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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 cells 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 antigens 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 neuronal 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, medulloblastomas, astrocytomas, melanomas, small-cell lung cancer, osteosarcomas and other soft tissue sarcomas. 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.^[1]^[2]

History

Cancer immunotherapy has arisen from advances in both oncology and immunology fields over the last few centuries. Immunotherapy began in 1796 when Edward Jenner produced the first vaccine involving immunisation with cowpox to prevent smallpox. Towards the end of the 19th century Emil von Behring and Shibasabo Kitasato discovered that injecting animals with diphtheria toxin produced blood serum with anti-toxins to it. Following this Paul Ehrlich's research gave rise to the "magic bullet" concept; using antibodies to specifically target a disease. The production of pure monoclonal antibodies for therapeutic use was not available until 1975 when Georges J. F. Köhler and Cesar Milstein produced the hybridoma technology, although it wasn't until 1997 when Rituximab, the first antibody treatment for cancer, was approved by the FDA for treatment of follicular lymphoma. Since this approval, 11 other antibodies have been approved for cancer; Trastuzumab (1998), Gemtuzumab ozogamicin (2000), Alemtuzumab (2001), Ibritumomab tiuxetan (2002), Tositumomab (2003), Cetuximab (2004), Bevacizumab (2004), Panitumumab (2006), Ofatumumab (2009), Ipilimumab (2011) and Brentuximab vedotin (2011). The production of vaccines for cancer came later than the use of monoclonal antibodies. As our understanding of human immunology has improved, so has our potential to produce effective cancer vaccines. The first cell-based immunotherapy cancer vaccine, Sipuleucel-T, was approved in 2010 for the treatment of prostate cancer.^[3]^[4]

Cell-Based immunotherapy

Adoptive T-cell therapy

Adoptive T-cell therapy is form of passive immunization by the transfusion of T-cells, which are cells of the immune system. They are found in blood and tissue and usually activate when they find foreign pathogens. Specifically they activate when the T-cell's surface receptors encounter other cells that display small parts of foreign proteins on their surface MHC molecules, known as antigens. These can be either infected cells, or specialised immune cells known as antigen presenting cells (APCs). They are found in normal tissue and in tumor tissue, where they are known as tumor infiltrating lymphocytes (TILs). They are activated by the presence of APCs, such as dendritic cells that present tumor antigens to the T-cells. Although these cells have the capability of attacking the tumor, the environment within the tumor is highly immunosuppressive, preventing immune-mediated tumour death. There are multiple ways of producing and obtaining tumour targeted T-cells. T-cells specific to a tumor antigen can either be removed from a tumor sample (TILs) or T-cells can be removed from the blood and genetically engineered to be tumor specific. Subsequent activation and expansion of these cells is performed outside the body (ex vivo) and then they are transfused into the recipient. Although research has made major advances in this form of therapy, there is no approved adoptive T-cell therapy as yet.^[5]^[6]

The tumor specific T-cells used for treatment will be specific for a particular antigen present within the tumor, or for the stroma or vasculature, which the tumor may be dependent on. Examples of T-cell targets are tissue differentiation antigens, mutant protein antigens, oncogenic viral antigens, cancer-testis antigens and vascular or stromal specific antigens. Tissue differentiation antigens are those that are specific to a certain type of tissue. T-cells specific to these antigens will target normal cells that contain these antigens as well as cancer cells (e.g. carcinoembryonic antigen; CEA). Mutant protein antigens are likely to be much more specific to cancer cells because normal cells shouldn't contain these proteins. Normal cells will display the normal protein antigen on their MHC molecules, whereas cancer cells will display the mutant version. T-cells can differentiate between these two, selectively targeting the cancer cell. Some viral proteins are implicated in forming cancer (oncogenesis), and therefore T-cells that are specific to viral antigens can be used to attack infected cells (which will include cancer cells). Cancer-testis antigens are antigens expressed primarily in the germ cells of the testes, but also in fetal ovaries and the trophoblast. Some cancer cells aberrantly express these proteins and therefore present these antigens, allowing attack by T-cells specific to these antigens. Example antigens of this type are CTAG1B and MAGEA1.^[6]

Dendritic cell therapy

Dendritic cell therapy comprises a group of methods that provoke anti-tumor responses by causing dendritic cells to present tumor antigens. Dendritic cells present antigens to lymphocytes, which activates them, priming them to kill cells which also present the antigen. They are utilised in cancer treatment to specifically target cancer antigens.^[7] This group of cell-based therapy boasts the only approved treatment for cancer, Sipuleucel-T.

One method of inducing dendritic cells to present tumor antigens is by vaccination with short peptides (small parts of protein that correspond to the protein antigens on cancer cells). These peptides on their own do not stimulate a strong immune response and may be given in combination with highly immunogenic substances known as adjuvants. This provokes a strong response to the adjuvant being used, while also producing a (sometimes) robust anti-tumor response by the immune system. Other adjuvants being used are proteins or other chemicals that attract and/or activate dendritic cells, such as granulocyte macrophage colony-stimulating factor (GM-CSF). Dendritic cells can also be activated within the body (in vivo) by making tumour cells to express (GM-CSF). This can be achieved by either genetically engineering tumor cells that produce GM-CSF or by infecting tumor cells with an oncolytic virus that expresses GM-CSF. Another strategy used in dendritic cell therapy is to remove dendritic cells from the blood of a person with cancer and activate them outside the body (ex vivo). The dendritic cells are activated in the presence of tumor antigens, which may be a single tumor specific peptide/protein or a tumor cell lysate (a solution of broken down tumor cells). These activated dendritic cells are put back into the body where they provoke an immune response to the cancer cells. Adjuvants are sometimes used systemically to increase the anti-tumor response provided by ex vivo activated dendritic cells. More modern dendritic cell therapies include the use of antibodies that bind to receptors on the surface of dendritic cells. Antigens can be added to the antibody and can induce the dendritic cells to mature and provide immunity to the tumor. Dendritic cell receptors such as TLR3, TLR7, TLR8 or CD40 have been used as targets by antibodies to produce immune responses.^[7]

Sipuleucel-T

Sipuleucel-T (Provenge) is the first approved cancer vaccine. It was approved for treatment of asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer in 2010. The treatment consists of removal of antigen presenting cells from blood by leukapheresis, and growing them with the fusion protein PA2024 made from GM-CSF and prostatic acid phosphatase (PAP). These cells are infused back into the recipient to induce an immune response against the tumor because the PAP protein is prostate specific. This process is repeated three times.^[8]^[9]^[10]^[11]

Monoclonal antibody therapy

Antibodies 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.

Types of monoclonal antibodies

Two types of monoclonal antibodies are used in cancer treatments:^[12]

Naked monoclonal antibodies are antibodies without modification. Most of the currently used antibodies therapies fall into this category.
Conjugated monoclonal antibodies are joined to another molecule, which is either toxic to cells or radioactive. The toxic chemicals are usually routinely used chemotherapy drugs but other toxins can be used. The antibody binds to specific antigens on the surface of cancer cells and directs the drug or radiation to the tumor. Radioactive compound-linked antibodies are referred to as radiolabelled. If the antibodies are labelled with chemotherapy or toxins, they are known as chemolabelled or immunotoxins, respectively.

Antibodies are also referred to as murine, chimeric, humanized and human. Murine antibodies were the first type of antibody to be produced, and they carry a great risk of immune reaction by the recipient because the antibodies are from a different species. Chimeric antibodies were the first attempt to reduce the immunogenicity of these antibodies. They are murine antibodies with a specific part of the antibody replaced with the corresponding human counterpart, known as the constant region. Humanized antibodies are almost completely human; only the complementarity determining regions of the variable regions are derived from murine antibodies. Human antibodies have a completely human amino acid sequence.^[13]

Mechanisms of cell death

Antibody-dependent cell-mediated cytotoxicity (ADCC)

Antibody-dependent cell-mediated cytotoxicity (ADCC) is a mechanism of attack by the immune system that requires the presence of antibodies bound to the surface of target cells. Antibodies are formed of a binding region (Fab) and the Fc region that can be detected by immune cells via Fc receptors on their surface. These Fc receptors are found on the surface of many cells of the immune system, including natural killer cells. When a natural killer cells encounter cells coated with antibodies, the Fc regions interact with their Fc receptors, leading to the release of perforin and granzyme B. These two chemicals lead to the tumor cell initiating programmed cell death (apoptosis). Antibodies known to induce this method of cell killing include Rituximab, Ofatumumab, Trastuzumab, Cetuximab and Alemtuzumab. Third generation antibodies that are currently being developed have altered Fc regions that have higher affinity for a specific type of Fc receptor, FcγRIIIA, which can increase the rate of ADCC dramatically.^[14]^[15]

Complement

The complement system comprises a number of blood proteins that can cause cell death after an antibody binds to the cell surface (this is the classical complement pathway, other ways of complement activation do exist). Generally the system is employed to deal with foreign pathogens but can be activated by the use of therapeutic antibodies in cancer. The system can be triggered if the antibody is chimeric, humanized or human; containing the IgG1 Fc region. Complement can lead to cell death by activation of the membrane attack complex, known as complement-dependent cytotoxicity; enhancement of antibody-dependent cell-mediated cytotoxicity; and CR3-dependent cellular cytotoxicity. Complement-dependent cytotoxicity occurs when antibodies bind to the cancer cell surface, the C1 complex binds to these antibodies and subsequently protein pores are formed in the cancer cell membrane.^[16]

Cell signalling

Antibodies that bind to molecules on the surface of the cancer cells, or bind to molecules in the blood can affect cell signalling in various ways. The antibodies can bind to a receptor and prevent binding from external proteins, peptides or small molecules that would normally bind to the receptor (called ligands). Receptors that have been extensively researched for antibody targeting are growth factor receptors (targeted by Cetuximab and Trastuzumab). Antibodies can also bind the ligands themselves such as vascular endothelial growth factor (VEGF); involved in blood vessel formation. Bevacizumab is a clinically used antibody that binds VEGF. These receptor-ligand interactions may be essential for the cancer cell to survive, so blocking them can induce the death of these cancer cells. Antibodies like these are known as antagonists, but antibodies can also activate signalling by binding to receptors, then they are known as agonists. One signalling pathway that is activated by antibodies is the programmed cell death (apoptosis) pathway.^[12]

Payload

Conjugated antibodies carry a payload that is either a drug (usually a chemotherapeutic), toxin, small interfering RNA or radioisotope. Radioimmunotherapy is the term used with the use of antibodies conjugated to a radioisotope against cellular antigens. Most research currently involves their application to lymphomas, as these are highly radio-sensitive malignancies.^[17] Out of the 12 approved antibodies used in cancer, two use toxic compounds (Gemtuzumab ozogamicin - calicheamicin and Brentuximab vedotin - monomethyl auristatin E) and two are radiolabelled (Tositumomab - ¹³¹I and Ibritumomab tiuxetan - ⁹⁰Y). These antibodies specifically bind to their targets on the surface of cancer cells and the payloads they are attached to lead to cancer cell death.^[12]

Approved antibodies

**Cancer immunotherapy:Monoclonal antibodies**^[12]^[18]
Antibody	Brand name	Type	Target	Approval date	Approved treatment(s)
Alemtuzumab	Campath	humanized	CD52	2001	B-cell Chronic lymphocytic leukemia (CLL)^[19]
Bevacizumab	Avastin	humanized	vascular endothelial growth factor	2004	metastatic colorectal cancer ^[20]
				2006	non-small cell lung cancer^[21]
				2009	renal cell carcinoma^[22]
				2009	glioblastoma multiforme^[23]
Brentuximab vedotin	Adcetris	chimeric	CD30	2011	relapsed Hodgkin lymphoma^[24]
Brentuximab vedotin	Adcetris	chimeric	CD30	2011	relapsed Anaplastic large-cell lymphoma^[24]
Cetuximab	Erbitux	chimeric	epidermal growth factor receptor	2004	colorectal cancer^[25]
				2006	advanced squamous cell carcinoma of the head and neck (SCCHN)^[25]
				2011	recurrent locoregional or metastatic squamous cell head and neck cancer^[26]
				2012	EGFR-expressing metastatic colorectal cancer^[25]
Gemtuzumab ozogamicin	Mylotarg	humanized	CD33	2000	acute myelogenous leukemia (with calicheamicin)^[27]
Ibritumomab tiuxetan	Zevalin	murine	CD20	2002	non-Hodgkin lymphoma (with yttrium-90)^[28]
Ipilimumab	Yervoy	human	CTLA4	2011	metastatic melanoma^[29]
Ofatumumab	Arzerra	human	CD20	2009	refractory CLL^[30]
Panitumumab	Vectibix	human	epidermal growth factor receptor	2006	metastatic colorectal cancer^[31]
Rituximab	Rituxan, Mabthera	chimeric	CD20	1997	non-Hodgkin lymphoma^[32]
Rituximab	Rituxan, Mabthera	chimeric	CD20	2010	CLL^[33]
Tositumomab	Bexxar	murine	CD20	2003	Non-Hodgkin lymphoma^[34]
Trastuzumab	Herceptin	humanized	ErbB2	1998	breast cancer^[35]

Alemtuzumab

Alemtuzumab (Campeth-1H) is an anti-CD52 humanized IgG1 monoclonal antibody indicated for the treatment of fludarabine-refractory chronic lymphocytic leukemia (CLL), cutaneous T-cell lymphoma, peripheral T-cell lymphoma and T-cell prolymphocytic leukemia. CD52 is found on >95% of peripheral blood lymphocytes (both T-cells and B-cells) and monocytes, but its function in lymphocytes is unknown. Upon binding to CD52, alemtuzumab initiates its cytotoxic effect by complement fixation and antibody-dependent cell-mediated cytotoxicity mechanisms. Due to the antibody target (cells of the immune system) common complications of alemtuzumab therapy are infection, toxicity and myelosuppression.^[36]^[37]^[38]^[39]

Bevacizumab

Bevacizumab (Avastin) is a humanized IgG1 monoclonal antibody which binds to vascular endothelial growth factor-A (VEGF-A), referred to commonly as VEGF without a suffix. Normally VEGF will bind to the VEGF-receptor on the cell's surface, activating signalling pathways within blood vessel endothelial cells. A marked increase in VEGF expression within the tumor environment stimulates the production of blood vessels, a process known as angiogenesis, which is essential for growth of a tumor. These blood vessels, however, are not formed well and lead to poor blood flow in the tumor, which also affects drug delivery to cancer cells.^[40]^[41]^[42]

Bevacizumab binds to and physically blocks VEGF, preventing receptor activation, known as steric interference. Bevacizumab's action on VEGF has three possible effects on tumor vasculature: it may cause microvessels to regress; it can normalise tumor blood vessels, allowing better delivery of other drugs to the tumor; and it can prevent the formation of new vasculature. Normalisation of faulty vessels may be the reason why Bevacizumab is particularly effective in combination with conventional drugs.^[41]^[42]^[43]

Bevacizumab is licensed for colon cancer, kidney cancer, lung cancer, ovarian cancer, glioblastoma and breast cancer, although licenses may vary between countries. Bevacizumab increases the duration of survival, progression-free survival, the rate of response and the duration of response in these cancers, but because of its mechanism of action does not cure them.^[42]^[43]^[44]

Brentuximab vedotin

Brentuximab vedotin is a second generation chimeric IgG1 antibody drug conjugate used in the treatment of Hodgkin lymphoma and anaplastic large cell lymphoma (ALCL). It is an antibody conjugated to monomethyl auristatin E, a drug that prevents cell division by disrupting microtubules. The antibody binds to CD30, often found highly expressed on the surface of Hodgkin lymphoma and ALCL cells, and is then internalised where the drug is detached from the antibody and exerts its cellular effects. By preventing cell division it kills cancer cells by the induction of programmed cell death.^[45]^[46]

Cetuximab

Cetuximab (Erbitux) is a chimeric IgG1 monoclonal antibody that targets the extracellular domain (part of the receptor outside the cell) of the epidermal growth factor receptor (EGFR). It is used in the treatment of colorectal cancer and head and neck cancer. Once a ligand binds to the EGFR on the surface of the cell, signalling pathways are activated inside the cell that are associated with malignant characteristics. These include the PI3K/AKT and KRAS/BRAF/MEK/ERK pathways that cause cancer cell proliferation, invasion, differentiation and cancer stem cell renewal.^[39]^[44]^[47]

Cetuximab functions by competitively inhibiting ligand binding, thereby preventing EGFR activation and subsequent cellular signalling. It also induces ADCC and leads to increased levels of a protein known as Bax, which activates programmed cell death (apoptosis). KRAS, a down-stream protein of the EGFR, may be mutated in some cases of cancer and remains constitutively active, irrespective of EGFR blocking. Cetuximab is only effective in the treatment of colorectal cancers with wild-type (unmutated) KRAS genes, which includes approximately 40% of cases.^[39]^[44]

Other anti-EGFR monoclonal antibodies in development include: ABX-EGF, hR3, and EMD 72000. Although they hold significant promise for the future, none of the agents are currently beyond phase I clinical trials.

Gemtuzumab ozogamicin

Gemtuzumab ozogamicin is an “immuno-conjugate” of an IgG4 anti-CD33 antibody chemically linked to a cytotoxic calicheamicin derivative.^[48] It was used for the treatment of acute myeloid leukaemia (AML) after accelerated approval by the Food and Drug Administration in May 2000, but in June 2010 it was withdrawn from the market regarding safety concerns.^[49] Further research and clinical trials indicate that gemtuzumab ozogamicin might be safe and effective in a subset of AML with favourable prognoses.^[50]

The antibody binds to the CD33 antigen, which is found on the surface of immature precursor cells (myeloblasts) in AML in approximately 80% of cases. The antibody is liked to a chemical derivative of calicheamicin, (N-acetyl-γ calicheamicin 1,2-dimethyl hydrazine dichloride) which is highly toxic to cells due to its ability to bind to DNA. Because the antibody is an IgG4 isotype, it doesn't activate antibody-dependent cell-mediated cytotoxicity or complement-mediated cytotoxicity, but instead is internalised into the cancer cells. Inside lysozomes within the cell, the pH is very acidic (approximately pH 4) causing the release of the calicheamicin from the antibody. Once released it is activated and free to bind to DNA, which leads to breakage of DNA and subsequent cell death.^[48]

Ibritumomab tiuxetan

Ibritumomab tiuxetan (Zevalin) is a murine anti-CD20 antibody chemically linked to a chelating agent that binds the radioisotope yttrium-90 (⁹⁰Y). It is used to treat a specific type of non-Hodgkin lymphoma, follicular lymphoma, which is a tumor of B-cells. The antibody target, CD20, is primarily expressed on the surface of B-cells which allows the ⁹⁰Y to emit a targeted dose of beta radiation to the tumor. ⁹⁰Y has a half-life of 64 hours (2.67 days) and a tissue penetration of 1-5 millimetres (90% of its energy is absorbed within a 5.3mm sphere). Ibritumomab tiuxetan and the radioisotope are obtained separately and mixed shortly before administration. The tiuxetan chelating agent attached to the antibody binds the radioisotope forming the active drug.^[51]^[52]

Ipilumumab

Ipilimumab (Yervoy) is a human IgG1 antibody that binds the surface protein CTLA4. In normal physiology T-cells are activated by two signals: the T-cell receptor binding to and antigen-MHC complex and T-cell surface receptor CD28 binding to CD80 or CD86 on the surface of antigen presenting cells. CTLA4 binds to CD80 or CD86, preventing the binding of CD28 to these surface proteins and therefore negatively regulating the activation of T-cells.^[53]^[54]^[55]^[56]

Active cytotoxic T-cells are required for the immune system to attack melanoma cells. By blocking CTLA4 with ipilumumab, active melanoma-specific cytotoxic T-cells that would normally be inhibited can produce an effective anti-tumor response. Also, ipilumumab can cause a shift in the ratio of regulatory T-cells to cytotoxic T-cells. Regulatory T-cells inhibit other T-cells, which may act to the benefit of the tumor so increasing the amount of cytotoxic T-cells and decreasing the regulatory T-cells is another mechanism in which ipilumumab increases the anti-tumor response.^[53]^[54]^[55]^[56]

Ofatumumab

Ofatumumab is a second generation human IgG1 antibody that binds to CD20. It is used in the treatment of chronic lymphocytic leukemia (CLL) because the cancerous cells of CLL are usually CD20-expressing B-cells. Unlike Rituximab, which binds to a large loop of the CD20 protein, Ofatumumab binds to a separate small loop. This may be the reason for the two drug's different characteristics. Compared to Rituximab, Ofatumumab induces complement-dependent cytotoxicity at a lower dose and has less immunogenicity.^[57]^[58]

Panitumumab

Panitumumab (Vectibix) is a human IgG2 antibody that binds to the EGF receptor. Like Cetuximab, it prevents cell signalling by the receptor by blocking the interaction between the receptor and its ligand. It is used in the treatment of colorectal cancer.^[59]^[60]

Rituximab

Rituximab is a chimeric monoclonal IgG1 antibody specific for CD20, developed from its parent antibody Ibritumomab. As with Ibritumomab, Rituximab targets CD20, which is present on a specific type of immune cells called B-cells. For this reason it is effective in treating certain types of malignancies that are formed from cancerous B-cells. These include aggressive and indolent lymphomas such as diffuse large B-cell lymphoma and follicular lymphoma, and leukaemias such as B-cell chronic lymphocytic leukaemia. Although the function of CD20 is relatively unknown it has been suggested that CD20 could be a calcium channel involved in the activation of B-cells. The antibody's mode of action is primarily through the induction of antibody-dependent cell-mediated cytotoxicity and complement-mediated cytotoxicity but other mechanisms have been found. These include activation of apoptosis and cellular growth arrest. Rituximab also increases the sensitivity of cancerous B-cells to chemotherapy.^[61]^[62]^[63]^[64]^[65]^[66]

Tositumomab/iodine (¹³¹I) tositumomab regimen

Tositumomab 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.^[67] Clinical trials have established the efficacy of a sequential application of tositumomab and iodine (¹³¹I) tositumomab in patients with relapsed follicular lymphoma.^[68]

Trastuzumab

Trastuzumab 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.^[69] 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.^[70]

Cytokine therapy

Cytokines are a broad group of proteins produced by many types of cells present within a tumor. They have the ability to modulate immune responses and are often utilised by the tumor to allow it to grow and manipulate the immune response. These immune-modulating effects allow them to be used as drugs to provoke an immune response against the tumor. Two commonly used groups of cytokines are the ppinterferon]]s and interleukins.^[71]

Interferon

Interferons are cytokines produced by the immune system usually involved in anti-viral response, but also have use in the treatment of cancer. There are three groups of interferons (IFNs): type I (IFNα and IFNβ), type 2 (IFNγ) and the relatively newly discovered type III (IFNλ). IFNα has been approved for use in hairy-cell leukaemia, AIDS-related Kaposi's sarcoma, follicular lymphoma, chronic myeloid leukaemia and melanoma. Type I and II IFNs have been researched extensively and although both types promote the anti-tumor effects of the immune system, only type I IFNs have been shown to be clinically effective in cancer treatment. IFNλ has been tested for its anti-tumor effects in animal models, and shows promise.^[72]^[73]

Interleukins

Interleukins are a group of cytokines with a wide array of effects on the immune system. Interleukin-2 is used in the treatment of malignant melanoma and renal cell carcinoma. In normal physiology it promotes both effector T cells (cells that produce the immune response) and T-regulatory cells (cells that repress the immune response), but its exact mechanism in the treatment of cancer is unknown.^[71]^[74]

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 immunosuppressive, 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 cytokines, 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 effects 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 deliver 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 (an antibody-drug conjugate). 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.^[75]

Anti-CD47 antibodies, which block the protein CD47 from telling the cancer's host human immune system not to attack it, have been shown to eliminate or inhibit the growth of a wide range of cancers and tumors because CD47 is present on all known cancer cells (it is also present on many healthy cells of the body). After the cancer cells have been engulfed by macrophages, the host immune system's CD8+ T Cells become mobilized against the cancer and attack it on their own in addition to the macrophages, producing a personalized attack on virtually any form of cancer. When the immunotherapy technique was tested on human tumors transplanted in to mice, it stopped the spread of cancer 90 percent of the time and often eliminated all signs of the cancer. Phase 1 human trials are set to begin in 2014.^[76]^[77]

Immune checkpoint blockade

It appears that upregulation of PD-L1 may allow cancers to evade the host immune system. PD-L1 on the tumor cell surface inhibits T cells that might otherwise attack the tumor cell. An analysis of 196 tumor specimens from patients with Renal cell carcinoma found that high tumor expression of PD-L1 was associated with increased tumor aggressiveness and a 4.5-fold increased risk of death.^[78] Ovarian cancer patients with higher expression of PD-L1 had a significantly poorer prognosis than those with lower expression. PD-L1 expression correlated inversely with intraepithelial CD8+ T-lymphocyte count, suggesting that PD-L1 on tumor cells may suppress antitumor CD8+ T cells.^[79] This has encouraged development of PD-L1 blockers (a type of immune checkpoint blockade) which As of April 2013^[update] have started clinical trials.^[80]

Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to achieve US FDA approval.^[81] Ipilimumab was approved by US FDA for melanoma in 2011.

Natural products

Plants, fungi, bacteria and marine organisms are potential sources of anti-cancer drugs. Plants and bacteria have been the most successful sources of drugs, which include anthracycline, the taxanes and vinca alkaloids. These drugs intercalate DNA and are known as cytotoxic drugs. In addition to these kinds of drugs, natural products are also known to stimulate the immune system, which can be utilised in the treatment of cancer.^[82]

Certain compounds in medicinal mushrooms, primarily polysaccharide compounds, can up-regulate the immune system and have anti-cancer properties. Beta-glucans, such as lentinan, 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.^[83] Agaricus subrufescens, (often mistakenly called Agaricus blazei), Lentinula edodes (Shiitake mushrooom), Grifola frondosa and Hericium erinaceus are fungi known to produce beta-glucans and have been tested for their anti-cancer potential.^[82] Polysaccharide-K, isolated from Trametes versicolor, is another polysaccharide that has anti-cancer properties.^[84]^[85]

Japan's Ministry of Health, Labour and Welfare approved the use of Polysaccharide-K (produced by Coriolus versicolor) in the 1980s, to stimulate the immune systems of patients undergoing chemotherapy.^[85] In Australia, a pharmaceutical based on a mixture of several mycological extracts including lentinan and Polysaccharide-K is sold commercially as MC-S.

Public awareness of the power of immunotherapy and latest developments

Starting with the FDA approval in 2010 of the therapeutic vaccine sipuleucel-T (Provenge) for prostate cancer and, in 2011, of ipilimumab (Yervoy) for melanoma, public awareness of cancer immunotherapy has increased thanks to a growing number of mainstream news articles covering this field of cancer therapy.^[86]^[87]^[88]^[89] In light of these developments, in 2013 the Cancer Research Institute, a nonprofit organization dedicated to cancer immunotherapy, proclaimed June Cancer Immunotherapy Awareness Month.^[90] The goal of this month is to raise public awareness of the potential for immunotherapy to transform cancer treatment as well as the need for the public to support research to bring immunotherapies to more cancer patients sooner.

The new PD-1 blockader drugs Nivolumab (BMS-936558 MDX-1106 ONO-4538) and MK-3475 (Lambrolizumab) from Merck seem to cure a large percentage of advanced cancers outright. Unfortunately not all cancer types and patients respond. The early Trials in 2011 found that patients with lung cancer, all renal cancer and melanoma fared better with nearly 25% being cured. Further types of cancer, such as gastric cancer are being added to this list. Never has a single agent been so effective. The side effects are minimal, apart from some auto-immune incidents. People with a history of auto-immune illness may not benefit.

It is possible that similar blockaders taken in combination or sequence could cure a mojority of cancer patients. The cancer has to dupe the immune system to survive in the body. In order to do this it communicates through pathways to the immune system, limiting or disabling it. Each blockader stops communication on one or more pathways. If all pathways are blocked, the immune system should destroy the cancer. Several pathways can be blocked today.

External links

References

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[1] "Elevated TB risk seen with anti-TNF antibody therapy - The Doctor's Channel". Thedoctorschannel.com. Retrieved 2013-08-25.

[2] "Tuberculosis Guidelines". Brit-thoracic.org.uk. Retrieved 2013-08-25.

[3] Strebhardt, K (June 2008). "Paul Ehrlich's magic bullet concept: 100 years of progress". Nature reviews. Cancer. 8 (6): 473–80. doi:10.1038/nrc2394. PMID 18469827. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

[4] Waldmann, TA (March 2003). "Immunotherapy: past, present and future". Nature Medicine. 9 (3): 269–77. doi:10.1038/nm0303-269. PMID 12612576.

[5] June, CH (June 2007). "Adoptive T cell therapy for cancer in the clinic". The Journal of Clinical Investigation. 117 (6): 1466–76. doi:10.1172/JCI32446. PMC 1878537. PMID 17549249.

[pmid2243739-6] Restifo, NP (Mar 22, 2012). "Adoptive immunotherapy for cancer: harnessing the T cell response". Nature reviews. Immunology. 12 (4): 269–81. doi:10.1038/nri3191. PMID 22437939. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

[pmid23890062-7] Palucka, K (Jul 25, 2013). "Dendritic-cell-based therapeutic cancer vaccines". Immunity. 39 (1): 38–48. doi:10.1016/j.immuni.2013.07.004. PMID 23890062. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

[8] Gardner, TA (April 2012). "Sipuleucel-T (Provenge) autologous vaccine approved for treatment of men with asymptomatic or minimally symptomatic castrate-resistant metastatic prostate cancer". Human vaccines & immunotherapeutics. 8 (4): 534–9. doi:10.4161/hv.19795. PMID 22832254. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

[9] Oudard, S (May 2013). "Progress in emerging therapies for advanced prostate cancer". Cancer treatment reviews. 39 (3): 275–89. doi:10.1016/j.ctrv.2012.09.005. PMID 23107383.

[10] Sims, RB (Jun 19, 2012). "Development of sipuleucel-T: autologous cellular immunotherapy for the treatment of metastatic castrate resistant prostate cancer". Vaccine. 30 (29): 4394–7. doi:10.1016/j.vaccine.2011.11.058. PMID 22122856.

[11] Shore, ND (January 2013). "Building on sipuleucel-T for immunologic treatment of castration-resistant prostate cancer". Cancer control : journal of the Moffitt Cancer Center. 20 (1): 7–16. PMID 23302902. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

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@@ Line 166: / Line 166: @@
 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 (cellular)|differentiation]].<ref>{{cite journal | pmid = 10376526 | author-separator =, | last1 = Jones | author-name-separator= | first1 = FE| doi=10.1038/sj.onc.1202698 | last2 = Stern | first2 = DF | title = Expression of dominant-negative ErbB2 in the mammary gland of transgenic mice reveals a role in lobuloalveolar development and lactation. | journal = Oncogene | volume=18 | issue=23 |date=June 1999 | pages=3481–90}}</ref> 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.<ref>{{cite journal | doi = 10.1126/science.2470152 | last1 = Slamon | first1 = DJ | last2 = Godolphin | first2 = W | last3 = Jones | first3 = LA | author-separator =, | last4 = Holt | author-name-separator= | first4 = JA| year = 1989 | last5 = Wong | first5 = SG | last6 = Keith | first6 = DE | last7 = Levin | first7 = WJ | last8 = Stuart | first8 = SG | last9 = Udove | first9 = J | last10 = Ullrich | first10 = A | last11 = Et | first11 = al. | title = Studies of the HER-2/neu proto oncogene in human breast and ovarian cancer | url = | journal = Science | volume = 244 | issue = 4905| pages = 707–712 | pmid = 2470152 | display-authors = 8 }}</ref>
+==Cytokine therapy==
-==Interferon==
-[[Interferon]]s are proteins produced by the immune system. There are three groups of [[interferon]]s (IFNs): [[Interferon type I|type I]] (IFNα and IFNβ), [[Interferon type II|type 2]] (IFNγ) and the relatively newly discovered [[type III interferon|type III]] (IFNλ). IFNα has been approved for use in [[hairy-cell leukaemia]], [[AIDS]]-related [[Kaposi's sarcoma]], [[follicular lymphoma]], [[chronic myeloid leukaemia]] and [[melanoma]]. Type I and II IFNs have been researched extensively and although both types promote the anti-tumor effects of the immune system, only type I IFNs have been shown to be clinically effective in cancer treatment. IFNλ has been tested for its anti-tumor effects in [[animal model]]s, and shows promise.<ref>{{cite journal|last=Dunn|first=GP|coauthors=Koebel, CM; Schreiber, RD|title=Interferons, immunity and cancer immunoediting.|journal=Nature reviews. Immunology|date=November 2006|volume=6|issue=11|pages=836–48|pmid=17063185|doi=10.1038/nri1961}}</ref><ref>{{cite journal|last=Lasfar|first=A|coauthors=Abushahba, W; Balan, M; Cohen-Solal, KA|title=Interferon lambda: a new sword in cancer immunotherapy.|journal=Clinical & developmental immunology|year=2011|volume=2011|pages=349575|pmid=22190970|doi=10.1155/2011/349575}}</ref>
+[[Cytokine]]s are a broad group of proteins produced by many types of cells present within a tumor. They have the ability to modulate immune responses and are often utilised by the tumor to allow it to grow and manipulate the immune response. These immune-modulating effects allow them to be used as drugs to provoke an immune response against the tumor. Two commonly used groups of cytokines are the ppinterferon]]s and [[interleukin]]s.<ref name="pmid14708024">{{cite journal|last=Dranoff|first=G|title=Cytokines in cancer pathogenesis and cancer therapy.|journal=Nature reviews. Cancer|date=2004 Jan|volume=4|issue=1|pages=11-22|pmid=14708024}}</ref>
+===Interferon===
+[[Interferon]]s are cytokines produced by the immune system usually involved in anti-viral response, but also have use in the treatment of cancer. There are three groups of [[interferon]]s (IFNs): [[Interferon type I|type I]] (IFNα and IFNβ), [[Interferon type II|type 2]] (IFNγ) and the relatively newly discovered [[type III interferon|type III]] (IFNλ). IFNα has been approved for use in [[hairy-cell leukaemia]], [[AIDS]]-related [[Kaposi's sarcoma]], [[follicular lymphoma]], [[chronic myeloid leukaemia]] and [[melanoma]]. Type I and II IFNs have been researched extensively and although both types promote the anti-tumor effects of the immune system, only type I IFNs have been shown to be clinically effective in cancer treatment. IFNλ has been tested for its anti-tumor effects in [[animal model]]s, and shows promise.<ref>{{cite journal|last=Dunn|first=GP|coauthors=Koebel, CM; Schreiber, RD|title=Interferons, immunity and cancer immunoediting.|journal=Nature reviews. Immunology|date=November 2006|volume=6|issue=11|pages=836–48|pmid=17063185|doi=10.1038/nri1961}}</ref><ref>{{cite journal|last=Lasfar|first=A|coauthors=Abushahba, W; Balan, M; Cohen-Solal, KA|title=Interferon lambda: a new sword in cancer immunotherapy.|journal=Clinical & developmental immunology|year=2011|volume=2011|pages=349575|pmid=22190970|doi=10.1155/2011/349575}}</ref>
+===Interleukins===
+[[Interleukin]]s are a group of cytokines with a wide array of effects on the immune system. [[Interleukin-2]] is used in the treatment of [[malignant melanoma]] and [[renal cell carcinoma]]. In normal physiology it promotes both [[effector T cell]]s (cells that produce the immune response)  and [[T-regulatory cell]]s (cells that repress the immune response), but its exact mechanism in the treatment of cancer is unknown.<ref name="pmid14708024"/><ref>{{cite journal|last=Coventry|first=BJ|coauthors=Ashdown, ML|title=The 20th anniversary of interleukin-2 therapy: bimodal role explaining longstanding random induction of complete clinical responses.|journal=Cancer management and research|date=2012|volume=4|pages=215-21|pmid=22904643}}</ref>
 ==Advances in immunotherapy==