2 VEGFR Trastuzumab Ramucirumab Pertuzumab 31 mAB: neutralization of ligand Angiogenesis = new blood vessel formation a. Tumor cells produce VEGF and other angiogenic factors. Bevacizumab b-c. These stimulate resident endothelial cells to proliferate and migrate in order to synthesize new blood vessels needed to supply blood for O2 and nutrients to the growing mass of tumor. By blocking VEGF, we can suppress the angiogenesis, which may halt tumor progression. Since angiogenesis is required to support the growth of various types of solid tumors, these MABs are indicated for treatment in multiple cancer types. 32 VEGF= vascular endothelial growth factor mAB: neutralization of receptor mAb inhibitors of EGFR: cetuximab and panitumumab • EGFR is expressed on multiple types of cancer cells such as lung cancer, colon cancer, and head & neck cancer. • It belongs to a superfamily of receptor tyrosine kinase and signals by phosphorylation and activation of key proteins involved in proliferation, invasion, anti-apoptotis, metastasis, and angiogenesis. EGFR= epidermal growth factor receptor Other examples: HER2 Trastuzumab Pertuzumab VEGFR Ramucirumab • In many tumor types, EGFR has activating mutations, which makes it an attractive target. • EGFR is targeted mAB such as cetuximab and panitumumab. 33 mAB: cytotoxicity *** All antibodies except those without Fc can cause ADCC 1. Attachment of tumor-specific antibodies to the antigen expressed on the tumor cells. 2. Recognition of the Fc portion of the antibodies by the Fc receptors present on the immunocompetent cells such as NK cells. 3. Destruction of the target tumor cell by the NK cells through degranulation and perforation in the cell membrane (osmotic lysis). • Degranulation is a process which causes the release of granules containing perforin and granzymin B. • Perforation causes holes in the cell membrane, disrupting the osmotic barrier and killing the cell via osmotic lysis. 34 mAB: cytotoxicity 1. Recognition and attachment of complement-fixing antibodies to tumor specific surface antigens. 2. Activation of components of the complement system. 3. Formation of the membrane attack complex (MAC) which forms transmembrane pores that disrupt the osmotic barrier of the membrane and lead to osmotic lysis. The MACs function similarly to the perforin molecules released by cytolytic T cells and NK cells, killing cells by osmotic lysis. 35 mAB: cytotoxicity Apoptosis = programmed cell death • Apoptosis is physiologically advantageous compared to cell lysis induced by ADCC or CDC or necrosis because early apoptotic cells are cleared by phagocytosis before they lose their plasma membrane barrier. • In this manner, apoptotic cells are degraded within the macrophages, and are removed without causing damage to the surrounding tissue. • A hallmark of apoptosis is the activation of a caspase cascade, resulting in cleavage of numerous structural and signaling proteins. • 2 major cellular signaling pathways, known as the intrinsic (mitochondrial) pathway and the extrinsic pathway (death receptor pathway). • The intrinsic (mitochondrial) pathway is controlled by the pro- and anti-apoptotic members of the Bcl-2 family of proteins. • The extrinsic pathway is induced by ligand binding to the cell surface death receptors and activating its cytoplasmic death domain, leading to cell death via activation of caspase 8. • MABs may participate and engage both extrinsic and intrinsic pathways to 36 induce apoptosis. mAB: cytotoxicity e.g. EGFR • Cetuximab • Panitumumab HER2 VEGFR Trastuzumab Ramucirumab Pertuzumab APOPTOSIS Insult 37 Summary of MOA of mABs Monoclonal antibodies Cytotoxicity Neutralization Inactivation of growth factors Inactivation of growth factor receptors Target is important in tumor initiation and progression ADCC CDC Apoptosis Target is selectively expressed on tumor cells ADCC= antibody-dependent cell-mediated cytotoxicity CDC= complement-dependent cytotoxicity 38 Question The neutralization function of monoclonal antibodies used in cancer is the most effective when the target plays a role in cancer cell biology? A. True B. False 39