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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.
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 involving Natural Killer Cells (NK) cells and cytotoxic T Lymphocytes(CTLs) is being practised in various Asian Countries especially in Japan and Malaysia. In addition, a method derived from the adoptive cell based therapy ideas begun by Rosenberg et al. called ALECSAT is currently undergoing phase I clinical trials in Denmark. mRNA -based cancer immunotherapy is currently investigated by a company called CureVac. This novel class of therapies induces a balanced immune response after being injected into the skin (intradermally) and taken up by antigen-presenting cells, such as dendritic cells. They are currently being evaluated in an international Phase 2b trial in patients with castration-resistant prostate cancer.
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:
- Naked mAbs are antibodies that work by themselves. There is no drug or radioactive material attached to them. These are the most commonly used mAbs at this time.
- Conjugated mAbs are those joined to a chemotherapy drug, radioactive particle, or a toxin (a substance that poisons cells). These mAbs work, at least in part, by acting as homing devices to take these substances directly to the cancer cells.
Conjugated mAbs are also sometimes referred to as tagged, labeled, or loaded antibodies. They can be divided into groups depending on what they are linked to.
- mAbs with radioactive particles attached are referred to as Radiolabeled, and treatment with this type of antibody is known as radioimmunotherapy (RIT).
- mAbs with chemotherapy drugs attached are referred to as Chemolabeled.
- mAbs attached to cell toxins are called Immunotoxins.
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||Campath||2001||humanized||CD52||Chronic lymphocytic leukemia|
|Bevacizumab||Avastin||2004||humanized||vascular endothelial growth factor||colorectal cancer|
|Brentuximab vedotin||Adcetris||2011||chimeric||CD30||Hodgkin lymphoma, Anaplastic large-cell lymphoma|
|Cetuximab||Erbitux||2004||chimeric||epidermal growth factor receptor||colorectal cancer|
|Gemtuzumab ozogamicin||Mylotarg||2000||humanized||CD33||acute myelogenous leukemia (with calicheamicin)|
|Ibritumomab tiuxetan||Zevalin||2002||murine||CD20||non-Hodgkin lymphoma (with yttrium-90 or indium-111)|
|Panitumumab||Vectibix||2006||human||epidermal growth factor receptor||colorectal cancer|
|Rituximab||Rituxan, Mabthera||1997||chimeric||CD20||non-Hodgkin lymphoma|
Alemtuzumab 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 lymphocytes and monocytes. 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.
Bevacizumab 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.
Cetuximab 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, none of the agents are currently beyond phase I clinical trials.
Gemtuzumab ozogamicin 
Gemtuzumab ozogamicin 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.
Rituximab 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 primates 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%.
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. 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.
Radioimmunotherapy 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 tiuxetan 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.
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. Clinical trials have established the efficacy of a sequential application of tositumomab and iodine (131I) tositumomab in patients with relapsed follicular lymphoma.
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 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 (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.
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. 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. This has encouraged development of PD-L1 blockers (a type of immune checkpoint blockade) which As of April 2013[update] have started clinical trials.
Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to achieve US FDA approval. Ipilimumab was approved by US FDA for melanoma in 2011.
Natural products 
Some types of natural products have shown promise to stimulate the immune system. Research suggests that mushrooms like Reishi and Agaricus subrufescens, (often mistakenly called Agaricus blazei) may be able to stimulate the immune system. Research has shown that Agaricus subrufescens may be a potent stimulator of natural killer cells. Agaricus subrufescens 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.
See also 
- Autologous Immune Enhancement therapy for Cancer
- Association for Immunotherapy of Cancer
- Society for Immunotherapy of Cancer
- Cancer Immunotherapy Consortium
- Cancer Immunotherapy Explained
- Immunotherapy Information
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