Cancer immunotherapy is a rapidly advancing medical therapy that takes advantage of the immune system Immune system The body's defense mechanism against foreign organisms or substances and deviant native cells. It includes the humoral immune response and the cell-mediated response and consists of a complex of interrelated cellular, molecular, and genetic components. Primary Lymphatic Organs to contain or eliminate cancer cells. Currently, immunotherapies have been incorporated into treatment regimens for different types of cancer. Various therapeutic approaches exist, including using cytokines Cytokines Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. Adaptive Immune Response, vaccines, oncolytic viruses Viruses Minute infectious agents whose genomes are composed of DNA or RNA, but not both. They are characterized by a lack of independent metabolism and the inability to replicate outside living host cells. Virology, T-cell manipulation or cellular adoptive immunotherapy, or antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions to immune checkpoint molecules. These therapies provide new options for advanced cancers, including melanoma Melanoma Melanoma is a malignant tumor arising from melanocytes, the melanin-producing cells of the epidermis. These tumors are most common in fair-skinned individuals with a history of excessive sun exposure and sunburns. Melanoma, renal cell carcinoma Renal cell carcinoma Renal cell carcinoma (RCC) is a tumor that arises from the lining of the renal tubular system within the renal cortex. Renal cell carcinoma is responsible for 80%-85% of all primary renal neoplasms. Most RCCs arise sporadically, but smoking, hypertension, and obesity are linked to its development. Renal Cell Carcinoma, prostate Prostate The prostate is a gland in the male reproductive system. The gland surrounds the bladder neck and a portion of the urethra. The prostate is an exocrine gland that produces a weakly acidic secretion, which accounts for roughly 20% of the seminal fluid. Prostate, Seminal, and Bulbourethral Glands: Anatomy adenocarcinoma, lung cancer Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. Lung Cancer, urothelial carcinoma, Hodgkin lymphoma Hodgkin lymphoma Hodgkin lymphoma (HL) is a malignancy of B lymphocytes originating in the lymph nodes. The pathognomonic histologic finding of HL is a Hodgkin/Reed-Sternberg (HRS) cell (giant multinucleated B cells with eosinophilic inclusions). The disease presents most commonly with lymphadenopathy, night sweats, weight loss, fever, splenomegaly and hepatomegaly. Hodgkin Lymphoma, and refractory B-cell ALL. With the immune system Immune system The body's defense mechanism against foreign organisms or substances and deviant native cells. It includes the humoral immune response and the cell-mediated response and consists of a complex of interrelated cellular, molecular, and genetic components. Primary Lymphatic Organs involved, these agents carry serious and potentially fulminant adverse effects and toxicities.
Last updated: 10 May, 2022
The immune system Immune system The body’s defense mechanism against foreign organisms or substances and deviant native cells. It includes the humoral immune response and the cell-mediated response and consists of a complex of interrelated cellular, molecular, and genetic components. Primary Lymphatic Organs provides defense (immunity) against invading pathogens ranging from viruses Viruses Minute infectious agents whose genomes are composed of DNA or RNA, but not both. They are characterized by a lack of independent metabolism and the inability to replicate outside living host cells. Virology to parasites, and components are interconnected by blood and the lymphatic circulation Circulation The movement of the blood as it is pumped through the cardiovascular system. ABCDE Assessment.
The 2 lines of defense Lines of Defense Inflammation (that overlap):
Over 20,000 DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure-damaging events occur each day, which undergo repair via specific pathways, thus causing no lasting effect.
The 2-signal model of T-cell dependence on
costimulation
Costimulation
Adaptive Cell-mediated Immunity:
When both signal 1 (T-cell
receptor
Receptor
Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell.
Receptors (
TCR
TCR
Molecules on the surface of T-lymphocytes that recognize and combine with antigens. The receptors are non-covalently associated with a complex of several polypeptides collectively called CD3 antigens. Recognition of foreign antigen and the major histocompatibility complex is accomplished by a single heterodimeric antigen-receptor structure, composed of either alpha-beta or gamma-delta chains.
Adaptive Cell-mediated Immunity) binding the cognate
antigen
Antigen
Substances that are recognized by the immune system and induce an immune reaction.
Vaccination presented by the MHC molecule in the
antigen
Antigen
Substances that are recognized by the immune system and induce an immune reaction.
Vaccination-presenting cell) and signal 2 (
costimulatory molecule
Costimulatory molecule
T cells: Types and Functions interaction between the
antigen
Antigen
Substances that are recognized by the immune system and induce an immune reaction.
Vaccination-presenting cell and the T cell) are present, the mature T cell is fully activated.
The orange spot indicates proper binding between
antigen
Antigen
Substances that are recognized by the immune system and induce an immune reaction.
Vaccination and
TCR
TCR
Molecules on the surface of T-lymphocytes that recognize and combine with antigens. The receptors are non-covalently associated with a complex of several polypeptides collectively called CD3 antigens. Recognition of foreign antigen and the major histocompatibility complex is accomplished by a single heterodimeric antigen-receptor structure, composed of either alpha-beta or gamma-delta chains.
Adaptive Cell-mediated Immunity.
Immunoediting is a process consisting of immunologic tumor Tumor Inflammation suppression Suppression Defense Mechanisms but can lead to tumor Tumor Inflammation progression. Immunoediting occurs in 3 main phases:
Carcinogenesis
Carcinogenesis
The origin, production or development of cancer through genotypic and phenotypic changes which upset the normal balance between cell proliferation and cell death. Carcinogenesis generally requires a constellation of steps, which may occur quickly or over a period of many years.
Carcinogenesis by immune evasion:
When
tumor
Tumor
Inflammation cells transform from normal cells, the innate and adaptive immune systems detect and eliminate the transformed cells even before disease is clinically apparent (elimination). The process enters equilibrium, as
tumor
Tumor
Inflammation-cell variants may not be completely eliminated. However, the
immune system
Immune system
The body’s defense mechanism against foreign organisms or substances and deviant native cells. It includes the humoral immune response and the cell-mediated response and consists of a complex of interrelated cellular, molecular, and genetic components.
Primary Lymphatic Organs attempts to control
tumor
Tumor
Inflammation-cell outgrowth by exerting selective pressure on highly immunogenic
tumor
Tumor
Inflammation cells.
Tumor
Tumor
Inflammation-cell immunogenicity is edited, leaving cells with reduced immunogenicity to grow and evade immunosurveillance, leading to progression of the cells into the escape phase, where the less immunogenic cells grow progressively and become clinically apparent cancer.
Cancer immunotherapy stimulates the immune system Immune system The body’s defense mechanism against foreign organisms or substances and deviant native cells. It includes the humoral immune response and the cell-mediated response and consists of a complex of interrelated cellular, molecular, and genetic components. Primary Lymphatic Organs to respond to a malignancy Malignancy Hemothorax, activating different aspects of the immune system Immune system The body’s defense mechanism against foreign organisms or substances and deviant native cells. It includes the humoral immune response and the cell-mediated response and consists of a complex of interrelated cellular, molecular, and genetic components. Primary Lymphatic Organs to attack cancer cells.
These therapies are developed based on the manipulation of the individual’s cells through in vitro expansion of tumor Tumor Inflammation-specific T cells T cells Lymphocytes responsible for cell-mediated immunity. Two types have been identified – cytotoxic (t-lymphocytes, cytotoxic) and helper T-lymphocytes (t-lymphocytes, helper-inducer). They are formed when lymphocytes circulate through the thymus gland and differentiate to thymocytes. When exposed to an antigen, they divide rapidly and produce large numbers of new T cells sensitized to that antigen. T cells: Types and Functions, which are reinfused by autologous transplantation.
Techniques of manipulating T cells T cells Lymphocytes responsible for cell-mediated immunity. Two types have been identified – cytotoxic (t-lymphocytes, cytotoxic) and helper T-lymphocytes (t-lymphocytes, helper-inducer). They are formed when lymphocytes circulate through the thymus gland and differentiate to thymocytes. When exposed to an antigen, they divide rapidly and produce large numbers of new T cells sensitized to that antigen. T cells: Types and Functions (and other immune cell types):
Cellular adaptive immunotherapy:
1)
T cells
T cells
Lymphocytes responsible for cell-mediated immunity. Two types have been identified – cytotoxic (t-lymphocytes, cytotoxic) and helper T-lymphocytes (t-lymphocytes, helper-inducer). They are formed when lymphocytes circulate through the thymus gland and differentiate to thymocytes. When exposed to an antigen, they divide rapidly and produce large numbers of new T cells sensitized to that antigen.
T cells: Types and Functions are collected.
2) The
T cells
T cells
Lymphocytes responsible for cell-mediated immunity. Two types have been identified – cytotoxic (t-lymphocytes, cytotoxic) and helper T-lymphocytes (t-lymphocytes, helper-inducer). They are formed when lymphocytes circulate through the thymus gland and differentiate to thymocytes. When exposed to an antigen, they divide rapidly and produce large numbers of new T cells sensitized to that antigen.
T cells: Types and Functions are engineered to express chimeric
antigen
Antigen
Substances that are recognized by the immune system and induce an immune reaction.
Vaccination
receptors
Receptors
Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell.
Receptors (CARs), followed by in vitro expansion.
3) These cells are then infused into the same individual. These cells go into
circulation
Circulation
The movement of the blood as it is pumped through the cardiovascular system.
ABCDE Assessment, recognizing and destroying malignant cells.
4) Subsequent monitoring of disease response follows.
Immune checkpoint inhibitors:
Top:
Antigen-presenting cells
Antigen-presenting cells
A heterogeneous group of immunocompetent cells that mediate the cellular immune response by processing and presenting antigens to the T-cells. Traditional antigen-presenting cells include macrophages; dendritic cells; langerhans cells; and B-lymphocytes. Follicular dendritic cells are not traditional antigen-presenting cells, but because they hold antigen on their cell surface in the form of immune complexes for b-cell recognition they are considered so by some authors.
Adaptive Immune Response process
tumor
Tumor
Inflammation-associated antigens (TAAs) and complex them to MHC molecules.
The
antigen-presenting cells
Antigen-presenting cells
A heterogeneous group of immunocompetent cells that mediate the cellular immune response by processing and presenting antigens to the T-cells. Traditional antigen-presenting cells include macrophages; dendritic cells; langerhans cells; and B-lymphocytes. Follicular dendritic cells are not traditional antigen-presenting cells, but because they hold antigen on their cell surface in the form of immune complexes for b-cell recognition they are considered so by some authors.
Adaptive Immune Response migrate to the
lymph
Lymph
The interstitial fluid that is in the lymphatic system.
Secondary Lymphatic Organs node (in T-cell–dominant areas) and present TAAs to the naive
T cells
T cells
Lymphocytes responsible for cell-mediated immunity. Two types have been identified – cytotoxic (t-lymphocytes, cytotoxic) and helper T-lymphocytes (t-lymphocytes, helper-inducer). They are formed when lymphocytes circulate through the thymus gland and differentiate to thymocytes. When exposed to an antigen, they divide rapidly and produce large numbers of new T cells sensitized to that antigen.
T cells: Types and Functions.
Activation of the T cell requires 2 signals. The 1st is mediated by the binding of
TAA
TAA
Thoracic aortic aneurysm (TAA) is the abnormal dilation of a segment of the thoracic aorta, usually the ascending aorta. Most TAAs are due to degenerative aortic disorders, commonly in patients > 65 years of age. Most TAAs are asymptomatic (incidentally found in imaging) but could present with symptoms from its effects on surrounding structures.
Thoracic Aortic Aneurysms to a T-cell
receptor
Receptor
Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell.
Receptors (
TCR
TCR
Molecules on the surface of T-lymphocytes that recognize and combine with antigens. The receptors are non-covalently associated with a complex of several polypeptides collectively called CD3 antigens. Recognition of foreign antigen and the major histocompatibility complex is accomplished by a single heterodimeric antigen-receptor structure, composed of either alpha-beta or gamma-delta chains.
Adaptive Cell-mediated Immunity). The 2nd signal can be from the binding of T-cell
CD28
CD28
Costimulatory t-lymphocyte receptors that have specificity for CD80 antigen and CD86 antigen. Activation of this receptor results in increased t-cell proliferation, cytokine production and promotion of t-cell survival.
T cells: Types and Functions to costimulatory CD80/CD86, which activates the T cell.
However, when the T-cell-CTLA-4 interacts with the same CD80/CD86
antigen
Antigen
Substances that are recognized by the immune system and induce an immune reaction.
Vaccination-presenting–cell molecules, the effect is inhibitory (T-cell anergy or no T-cell activation occurs).
Therefore, CTLA-4 and
CD28
CD28
Costimulatory t-lymphocyte receptors that have specificity for CD80 antigen and CD86 antigen. Activation of this receptor results in increased t-cell proliferation, cytokine production and promotion of t-cell survival.
T cells: Types and Functions compete for the binding to CD80/CD86
proteins
Proteins
Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein.
Energy Homeostasis. The anti-CTLA-4 blocking action of ipilimumab restores
CD28
CD28
Costimulatory t-lymphocyte receptors that have specificity for CD80 antigen and CD86 antigen. Activation of this receptor results in increased t-cell proliferation, cytokine production and promotion of t-cell survival.
T cells: Types and Functions proactivator signaling, resulting in antitumor T-lymphocyte responses.
Bottom: In peripheral tissues, the activated T cell can be deactivated by the binding of T-cell programmed death cell-1 (
PD-1
PD-1
An inhibitory t-lymphocyte receptor that has specificity for CD274 antigen and programmed cell death 1 ligand 2 protein. Signaling by the receptor limits T cell proliferation and interferon gamma synthesis. The receptor also may play an essential role in the regulatory pathway that induces peripheral tolerance.
T cells: Types and Functions) with programmed
cell death
Cell death
Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects.
Cell Injury and Death ligand 1 (
PD
PD
Parkinson’s disease (PD) is a chronic, progressive neurodegenerative disorder. Although the cause is unknown, several genetic and environmental risk factors are currently being studied. Individuals present clinically with resting tremor, bradykinesia, rigidity, and postural instability.
Parkinson’s Disease-L1) (or
PD
PD
Parkinson’s disease (PD) is a chronic, progressive neurodegenerative disorder. Although the cause is unknown, several genetic and environmental risk factors are currently being studied. Individuals present clinically with resting tremor, bradykinesia, rigidity, and postural instability.
Parkinson’s Disease-L2) expressed on
tumor
Tumor
Inflammation cells. The anti-
PD-1
PD-1
An inhibitory t-lymphocyte receptor that has specificity for CD274 antigen and programmed cell death 1 ligand 2 protein. Signaling by the receptor limits T cell proliferation and interferon gamma synthesis. The receptor also may play an essential role in the regulatory pathway that induces peripheral tolerance.
T cells: Types and Functions or anti–
PD
PD
Parkinson’s disease (PD) is a chronic, progressive neurodegenerative disorder. Although the cause is unknown, several genetic and environmental risk factors are currently being studied. Individuals present clinically with resting tremor, bradykinesia, rigidity, and postural instability.
Parkinson’s Disease-L1 blocking action by monoclonal
antibodies
Antibodies
Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution.
Immunoglobulins: Types and Functions (e.g.,
nivolumab
Nivolumab
A genetically engineered, fully humanized immunoglobulin g4 monoclonal antibody that binds to the pd-1 receptor, activating an immune response to tumor cells. It is used as monotherapy or in combination with ipilimumab for the treatment of advanced malignant melanoma. It is also used in the treatment of advanced or recurring non-small cell lung cancer; renal cell carcinoma; and Hodgkin’s lymphoma.
Melanoma,
pembrolizumab
Pembrolizumab
Squamous Cell Carcinoma (SCC), atezolizumab) restores effective antitumor T-lymphocyte activity.
Therapeutic class | Agents | Indications |
---|---|---|
Immunostimulatory cytokines Cytokines Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. Adaptive Immune Response | IL–2 |
|
IFNα-2b |
|
|
Vaccines | Sipuleucel-T | Castration-resistant prostate Prostate The prostate is a gland in the male reproductive system. The gland surrounds the bladder neck and a portion of the urethra. The prostate is an exocrine gland that produces a weakly acidic secretion, which accounts for roughly 20% of the seminal fluid. Prostate, Seminal, and Bulbourethral Glands: Anatomy adenocarcinoma |
Bacille Calmette–Guérin (BCG) | Bladder Bladder A musculomembranous sac along the urinary tract. Urine flows from the kidneys into the bladder via the ureters, and is held there until urination. Pyelonephritis and Perinephric Abscess cancer | |
Immunomodulatory agents |
|
Multiple myeloma Multiple myeloma Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma |
Oncolytic viruses Viruses Minute infectious agents whose genomes are composed of DNA or RNA, but not both. They are characterized by a lack of independent metabolism and the inability to replicate outside living host cells. Virology | T-VEC | Melanoma Melanoma Melanoma is a malignant tumor arising from melanocytes, the melanin-producing cells of the epidermis. These tumors are most common in fair-skinned individuals with a history of excessive sun exposure and sunburns. Melanoma |
CAR T-cell therapy | Agents are available under the REMS program of the FDA (for autologous use only). |
|
BiTE ( CD3 CD3 Complex of at least five membrane-bound polypeptides in mature T-lymphocytes that are non-covalently associated with one another and with the T-cell receptor. The CD3 complex includes the gamma, delta, epsilon, zeta, and eta chains (subunits). When antigen binds to the T-cell receptor, the CD3 complex transduces the activating signals to the cytoplasm of the T-cell. The CD3 gamma and delta chains (subunits) are separate from and not related to the gamma/delta chains of the T-cell receptor. T cells: Types and Functions-directed therapy) | Blinatumomab | ALL |
Therapeutic class | Agents | Indications |
---|---|---|
Anti- PD-1 PD-1 An inhibitory t-lymphocyte receptor that has specificity for CD274 antigen and programmed cell death 1 ligand 2 protein. Signaling by the receptor limits T cell proliferation and interferon gamma synthesis. The receptor also may play an essential role in the regulatory pathway that induces peripheral tolerance. T cells: Types and Functions | Pembrolizumab Pembrolizumab Squamous Cell Carcinoma (SCC) |
|
Nivolumab Nivolumab A genetically engineered, fully humanized immunoglobulin g4 monoclonal antibody that binds to the pd-1 receptor, activating an immune response to tumor cells. It is used as monotherapy or in combination with ipilimumab for the treatment of advanced malignant melanoma. It is also used in the treatment of advanced or recurring non-small cell lung cancer; renal cell carcinoma; and Hodgkin’s lymphoma. Melanoma |
|
|
Dostarlimab |
|
|
Anti- PD PD Parkinson’s disease (PD) is a chronic, progressive neurodegenerative disorder. Although the cause is unknown, several genetic and environmental risk factors are currently being studied. Individuals present clinically with resting tremor, bradykinesia, rigidity, and postural instability. Parkinson’s Disease-L1 | Atezolizumab |
|
Avelumab |
|
|
Durvalumab |
|
|
Anti–CTLA-4 | Ipilimumab |
|