Cancer immunotherapy
Encyclopedia
Cancer immunotherapy is the use of the immune system
to reject cancer
. The main premise is stimulating the patient's immune system to attack the malignant tumor
cells that are responsible for the disease. This can be either through immunization
of the patient (e.g., by administering a cancer vaccine
, such as Dendreon's Provenge), in which case the patient's own immune system is trained to recognize tumor cells as targets to be destroyed, or through the administration of therapeutic antibodies as drugs, in which case the patient's immune system is recruited to destroy tumor cells by the therapeutic antibodies. Cell based immunotherapy is another major entity of cancer immunotherapy. This involves immune cells such as the Natural killer Cells (NK cells), Lymphokine Activated killer cell(LAK), Cytotoxic T Lymphocytes(CTLs), Dendritic Cells (DC), etc., which are either activated in vivo by administering certain cytokines such as Interleukins or they are isolated, enriched and transfused to the patient to fight against cancer.
Since the immune system responds to the environmental factors it encounters on the basis of discrimination between self and non-self, many kinds of tumor cell
s that arise as a result of the onset of cancer are more or less tolerated by the patient's own immune system since the tumor cells are essentially the patient's own cells that are growing, dividing
and spreading without proper regulatory control.
In spite of this fact, however, many kinds of tumor cells display unusual antigen
s that are either inappropriate for the cell type and/or its environment, or are only normally present during the organisms' development (e.g. fetal
antigens). Examples of such antigens include the glycosphingolipid GD2
, a disialoganglioside that is normally only expressed at a significant level on the outer surface membranes of neuron
al cells, where its exposure to the immune system is limited by the blood-brain barrier
. GD2 is expressed on the surfaces of a wide range of tumor cells including neuroblastoma
, medulloblastoma
s, astrocytoma
s, melanoma
s, small-cell lung cancer, osteosarcoma
s and other soft tissue sarcoma
s. GD2 is thus a convenient tumor-specific target for immunotherapies.
Other kinds of tumor cells display cell surface receptors that are rare or absent on the surfaces of healthy cells, and which are responsible for activating cellular signal transduction
pathways that cause the unregulated growth and division of the tumor cell. Examples include ErbB2, a constitutively active cell surface receptor that is produced at abnormally high levels on the surface of breast cancer
tumor cells.
The use of some agents can lead to the re-activation of latent tuberculosis
(TB) and this must be assessed for before those agents are used therapeutically.http://www.thedoctorschannel.com/go/reuters/2153.htmlhttp://www.brit-thoracic.org.uk/guidelines/tuberculosis-guidelines.aspx
It involves isolation of either allogenic or autologous immune cells, enriching them outside the body and transfusing them back to the patient. The injected immune cells are highly cytotoxic to the Cancer cells thereby helping to fight the cancer cells. This therapy is in routine clinical practice in Japan and Autologous immune enhancement therapy
involving Natural Killer Cells (NK) cells and cytotoxic T Lymphocytes(CTLs) is being practised in various Asian Countries.
are a key component of the adaptive immune response
, playing a central role in both in the recognition of foreign antigens and the stimulation of an immune response to them. It is not surprising therefore, that many immunotherapeutic approaches involve the use of antibodies. The advent of monoclonal antibody technology has made it possible to raise antibodies against specific antigens such as the unusual antigens that are presented on the surfaces of tumors.
A number of therapeutic monoclonal antibodies have been approved for use in humans; approvals mentioned here are by the U.S. Food and Drug Administration (FDA).
is an anti-CD52
humanized IgG1 monoclonal antibody indicated for the treatment of Chronic lymphocytic leukemia
(CLL), the most frequent form of leukaemia in Western countries. The function of CD52 is unknown, but it is found on >95% of peripheral blood lymphocyte
s and monocyte
s. Upon binding to CD52, alemtuzumab initiates its cytotoxic effect by complement
fixation and antibody-dependent cell-mediated cytotoxicity mechanisms. Alemtuzumab therapy is also indicated for T-prolymphocytic leukaemia (TPPL), for which no standard treatment exists. This is a highly aggressive tumour, with a median survival of 7.5 months.
is a humanized IgG1 monoclonal antibody which binds to and sterically interferes with the vascular endothelial growth factor
-A (VEGF-A), preventing receptor
activation. A marked increase in VEGF
expression is thought to play a role in tumor
angiogenesis
. Bevacizumab is indicated for colon cancer; but has been applied to numerous other cancers in small scale studies, especially renal cell carcinoma
. Results obtained showed that bevacizumab increased the duration of survival, progression-free survival, the rate of response and the duration of response in a statistically relevant manner.
is a chimeric IgG1 monoclonal antibody which targets the extracellular domain of the epidermal growth factor receptor
(EGFR). It functions by competitively inhibiting ligand
binding, thereby preventing EGFR activation, and is indicated for the treatment of colorectal cancer
. Studies have also been carried out on numerous other malignancies, especially non-small cell lung cancer and head and neck cancer
.
As a single agent, cetuximab showed a response rate of 10.8% in patients with EGFR overexpressed metastatic colon cancer. Other anti-EGFR monoclonal antibodies in development include: ABX-EGF, hR3, and EMD 72000. Although they hold significant promise for the future, as of yet none of the agents are currently beyond phase I clinical trial
s.
is an “immuno-conjugate” of an anti-CD33
antibody chemically linked to calicheamicin
, a cytotoxic agent. It is indicated for the treatment of acute myeloid leukaemia (AML). The patient group most likely to benefit from gemtuzumab is young adults, and trials have reported high complete responses (85%), when combined with intensive chemotherapy. There are minimal side-effects associated with Gemtuzumab therapy.
is a chimeric monoclonal antibody specific for CD20
. CD20 is widely expressed on B-cells. Although the function of CD20 is relatively unknown it has been suggested that CD20 could play a role in calcium
influx across plasma membrane, maintaining intracellular calcium concentration and allowing for the activation of B cells. The exact mode of action of rituximab is also unclear, but it has been found to have a general regulatory effect on the cell cycle
and on immune-receptor expression. Experiments involving primate
s showed that treatment with anti-CD20 reduced peripheral B-cells by 98%, and peripheral lymph node
and bone marrow
B-cells by up to 95%.
is a monoclonal IgG1 humanized antibody specific for the epidermal growth factor receptor
2 protein (HER2). It received FDA-approval in 1998, and is clinically used for the treatment of breast cancer
. The use of Trastuzumab is restricted to patients whose tumours over-express HER-2, as assessed by immunohistochemistry
(IHC) and either chromogenic or Fluorescent
in situ
hybridisation (FISH
), as well as numerous PCR-based methodologies.
HER-2 is a member of the epidermal growth factor receptor (EGFR) family of transmembrane tyrosine kinases, and is normally involved in regulation of cell proliferation and differentiation. Amplification or overexpression of HER-2 is present in 25-30% of breast carcinomas and has been associated with aggressive tumour phenotype, poor prognosis
, non-responsiveness to hormonal therapy and reduced sensitivity to conventional chemotherapeutic agents.
involves the use of radioactively conjugated murine antibodies against cellular antigens. Most research currently involved their application to lymphomas, as these are highly radio-sensitive malignancies. To limit radiation exposure, murine antibodies were especially chosen, as their high immunogenicity promotes rapid clearance from the body.
is a murine antibody chemically linked to a chelating agent which binds yttrium-90
. 90Y is a beta radiator, has a half-life
of 64 h and a tissue penetration of 1-5 millimetres. Its use has been investigated, primarily in the treatment of follicular lymphoma
.
is a murine IgG2a anti-CD20
antibody. Iodine (131I) tositumomab is covalently bound to Iodine
131. 131I emits both beta and gamma radiation, and is broken down rapidly in the body. Clinical trials have established the efficacy of a sequential application of tositumomab and iodine (131I) tositumomab in patients with relapse
d follicular lymphoma
.
, allowing even those tumors that present unusual antigens to survive and flourish in spite of the immune response generated by the cancer patient, against his or her own tumor tissue. Certain members of a group of molecules known as cytokine
s, such as Interleukin-2 also play a key role in modulating the immune response, and have been tried in conjunction with antibodies in order to generate an even more devastating immune response against the tumor. While the therapeutic administration of such cytokines may cause systemic inflammation, resulting in serious side effect
s and toxicity
, a new generation of chimeric molecules consisting of an immune-stimulatory cytokine attached to an antibody that targets the cytokine's activity to a specific environment such as a tumor, are able to generate a very effective yet localized immune response against the tumor tissue, destroying the cancer-causing cells without the unwanted side-effects. A different type of chimeric molecule is an artificial T cell receptor
.
The targeted delivery of cytokines by anti-tumor antibodies is one example of using antibodies to delivery payloads rather than simply relying on the antibody to trigger an immune response against the target cell. Another strategy is to deliver a lethal radioactive dose directly to the target cell, which has been utilized in the case of the Zevalin
therapeutic. A third strategy is to deliver a lethal chemical dose to the target, as used in the Mylotarg
therapeutic. Engineering the antibody-payload pair in such a way that they separate after entry into a cell by endocytosis
can potentially increase the efficacy of the payload. One strategy to accomplish this is the use of a disulfide linkage
which could be severed by the reducing conditions in the cellular interior. However, recent evidence suggests that the actual intracellular trafficking of the antibody-payload after endocytosis is such to make this strategy not generally applicable. Other potentially useful linkage types include hydrazone
and peptide
linkages.
In June 2008, it was announced that US doctors from the Clinical Research Division led by Cassian Yee at Fred Hutchinson Cancer Research Center
in Seattle have for the first time successfully treated a skin cancer
patient by using immune cells cloned from his own immune system
which were then re-injected into him. The patient, who was suffering from advanced skin cancer, was free from tumours within eight weeks of being injected with billions of his own immune cells in the first case of its kind. Experts say that this case could be a landmark in the treatment of cancer in general. Larger trials are now under way. http://www.telegraph.co.uk/earth/main.jhtml?xml=/earth/2008/06/18/scicanc118.xml
More new research is being conducted by Drs. Richard O'Reilly and Michel Sadelain. Drs. O'Reilly and Sadelain have done extensive research at Memorial Sloan-Kettering Cancer Center
hospital and are among leaders of the cancer adoptive Immunotherapy field
immunotherapy utilizes an immune enhancement cream (imiquimod
) which is an interferon
producer causing the patient's own killer T cells to destroy wart
s, actinic keratoses, basal cell carcinoma
, squamous cell carcinoma
, cutaneous T cell lymphoma
, and Superficial spreading melanoma
. Injection immunotherapy uses mumps
, candida
or trichophytin antigen injections to treat warts (HPV induced tumors).
may be able to stimulate the immune system. Research has shown that Agaricus blazei
may be a potent stimulator of natural killer cells.
Agaricus blazei
is rich in proteoglucans and beta-glucans, which are potent stimulators of macrophages.
Research on the compounds in medicinal mushrooms
most responsible for up-regulating the immune system and providing an anti-cancer effect, are a diverse collection of polysaccharide
compounds, particularly beta-glucans. Beta-glucans are known as "biological response modifiers", and their ability to activate the immune system is well documented. Specifically, beta-glucans stimulate the innate
branch of the immune system. Research has shown beta-glucans have the ability to stimulate macrophage
, NK cells, T cells, and immune system cytokines. The mechanisms in which beta-glucans stimulate the immune system is only partially understood. One mechanism in which beta-glucans are able to activate the immune system, is by interacting with the Macrophage-1 antigen (CD18
) receptor on immune cells.
Highly purified compounds isolated from medicinal mushrooms such as lentinan
(isolated from Shiitake
), and Polysaccharide-K
, (isolated from Trametes versicolor
), have become incorporated into the health care system of a few countries, such as Japan
. Japan's Ministry of Health, Labour and Welfare
approved the use of Polysaccharide-K
in the 1980s, to stimulate the immune systems of patients undergoing chemotherapy. In Australia
, a pharmaceutical based on a mixture of several mycological extracts including lentinan and Polysaccharide-K is sold commercially as MC-S.
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
to reject cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
. The main premise is stimulating the patient's immune system to attack the malignant tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
cells that are responsible for the disease. This can be either through immunization
Immunization
Immunization, or immunisation, is the process by which an individual's immune system becomes fortified against an agent ....
of the patient (e.g., by administering a cancer vaccine
Cancer vaccine
The term cancer vaccine refers to a vaccine that either prevents infections with cancer-causing viruses, treats existing cancer or prevents the development of cancer in certain high risk individuals...
, such as Dendreon's Provenge), in which case the patient's own immune system is trained to recognize tumor cells as targets to be destroyed, or through the administration of therapeutic antibodies as drugs, in which case the patient's immune system is recruited to destroy tumor cells by the therapeutic antibodies. Cell based immunotherapy is another major entity of cancer immunotherapy. This involves immune cells such as the Natural killer Cells (NK cells), Lymphokine Activated killer cell(LAK), Cytotoxic T Lymphocytes(CTLs), Dendritic Cells (DC), etc., which are either activated in vivo by administering certain cytokines such as Interleukins or they are isolated, enriched and transfused to the patient to fight against cancer.
Since the immune system responds to the environmental factors it encounters on the basis of discrimination between self and non-self, many kinds of tumor cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
s that arise as a result of the onset of cancer are more or less tolerated by the patient's own immune system since the tumor cells are essentially the patient's own cells that are growing, dividing
Cell division
Cell division is the process by which a parent cell divides into two or more daughter cells . Cell division is usually a small segment of a larger cell cycle. This type of cell division in eukaryotes is known as mitosis, and leaves the daughter cell capable of dividing again. The corresponding sort...
and spreading without proper regulatory control.
In spite of this fact, however, many kinds of tumor cells display unusual antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
s that are either inappropriate for the cell type and/or its environment, or are only normally present during the organisms' development (e.g. fetal
Fetus
A fetus is a developing mammal or other viviparous vertebrate after the embryonic stage and before birth.In humans, the fetal stage of prenatal development starts at the beginning of the 11th week in gestational age, which is the 9th week after fertilization.-Etymology and spelling variations:The...
antigens). Examples of such antigens include the glycosphingolipid GD2
GD2
GD2 is a disialoganglioside expressed on tumors of neuroectodermal origin, including human neuroblastoma and melanoma, with highly restricted expression on normal tissues, principally to the cerebellum and peripheral nerves in humans....
, a disialoganglioside that is normally only expressed at a significant level on the outer surface membranes of neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
al cells, where its exposure to the immune system is limited by the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
. GD2 is expressed on the surfaces of a wide range of tumor cells including neuroblastoma
Neuroblastoma
Neuroblastoma is the most common extracranial solid cancer in childhood and the most common cancer in infancy, with an annual incidence of about 650 cases per year in the US , and 100 cases per year in the UK . Close to 50 percent of neuroblastoma cases occur in children younger than two years old...
, medulloblastoma
Medulloblastoma
Medulloblastoma is a highly malignant primary brain tumor that originates in the cerebellum or posterior fossa.Previously, medulloblastomas were thought to represent a subset of primitive neuroectodermal tumor of the posterior fossa...
s, astrocytoma
Astrocytoma
Astrocytomas are a type of neoplasm of the brain. They originate in a particular kind of glial-cells, star-shaped brain cells in the cerebrum called astrocytes. This type of tumor does not usually spread outside the brain and spinal cord and it does not usually affect other organs...
s, melanoma
Melanoma
Melanoma is a malignant tumor of melanocytes. Melanocytes are cells that produce the dark pigment, melanin, which is responsible for the color of skin. They predominantly occur in skin, but are also found in other parts of the body, including the bowel and the eye...
s, small-cell lung cancer, osteosarcoma
Osteosarcoma
Osteosarcoma is an aggressive cancerous neoplasm arising from primitive transformed cells of mesenchymal origin that exhibit osteoblastic differentiation and produce malignant osteoid...
s and other soft tissue sarcoma
Soft tissue sarcoma
A soft-tissue sarcoma is a form of sarcoma that develops in connective tissue, though the term is sometimes applied to elements of the soft tissue that are not currently considered connective tissue.-Risk factors:...
s. GD2 is thus a convenient tumor-specific target for immunotherapies.
Other kinds of tumor cells display cell surface receptors that are rare or absent on the surfaces of healthy cells, and which are responsible for activating cellular signal transduction
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
pathways that cause the unregulated growth and division of the tumor cell. Examples include ErbB2, a constitutively active cell surface receptor that is produced at abnormally high levels on the surface of breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
tumor cells.
The use of some agents can lead to the re-activation of latent tuberculosis
Tuberculosis
Tuberculosis, MTB, or TB is a common, and in many cases lethal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. Tuberculosis usually attacks the lungs but can also affect other parts of the body...
(TB) and this must be assessed for before those agents are used therapeutically.http://www.thedoctorschannel.com/go/reuters/2153.htmlhttp://www.brit-thoracic.org.uk/guidelines/tuberculosis-guidelines.aspx
Cell Based immunotherapy
Adoptive Cell based Immunotherapy was first introduced by Rosenberg and his Colleagues of NIH, USA and it is now widely being used in various countries.It involves isolation of either allogenic or autologous immune cells, enriching them outside the body and transfusing them back to the patient. The injected immune cells are highly cytotoxic to the Cancer cells thereby helping to fight the cancer cells. This therapy is in routine clinical practice in Japan and Autologous immune enhancement therapy
Autologous immune enhancement therapy
Autologous immune enhancement therapy is a treatment method in which immune cells are taken out from the patient's body which are cultured and processed to activate them until their resistance to cancer is strengthened and then the cells are put back in the body...
involving Natural Killer Cells (NK) cells and cytotoxic T Lymphocytes(CTLs) is being practised in various Asian Countries.
Monoclonal antibody therapy
AntibodiesAntibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
are a key component of the adaptive immune response
Adaptive immune system
The adaptive immune system is composed of highly specialized, systemic cells and processes that eliminate or prevent pathogenic growth. Thought to have arisen in the first jawed vertebrates, the adaptive or "specific" immune system is activated by the “non-specific” and evolutionarily older innate...
, playing a central role in both in the recognition of foreign antigens and the stimulation of an immune response to them. It is not surprising therefore, that many immunotherapeutic approaches involve the use of antibodies. The advent of monoclonal antibody technology has made it possible to raise antibodies against specific antigens such as the unusual antigens that are presented on the surfaces of tumors.
A number of therapeutic monoclonal antibodies have been approved for use in humans; approvals mentioned here are by the U.S. Food and Drug Administration (FDA).
| Antibody | Brand name | Approval date | Type | Target | Approved treatment(s) |
|---|---|---|---|---|---|
| Alemtuzumab Alemtuzumab Alemtuzumab is a monoclonal antibody used in the treatment of chronic lymphocytic leukemia , cutaneous T-cell lymphoma and T-cell lymphoma... |
Campath | 2001 | humanized | CD52 CD52 CD52 is a protein present on the surface of mature lymphocytes, but not on the stem cells from which these lymphocytes were derived.It also is found in monocytes and dendritic cells.... |
Chronic lymphocytic leukemia Chronic lymphocytic leukemia B-cell chronic lymphocytic leukemia , also known as chronic lymphoid leukemia , is the most common type of leukemia. Leukemias are cancers of the white blood cells . CLL affects B cell lymphocytes. B cells originate in the bone marrow, develop in the lymph nodes, and normally fight infection by... |
| Bevacizumab Bevacizumab Bevacizumab is a drug that blocks angiogenesis, the growth of new blood vessels. It is commonly used to treat various cancers, including colorectal, lung, breast, kidney, and glioblastomas.... |
Avastin | 2004 | humanized | vascular endothelial growth factor Vascular endothelial growth factor Vascular endothelial growth factor is a signal protein produced by cells that stimulates vasculogenesis and angiogenesis. It is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate.... |
colorectal cancer Colorectal cancer Colorectal cancer, commonly known as bowel cancer, is a cancer caused by uncontrolled cell growth , in the colon, rectum, or vermiform appendix. Colorectal cancer is clinically distinct from anal cancer, which affects the anus.... |
| Brentuximab vedotin Brentuximab vedotin Brentuximab vedotin is an antibody-drug conjugate approved to treat anaplastic large cell lymphoma and Hodgkin lymphoma. The U.S... |
Adcetris | 2011 | chimeric | CD30 CD30 CD30, also known as TNFRSF8, is a cell membrane protein of the tumor necrosis factor receptor family and tumor marker.This receptor is expressed by activated, but not by resting, T and B cells. TRAF2 and TRAF5 can interact with this receptor, and mediate the signal transduction that leads to the... |
Hodgkin lymphoma, Anaplastic large-cell lymphoma |
| Cetuximab Cetuximab Cetuximab is a chimeric monoclonal antibody, an epidermal growth factor receptor inhibitor, given by intravenous infusion for treatment of metastatic colorectal cancer and head and neck cancer.- Distribution :Cetuximab is manufactured and distributed in North America by ImClone and Bristol-Myers... |
Erbitux | 2004 | chimeric | epidermal growth factor receptor Epidermal growth factor receptor The epidermal growth factor receptor is the cell-surface receptor for members of the epidermal growth factor family of extracellular protein ligands... |
colorectal cancer Colorectal cancer Colorectal cancer, commonly known as bowel cancer, is a cancer caused by uncontrolled cell growth , in the colon, rectum, or vermiform appendix. Colorectal cancer is clinically distinct from anal cancer, which affects the anus.... |
| Gemtuzumab ozogamicin Gemtuzumab ozogamicin Gemtuzumab ozogamicin is a drug-linked monoclonal antibody that was used to treat acute myelogenous leukemia from 2000-2010... |
Mylotarg | 2000 | humanized | CD33 CD33 CD33 or Siglec-3 is a transmembrane receptor expressed on cells of myeloid lineage. It is usually considered myeloid-specific, but it can also be found on some lymphoid cells.It binds sialic acids, therefore is a member of the SIGLEC family of lectins.... |
acute myelogenous leukemia (with calicheamicin Calicheamicin The calicheamicins are a class of enediyne antibiotics derived from the bacterium Micromonospora echinospora, with calicheamicin γ1 being the most notable. It was isolated originally from a rock collected by a Scripps Research Institute chemist while hiking in Waco, Texas. It is extremely toxic to... ) |
| Ibritumomab tiuxetan Ibritumomab tiuxetan Ibritumomab tiuxetan, sold under the trade name Zevalin, is a monoclonal antibody radioimmunotherapy treatment for some forms of B cell non-Hodgkin's lymphoma, a lymphoproliferative disorder and thus affects the lymphatic system... |
Zevalin | 2002 | murine | CD20 CD20 B-lymphocyte antigen CD20 or CD20 is an activated-glycosylated phosphoprotein expressed on the surface of all B-cells beginning at the pro-B phase and progressively increasing in concentration until maturity.... |
non-Hodgkin lymphoma Non-Hodgkin lymphoma The non-Hodgkin lymphomas are a diverse group of blood cancers that include any kind of lymphoma except Hodgkin's lymphomas. Types of NHL vary significantly in their severity, from indolent to very aggressive.... (with yttrium-90 Yttrium Yttrium is a chemical element with symbol Y and atomic number 39. It is a silvery-metallic transition metal chemically similar to the lanthanides and it has often been classified as a "rare earth element". Yttrium is almost always found combined with the lanthanides in rare earth minerals and is... or indium-111 Indium Indium is a chemical element with the symbol In and atomic number 49. This rare, very soft, malleable and easily fusible post-transition metal is chemically similar to gallium and thallium, and shows the intermediate properties between these two... ) |
| Panitumumab Panitumumab Panitumumab , formerly ABX-EGF, is a fully human monoclonal antibody specific to the epidermal growth factor receptor .... |
Vectibix | 2006 | human | epidermal growth factor receptor Epidermal growth factor receptor The epidermal growth factor receptor is the cell-surface receptor for members of the epidermal growth factor family of extracellular protein ligands... |
colorectal cancer Colorectal cancer Colorectal cancer, commonly known as bowel cancer, is a cancer caused by uncontrolled cell growth , in the colon, rectum, or vermiform appendix. Colorectal cancer is clinically distinct from anal cancer, which affects the anus.... |
| Rituximab Rituximab Rituximab, sold under the trade names Rituxan and MabThera, is a chimeric monoclonal antibody against the protein CD20, which is primarily found on the surface of B cells... |
Rituxan, Mabthera | 1997 | chimeric | CD20 CD20 B-lymphocyte antigen CD20 or CD20 is an activated-glycosylated phosphoprotein expressed on the surface of all B-cells beginning at the pro-B phase and progressively increasing in concentration until maturity.... |
non-Hodgkin lymphoma Non-Hodgkin lymphoma The non-Hodgkin lymphomas are a diverse group of blood cancers that include any kind of lymphoma except Hodgkin's lymphomas. Types of NHL vary significantly in their severity, from indolent to very aggressive.... |
| Trastuzumab Trastuzumab Trastuzumab is a monoclonal antibody that interferes with the HER2/neu receptor.The HER receptors are proteins that are embedded in the cell membrane and communicate molecular signals from outside the cell to inside the cell, and turn genes on and off... |
Herceptin | 1998 | humanized | ErbB2 | breast cancer Breast cancer Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas... |
Alemtuzumab
AlemtuzumabAlemtuzumab
Alemtuzumab is a monoclonal antibody used in the treatment of chronic lymphocytic leukemia , cutaneous T-cell lymphoma and T-cell lymphoma...
is an anti-CD52
CD52
CD52 is a protein present on the surface of mature lymphocytes, but not on the stem cells from which these lymphocytes were derived.It also is found in monocytes and dendritic cells....
humanized IgG1 monoclonal antibody indicated for the treatment of Chronic lymphocytic leukemia
Chronic lymphocytic leukemia
B-cell chronic lymphocytic leukemia , also known as chronic lymphoid leukemia , is the most common type of leukemia. Leukemias are cancers of the white blood cells . CLL affects B cell lymphocytes. B cells originate in the bone marrow, develop in the lymph nodes, and normally fight infection by...
(CLL), the most frequent form of leukaemia in Western countries. The function of CD52 is unknown, but it is found on >95% of peripheral blood lymphocyte
Lymphocyte
A lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...
s and monocyte
Monocyte
Monocytes are a type of white blood cell and are part of the innate immune system of vertebrates including all mammals , birds, reptiles, and fish. Monocytes play multiple roles in immune function...
s. Upon binding to CD52, alemtuzumab initiates its cytotoxic effect by complement
Complement system
The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...
fixation and antibody-dependent cell-mediated cytotoxicity mechanisms. Alemtuzumab therapy is also indicated for T-prolymphocytic leukaemia (TPPL), for which no standard treatment exists. This is a highly aggressive tumour, with a median survival of 7.5 months.
Bevacizumab
BevacizumabBevacizumab
Bevacizumab is a drug that blocks angiogenesis, the growth of new blood vessels. It is commonly used to treat various cancers, including colorectal, lung, breast, kidney, and glioblastomas....
is a humanized IgG1 monoclonal antibody which binds to and sterically interferes with the vascular endothelial growth factor
Vascular endothelial growth factor
Vascular endothelial growth factor is a signal protein produced by cells that stimulates vasculogenesis and angiogenesis. It is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate....
-A (VEGF-A), preventing receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
activation. A marked increase in VEGF
Vascular endothelial growth factor
Vascular endothelial growth factor is a signal protein produced by cells that stimulates vasculogenesis and angiogenesis. It is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate....
expression is thought to play a role in tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
angiogenesis
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
. Bevacizumab is indicated for colon cancer; but has been applied to numerous other cancers in small scale studies, especially renal cell carcinoma
Renal cell carcinoma
Renal cell carcinoma is a kidney cancer that originates in the lining of the proximal convoluted tubule, the very small tubes in the kidney that filter the blood and remove waste products. RCC is the most common type of kidney cancer in adults, responsible for approximately 80% of cases...
. Results obtained showed that bevacizumab increased the duration of survival, progression-free survival, the rate of response and the duration of response in a statistically relevant manner.
Cetuximab
CetuximabCetuximab
Cetuximab is a chimeric monoclonal antibody, an epidermal growth factor receptor inhibitor, given by intravenous infusion for treatment of metastatic colorectal cancer and head and neck cancer.- Distribution :Cetuximab is manufactured and distributed in North America by ImClone and Bristol-Myers...
is a chimeric IgG1 monoclonal antibody which targets the extracellular domain of the epidermal growth factor receptor
Epidermal growth factor receptor
The epidermal growth factor receptor is the cell-surface receptor for members of the epidermal growth factor family of extracellular protein ligands...
(EGFR). It functions by competitively inhibiting ligand
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
binding, thereby preventing EGFR activation, and is indicated for the treatment of colorectal cancer
Colorectal cancer
Colorectal cancer, commonly known as bowel cancer, is a cancer caused by uncontrolled cell growth , in the colon, rectum, or vermiform appendix. Colorectal cancer is clinically distinct from anal cancer, which affects the anus....
. Studies have also been carried out on numerous other malignancies, especially non-small cell lung cancer and head and neck cancer
Head and neck cancer
Head and neck cancer refers to a group of biologically similar cancers that start in the upper aerodigestive tract, including the lip, oral cavity , nasal cavity , paranasal sinuses, pharynx, and larynx. 90% of head and neck cancers are squamous cell carcinomas , originating from the mucosal lining...
.
As a single agent, cetuximab showed a response rate of 10.8% in patients with EGFR overexpressed metastatic colon cancer. Other anti-EGFR monoclonal antibodies in development include: ABX-EGF, hR3, and EMD 72000. Although they hold significant promise for the future, as of yet none of the agents are currently beyond phase I clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s.
Gemtuzumab ozogamicin
Gemtuzumab ozogamicinGemtuzumab ozogamicin
Gemtuzumab ozogamicin is a drug-linked monoclonal antibody that was used to treat acute myelogenous leukemia from 2000-2010...
is an “immuno-conjugate” of an anti-CD33
CD33
CD33 or Siglec-3 is a transmembrane receptor expressed on cells of myeloid lineage. It is usually considered myeloid-specific, but it can also be found on some lymphoid cells.It binds sialic acids, therefore is a member of the SIGLEC family of lectins....
antibody chemically linked to calicheamicin
Calicheamicin
The calicheamicins are a class of enediyne antibiotics derived from the bacterium Micromonospora echinospora, with calicheamicin γ1 being the most notable. It was isolated originally from a rock collected by a Scripps Research Institute chemist while hiking in Waco, Texas. It is extremely toxic to...
, a cytotoxic agent. It is indicated for the treatment of acute myeloid leukaemia (AML). The patient group most likely to benefit from gemtuzumab is young adults, and trials have reported high complete responses (85%), when combined with intensive chemotherapy. There are minimal side-effects associated with Gemtuzumab therapy.
Rituximab
RituximabRituximab
Rituximab, sold under the trade names Rituxan and MabThera, is a chimeric monoclonal antibody against the protein CD20, which is primarily found on the surface of B cells...
is a chimeric monoclonal antibody specific for CD20
CD20
B-lymphocyte antigen CD20 or CD20 is an activated-glycosylated phosphoprotein expressed on the surface of all B-cells beginning at the pro-B phase and progressively increasing in concentration until maturity....
. CD20 is widely expressed on B-cells. Although the function of CD20 is relatively unknown it has been suggested that CD20 could play a role in calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
influx across plasma membrane, maintaining intracellular calcium concentration and allowing for the activation of B cells. The exact mode of action of rituximab is also unclear, but it has been found to have a general regulatory effect on the cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
and on immune-receptor expression. Experiments involving primate
Primate
A primate is a mammal of the order Primates , which contains prosimians and simians. Primates arose from ancestors that lived in the trees of tropical forests; many primate characteristics represent adaptations to life in this challenging three-dimensional environment...
s showed that treatment with anti-CD20 reduced peripheral B-cells by 98%, and peripheral lymph node
Lymph node
A lymph node is a small ball or an oval-shaped organ of the immune system, distributed widely throughout the body including the armpit and stomach/gut and linked by lymphatic vessels. Lymph nodes are garrisons of B, T, and other immune cells. Lymph nodes are found all through the body, and act as...
and bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
B-cells by up to 95%.
Trastuzumab
TrastuzumabTrastuzumab
Trastuzumab is a monoclonal antibody that interferes with the HER2/neu receptor.The HER receptors are proteins that are embedded in the cell membrane and communicate molecular signals from outside the cell to inside the cell, and turn genes on and off...
is a monoclonal IgG1 humanized antibody specific for the epidermal growth factor receptor
Epidermal growth factor receptor
The epidermal growth factor receptor is the cell-surface receptor for members of the epidermal growth factor family of extracellular protein ligands...
2 protein (HER2). It received FDA-approval in 1998, and is clinically used for the treatment of breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
. The use of Trastuzumab is restricted to patients whose tumours over-express HER-2, as assessed by immunohistochemistry
Immunohistochemistry
Immunohistochemistry or IHC refers to the process of detecting antigens in cells of a tissue section by exploiting the principle of antibodies binding specifically to antigens in biological tissues. IHC takes its name from the roots "immuno," in reference to antibodies used in the procedure, and...
(IHC) and either chromogenic or Fluorescent
Fluorescence
Fluorescence is the emission of light by a substance that has absorbed light or other electromagnetic radiation of a different wavelength. It is a form of luminescence. In most cases, emitted light has a longer wavelength, and therefore lower energy, than the absorbed radiation...
in situ
In situ
In situ is a Latin phrase which translated literally as 'In position'. It is used in many different contexts.-Aerospace:In the aerospace industry, equipment on board aircraft must be tested in situ, or in place, to confirm everything functions properly as a system. Individually, each piece may...
hybridisation (FISH
Fluorescent in situ hybridization
FISH is a cytogenetic technique developed by biomedical researchers in the early 1980s that is used to detect and localize the presence or absence of specific DNA sequences on chromosomes. FISH uses fluorescent probes that bind to only those parts of the chromosome with which they show a high...
), as well as numerous PCR-based methodologies.
HER-2 is a member of the epidermal growth factor receptor (EGFR) family of transmembrane tyrosine kinases, and is normally involved in regulation of cell proliferation and differentiation. Amplification or overexpression of HER-2 is present in 25-30% of breast carcinomas and has been associated with aggressive tumour phenotype, poor prognosis
Prognosis
Prognosis is a medical term to describe the likely outcome of an illness.When applied to large statistical populations, prognostic estimates can be very accurate: for example the statement "45% of patients with severe septic shock will die within 28 days" can be made with some confidence, because...
, non-responsiveness to hormonal therapy and reduced sensitivity to conventional chemotherapeutic agents.
Radioimmunotherapy
RadioimmunotherapyRadioimmunotherapy
Radioimmunotherapy uses an antibody labeled with a radionuclide to deliver cytotoxic radiation to a target cell. In cancer therapy, an antibody with specificity for a tumor-associated antigen is used to deliver a lethal dose of radiation to the tumor cells...
involves the use of radioactively conjugated murine antibodies against cellular antigens. Most research currently involved their application to lymphomas, as these are highly radio-sensitive malignancies. To limit radiation exposure, murine antibodies were especially chosen, as their high immunogenicity promotes rapid clearance from the body.
Ibritumomab tiuxetan
Ibritumomab tiuxetanIbritumomab tiuxetan
Ibritumomab tiuxetan, sold under the trade name Zevalin, is a monoclonal antibody radioimmunotherapy treatment for some forms of B cell non-Hodgkin's lymphoma, a lymphoproliferative disorder and thus affects the lymphatic system...
is a murine antibody chemically linked to a chelating agent which binds yttrium-90
Yttrium-90
Yttrium-90 is a medically significant isotope of yttrium.It emits beta rays of 2.3 MeV.Yttrium-90 is a decay product of Strontium-90 which makes up about 5% of the Nuclear daughter isotopes when Uranium is fissioned....
. 90Y is a beta radiator, has a half-life
Half-life
Half-life, abbreviated t½, is the period of time it takes for the amount of a substance undergoing decay to decrease by half. The name was originally used to describe a characteristic of unstable atoms , but it may apply to any quantity which follows a set-rate decay.The original term, dating to...
of 64 h and a tissue penetration of 1-5 millimetres. Its use has been investigated, primarily in the treatment of follicular lymphoma
Follicular lymphoma
Follicular lymphoma is the most common of the indolent non-Hodgkin's lymphomas, and the second most common form of non-Hodgkin's lymphomas overall. It is defined as a lymphoma of follicle center B-cells , which has at least a partially follicular pattern...
.
Tositumomab/iodine (131I) tositumomab regimen
TositumomabTositumomab
Tositumomab is a drug for the treatment of follicular lymphoma. It is a IgG2a anti-CD20 monoclonal antibody derived from immortalized mouse cells....
is a murine IgG2a anti-CD20
CD20
B-lymphocyte antigen CD20 or CD20 is an activated-glycosylated phosphoprotein expressed on the surface of all B-cells beginning at the pro-B phase and progressively increasing in concentration until maturity....
antibody. Iodine (131I) tositumomab is covalently bound to Iodine
Iodine
Iodine is a chemical element with the symbol I and atomic number 53. The name is pronounced , , or . The name is from the , meaning violet or purple, due to the color of elemental iodine vapor....
131. 131I emits both beta and gamma radiation, and is broken down rapidly in the body. Clinical trials have established the efficacy of a sequential application of tositumomab and iodine (131I) tositumomab in patients with relapse
Relapse
Relapse, in relation to drug misuse, is resuming the use of a drug or a dependent substance after one or more periods of abstinence. The term is a landmark feature of both substance dependence and substance abuse, which are learned behaviors, and is maintained by neuronal adaptations that mediate...
d follicular lymphoma
Follicular lymphoma
Follicular lymphoma is the most common of the indolent non-Hodgkin's lymphomas, and the second most common form of non-Hodgkin's lymphomas overall. It is defined as a lymphoma of follicle center B-cells , which has at least a partially follicular pattern...
.
Advances in immunotherapy
The development and testing of second generation immunotherapies are already under way. While antibodies targeted to disease-causing antigens can be effective under certain circumstances, in many cases, their efficacy may be limited by other factors. In the case of cancer tumors, the microenvironment is immunosuppressiveImmunosuppression
Immunosuppression involves an act that reduces the activation or efficacy of the immune system. Some portions of the immune system itself have immuno-suppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse reaction to treatment of other...
, allowing even those tumors that present unusual antigens to survive and flourish in spite of the immune response generated by the cancer patient, against his or her own tumor tissue. Certain members of a group of molecules known as cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
s, such as Interleukin-2 also play a key role in modulating the immune response, and have been tried in conjunction with antibodies in order to generate an even more devastating immune response against the tumor. While the therapeutic administration of such cytokines may cause systemic inflammation, resulting in serious side effect
Adverse effect
In medicine, an adverse effect is a harmful and undesired effect resulting from a medication or other intervention such as surgery.An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. If it results from an unsuitable or incorrect dosage or...
s and toxicity
Toxicity
Toxicity is the degree to which a substance can damage a living or non-living organisms. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a substructure of the organism, such as a cell or an organ , such as the liver...
, a new generation of chimeric molecules consisting of an immune-stimulatory cytokine attached to an antibody that targets the cytokine's activity to a specific environment such as a tumor, are able to generate a very effective yet localized immune response against the tumor tissue, destroying the cancer-causing cells without the unwanted side-effects. A different type of chimeric molecule is an artificial T cell receptor
Artificial T cell receptor
Artificial T cell receptors are engineered receptors, which graft an arbitrary specificity onto an immune effector cell...
.
The targeted delivery of cytokines by anti-tumor antibodies is one example of using antibodies to delivery payloads rather than simply relying on the antibody to trigger an immune response against the target cell. Another strategy is to deliver a lethal radioactive dose directly to the target cell, which has been utilized in the case of the Zevalin
Ibritumomab tiuxetan
Ibritumomab tiuxetan, sold under the trade name Zevalin, is a monoclonal antibody radioimmunotherapy treatment for some forms of B cell non-Hodgkin's lymphoma, a lymphoproliferative disorder and thus affects the lymphatic system...
therapeutic. A third strategy is to deliver a lethal chemical dose to the target, as used in the Mylotarg
Gemtuzumab ozogamicin
Gemtuzumab ozogamicin is a drug-linked monoclonal antibody that was used to treat acute myelogenous leukemia from 2000-2010...
therapeutic. Engineering the antibody-payload pair in such a way that they separate after entry into a cell by endocytosis
Endocytosis
Endocytosis is a process by which cells absorb molecules by engulfing them. It is used by all cells of the body because most substances important to them are large polar molecules that cannot pass through the hydrophobic plasma or cell membrane...
can potentially increase the efficacy of the payload. One strategy to accomplish this is the use of a disulfide linkage
Disulfide bond
In chemistry, a disulfide bond is a covalent bond, usually derived by the coupling of two thiol groups. The linkage is also called an SS-bond or disulfide bridge. The overall connectivity is therefore R-S-S-R. The terminology is widely used in biochemistry...
which could be severed by the reducing conditions in the cellular interior. However, recent evidence suggests that the actual intracellular trafficking of the antibody-payload after endocytosis is such to make this strategy not generally applicable. Other potentially useful linkage types include hydrazone
Hydrazone
Hydrazones are a class of organic compounds with the structure R1R2C=NNH2. They are related to ketones and aldehydes by the replacement of the oxygen with the NNH2 functional group...
and peptide
Peptide bond
This article is about the peptide link found within biological molecules, such as proteins. A similar article for synthetic molecules is being created...
linkages.
Latest research
In 2001, two U.S. based non-profit organizations, the Cancer Research Institute and the Ludwig Institute for Cancer Research, formed the Cancer Vaccine Collaborative, a unique global network of clinical trial sites with special expertise in immunology, built to centrally design and coordinate early-stage clinical trials to be run in parallel in order to identify more quickly the optimal combination of reagents, or vaccine components, necessary for a successful therapeutic cancer vaccine. The Cancer Vaccine Collaborative has to-date (June 2009) completed or is currently running more than 40 clinical trials of different therapeutic cancer vaccines, including 37 phase I, 6 phase II, and 1 fully randomized phase II clinical trials, and has published more than 130 scientific papers in peer-reviewed journals. Nearly all of these trials featured vaccines targeting various forms of the cancer-testes antigen, NY-ESO-1, a highly immunogenic, prototypical protein marker limited in expression to a wide variety of cancer types but not in normal tissue, with the exception of the immune-privileged testes. Vaccines tested in Cancer Vaccine Collaborative trials have induced integrated immune responses composed of target-specific antibodies and CD4+ and CD8+ T lymphocytes, all of which are held to be essential for effective long-term control of cancer. Insights from these trials have generated a strong framework for the selection of components that will likely comprise an ideal therapeutic cancer vaccine, including: multiple cancer-antigens in various forms delivered with potent adjuvants and all administered in a prime-boost setting in conjunction with a modulator of cancer immunosuppression.In June 2008, it was announced that US doctors from the Clinical Research Division led by Cassian Yee at Fred Hutchinson Cancer Research Center
Fred Hutchinson Cancer Research Center
The Fred Hutchinson Cancer Research Center, is one of the world’s leading cancer research institutes...
in Seattle have for the first time successfully treated a skin cancer
Skin cancer
Skin neoplasms are skin growths with differing causes and varying degrees of malignancy. The three most common malignant skin cancers are basal cell cancer, squamous cell cancer, and melanoma, each of which is named after the type of skin cell from which it arises...
patient by using immune cells cloned from his own immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
which were then re-injected into him. The patient, who was suffering from advanced skin cancer, was free from tumours within eight weeks of being injected with billions of his own immune cells in the first case of its kind. Experts say that this case could be a landmark in the treatment of cancer in general. Larger trials are now under way. http://www.telegraph.co.uk/earth/main.jhtml?xml=/earth/2008/06/18/scicanc118.xml
More new research is being conducted by Drs. Richard O'Reilly and Michel Sadelain. Drs. O'Reilly and Sadelain have done extensive research at Memorial Sloan-Kettering Cancer Center
Memorial Sloan-Kettering Cancer Center
Memorial Sloan–Kettering Cancer Center is a cancer treatment and research institution founded in 1884 as the New York Cancer Hospital...
hospital and are among leaders of the cancer adoptive Immunotherapy field
Topical immunotherapy
Dermatologists use new creams and injections in the management of benign and malignant skin tumors. TopicalTopical
In medicine, a topical medication is applied to body surfaces such as the skin or mucous membranes such as the vagina, anus, throat, eyes and ears.Many topical medications are epicutaneous, meaning that they are applied directly to the skin...
immunotherapy utilizes an immune enhancement cream (imiquimod
Imiquimod
Imiquimod is a prescription medication that acts as an immune response modifier. It is marketed by Meda AB, Graceway Pharmaceuticals and iNova Pharmaceuticals under the trade names Aldara and Zyclara, and by Mochida as Beselna. It is also referred to as R-837.- History :The original FDA approval...
) which is an interferon
Interferon
Interferons are proteins made and released by host cells in response to the presence of pathogens—such as viruses, bacteria, or parasites—or tumor cells. They allow communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors.IFNs belong to...
producer causing the patient's own killer T cells to destroy wart
Wart
A wart is generally a small, rough growth, typically on a human’s hands or feet but often other locations, that can resemble a cauliflower or a solid blister. They are caused by a viral infection, specifically by human papillomavirus 2 and 7. There are as many as 10 varieties of warts, the most...
s, actinic keratoses, basal cell carcinoma
Basal cell carcinoma
Basal-cell carcinoma is the most common type of skin cancer. It rarely metastasizes or kills. However, because it can cause significant destruction and disfigurement by invading surrounding tissues, it is still considered malignant. Statistically, approximately 3 out of 10 Caucasians may develop a...
, squamous cell carcinoma
Squamous cell carcinoma
Squamous cell carcinoma , occasionally rendered as "squamous-cell carcinoma", is a histologically distinct form of cancer. It arises from the uncontrolled multiplication of malignant cells deriving from epithelium, or showing particular cytological or tissue architectural characteristics of...
, cutaneous T cell lymphoma
Cutaneous T Cell lymphoma
Cutaneous T cell lymphoma is a class of non-Hodgkin's lymphoma, which is a type of cancer of the immune system. Unlike most non-Hodgkin's lymphomas , CTCL is caused by a mutation of T cells. The malignant T cells in the body initially migrate to the skin, causing various lesions to appear...
, and Superficial spreading melanoma
Superficial spreading melanoma
Superficial spreading melanoma is usually characterized as the most common form of cutaneous melanoma in Caucasians...
. Injection immunotherapy uses mumps
Mumps
Mumps is a viral disease of the human species, caused by the mumps virus. Before the development of vaccination and the introduction of a vaccine, it was a common childhood disease worldwide...
, candida
Candida (genus)
Candida is a genus of yeasts. Many species are harmless commensals or endosymbionts of animal hosts including humans, but other species, or harmless species in the wrong location, can cause disease. Candida albicans can cause infections in humans and other animals, especially in immunocompromised...
or trichophytin antigen injections to treat warts (HPV induced tumors).
Natural products
Some types of natural products have shown promise to stimulate the immune system. Research suggests that mushrooms like Reishi and Agaricus blazeiAgaricus blazei
Agaricus subrufescens is a species of mushroom, commonly known as almond mushroom, mushroom of the sun, God's mushroom, mushroom of life, royal sun agaricus, jisongrong or himematsutake and by a number of other...
may be able to stimulate the immune system. Research has shown that Agaricus blazei
Agaricus blazei
Agaricus subrufescens is a species of mushroom, commonly known as almond mushroom, mushroom of the sun, God's mushroom, mushroom of life, royal sun agaricus, jisongrong or himematsutake and by a number of other...
may be a potent stimulator of natural killer cells.
Agaricus blazei
Agaricus blazei
Agaricus subrufescens is a species of mushroom, commonly known as almond mushroom, mushroom of the sun, God's mushroom, mushroom of life, royal sun agaricus, jisongrong or himematsutake and by a number of other...
is rich in proteoglucans and beta-glucans, which are potent stimulators of macrophages.
Research on the compounds in medicinal mushrooms
Medicinal mushrooms
Medicinal mushrooms are mushrooms, or mushroom extracts, that are used or studied as possible treatments for diseases. Lentinula edodes , Grifola frondosa , Ganoderma lucidum , and Cordyceps, have a history of medicinal use spanning millennia in parts of Asia...
most responsible for up-regulating the immune system and providing an anti-cancer effect, are a diverse collection of polysaccharide
Polysaccharide
Polysaccharides are long carbohydrate molecules, of repeated monomer units joined together by glycosidic bonds. They range in structure from linear to highly branched. Polysaccharides are often quite heterogeneous, containing slight modifications of the repeating unit. Depending on the structure,...
compounds, particularly beta-glucans. Beta-glucans are known as "biological response modifiers", and their ability to activate the immune system is well documented. Specifically, beta-glucans stimulate the innate
Innate immune system
The innate immune system, also known as non-specific immune system and secondary line of defence, comprises the cells and mechanisms that defend the host from infection by other organisms in a non-specific manner...
branch of the immune system. Research has shown beta-glucans have the ability to stimulate macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
, NK cells, T cells, and immune system cytokines. The mechanisms in which beta-glucans stimulate the immune system is only partially understood. One mechanism in which beta-glucans are able to activate the immune system, is by interacting with the Macrophage-1 antigen (CD18
CD18
Integrin beta-2 is a protein that in humans is encoded by the ITGB2 gene.It is the beta subunit of four different structures:* LFA-1 * Macrophage-1 antigen * Integrin alphaXbeta2...
) receptor on immune cells.
Highly purified compounds isolated from medicinal mushrooms such as lentinan
Lentinan
Lentinan is a beta-glucan with a glycosidic β-1,3:β-1,6 linkage. It is an anti-tumor polysaccharide from the shiitake mushroom. Lentinan is a polysaccharide that has a molecular weight of approximately 500,000 Da...
(isolated from Shiitake
Shiitake
The Shiitake is an edible mushroom native to East Asia, which is cultivated and consumed in many Asian countries, as well as being dried and exported to many countries around the world. It is a feature of many Asian cuisines including Vietnamese, Chinese, Japanese, Korean and Thai...
), and Polysaccharide-K
Polysaccharide-K
Polysaccharide-K is a protein-bound polysaccharide, which is used as an immune system boosting agent in the treatment of cancer in some countries in Europe as well as China and Japan. In Japan, PSK is approved as an adjuvant for cancer therapy and is covered by government health insurance...
, (isolated from Trametes versicolor
Trametes versicolor
Trametes versicolor — formerly known as Coriolus versicolor and Polyporus versicolor — is an extremely common polypore mushroom which can be found throughout the world. Versicolor means 'of several colours' and it is true that this mushroom is found in a wide variety of different colours. T...
), have become incorporated into the health care system of a few countries, such as Japan
Japan
Japan is an island nation in East Asia. Located in the Pacific Ocean, it lies to the east of the Sea of Japan, China, North Korea, South Korea and Russia, stretching from the Sea of Okhotsk in the north to the East China Sea and Taiwan in the south...
. Japan's Ministry of Health, Labour and Welfare
Ministry of Health, Labour and Welfare (Japan)
The ' is a cabinet level ministry of the Japanese government. It is commonly known as Kōrō-shō in Japan. This ministry provides regulations on maximum residue limits for agricultural chemicals in foods, basic food and drug regulations, standards for foods, food additives, etc.It was formed with...
approved the use of Polysaccharide-K
Polysaccharide-K
Polysaccharide-K is a protein-bound polysaccharide, which is used as an immune system boosting agent in the treatment of cancer in some countries in Europe as well as China and Japan. In Japan, PSK is approved as an adjuvant for cancer therapy and is covered by government health insurance...
in the 1980s, to stimulate the immune systems of patients undergoing chemotherapy. In Australia
Australia
Australia , officially the Commonwealth of Australia, is a country in the Southern Hemisphere comprising the mainland of the Australian continent, the island of Tasmania, and numerous smaller islands in the Indian and Pacific Oceans. It is the world's sixth-largest country by total area...
, a pharmaceutical based on a mixture of several mycological extracts including lentinan and Polysaccharide-K is sold commercially as MC-S.
See also
- Antigen 5T4
- Cancer vaccineCancer vaccineThe term cancer vaccine refers to a vaccine that either prevents infections with cancer-causing viruses, treats existing cancer or prevents the development of cancer in certain high risk individuals...
- ImmunotherapyImmunotherapyImmunotherapy is a medical term defined as the "treatment of disease by inducing, enhancing, or suppressing an immune response". Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies. While immunotherapies that reduce or suppress are...
- Coley's ToxinsColey's ToxinsColey's toxins is a mixture consisting of killed bacteria of species Streptococcus pyogenes and Serratia marcescens, named after William Coley, a surgical oncologist who developed the mixture in the late 19th century as a treatment for cancer.- History :Observations of...
- Tumor antigenTumor antigenTumor antigen is an antigenic substance produced in tumor cells, i.e., it triggers an immune response in the host. Tumor antigens are useful in identifying tumor cells and are potential candidates for use in cancer therapy.- Mechanism of tumor antigenesis:...