Cancer immunotherapy is the use of the immune system to treat cancer. There are three main groups of immunotherapy used to treat cancer: cell-based therapies, antibody therapies and cytokine therapies. They all exploit the fact that cancer cells often have subtly different molecules on their surface that can be detected by the immune system. These molecules, known as cancer antigens, are most commonly proteins but also include other molecules such as carbohydrates. Immunotherapy is used to provoke the immune system into attacking the tumor cells by using these cancer antigens as targets.
Cell-based therapies, also known as cancer vaccines, usually involve the removal of immune cells from someone with cancer, either from the blood or from a tumor. Immune cells specific for the tumor will be activated, grown and returned to the person with cancer where the immune cells provoke an immune response against the cancer. Cell types that can be used in this way are natural killer cells, lymphokine-activated killer cells, cytotoxic T cells and dendritic cells. The only cell-based therapy currently approved for use is Dendreon's Provenge, which is used for the treatment of prostate cancer.
Antibody therapies are currently the most successful form of immunotherapy, with many approved treatments for a wide range of cancers. Antibodies are proteins produced by the immune system that bind to a target antigen on the surface of a cell. In normal physiology they are used by the immune system to fight pathogens. Each antibody is specific to one or a few proteins and those that bind to cancer antigens are used in the treatment of cancer. Cell surface receptors are common targets for antibody therapies and include the epidermal growth factor receptor and HER2. Once bound to a cancer antigen, antibodies can induce antibody-dependent cell-mediated cytotoxicity, activate the complement system, prevent a receptor interacting with its ligand or deliver a payload of chemotherapy or radiation, all of which can lead to cell death. There are twelve antibodies currently approved for the treatment of cancer: Alemtuzumab, Bevacizumab, Brentuximab vedotin, Cetuximab, Gemtuzumab ozogamicin, Ibritumomab tiuxetan, Ipilimumab, Ofatumumab, Panitumumab, Rituximab, Tositumomab and Trastuzumab.
Interleukin-2 and interferon-α are examples of cytokines, proteins that regulate and coordinate the behaviour of the immune system. They have the ability to enhance the anti-tumor activity of the immune system and thus can be used as treatments in cancer. Interferon-α is used in the treatment of hairy-cell leukaemia, AIDS-related Kaposi's sarcoma, follicular lymphoma, chronic myeloid leukaemia and malignant melanoma. Interleukin-2 is used in the treatment of malignant melanoma and renal cell carcinoma.
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.
Cell-Based immunotherapy
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. 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.
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.
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 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.
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.
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.
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.
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. 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.
Approved antibodies
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.
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.
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.
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.
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.
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.
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.
Gemtuzumab ozogamicin
Gemtuzumab ozogamicin is an “immuno-conjugate†of an IgG4 anti-CD33 antibody chemically linked to a cytotoxic calicheamicin derivative. 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. Further research and clinical trials indicate that gemtuzumab ozogamicin might be safe and effective in a subset of AML with favourable prognoses.
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.
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.
Ipilmumab
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.
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.
Nimotuzumab
Nimotuzumab is a chimeric human-mouse anti-EGFR monoclonal antibody invented in Cuba that has been developed by several companies through an extensive out-licensing program. It has been approved for squamous cell carcinoma in head and neck (SCCHN) in India, Cuba, Argentina, Colombia, Ivory Coast, Gabon, Ukraine, Peru and Sri Lanka; for glioma (pediatric and adult) in Cuba, Argentina, Philippines and Ukraine; for nasopharyngeal cancer in China and has been granted orphan drug status for glioma in USA and for glioma and pancreatic cancer in Europe. It was in several Phase I and II clinical trials in other indications as of 2014.
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.
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.
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.
Tositumomab/iodine (131I) tositumomab regimen
Tositumomab was a murine IgG2a anti-CD20 antibody covalently bound to radioactive Iodine 131 known as "Bexxar" that was approved for treatment of Non-Hodgkin lymphoma, which was voluntarily withdrawn from the market in February 2014 due to lack of sales.
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. HER-2 is a member of the epidermal growth factor receptor (EGFR) family of transmembrane tyrosine kinases. Once activated on cancer cells it activates cell signalling pathways that promote cell proliferation, cell growth, angiogenesis and metastasis, and inhibits programmed cell death (apoptosis).
Amplification or overexpression of HER-2 is present in 15-25% 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. The use of Trastuzumab is restricted to patients whose tumours over-express HER-2, primarily assessed by immunohistochemistry (IHC) and Fluorescent in situ hybridisation (FISH). Other methods are less routinely used including PCR-based methodologies and chromogenic in situ hybridization.
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 interferons and interleukins.
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.
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.
Adjuvant treatment with Polysaccharide-K
Japan's Ministry of Health, Labour and Welfare approved the use of Polysaccharide-K extracted from the mushroom, Coriolus versicolor, in the 1980s, to stimulate the immune systems of patients undergoing chemotherapy. It is a dietary supplement in the US and other jurisdictions.
Research
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. Subsequent activation and expansion of these cells is performed outside the body (ex vivo) and then they are transfused into the recipient. Activation can take place through gene therapy, or by exposing the T cells to tumor antigens. Although research has made major advances in this form of therapy, there is no approved adoptive T-cell therapy as yet.
As of 2014, several clinical trials for ACT were underway; initial clinical trials showing complete remission of leukemia in some patients in two small clinical trials, announced in December 2013, generated tremendous commercial and clinical interest.
Another approach is adoptive transfer of haploidentical γδ T cells or NK cells from the healthy donor. Major advantage of this approach is that these cells do not cause GVHD. The disadvantage is a frequent impaired function of the transferred cells.
Anti-CD47 antibodies
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 in laboratory tests on cells and mice. CD47 is present on many cancer cells and on many healthy cells. 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 an attack on the cancer cells.
Anti-GD2 antibodies
Carbohydrate antigens on the surface of cells can be used as targets for immunotherapy. GD2 is a ganglioside found on the surface of many types of cancer cell including neuroblastoma, retinoblastoma, melanoma, small cell lung cancer, brain tumors, osteosarcoma, rhabdomyosarcoma, Ewing’s sarcoma, liposarcoma, fibrosarcoma, leiomyosarcoma and other soft tissue sarcomas. It is not usually expressed on the surface of normal tissues, making it a good target for immunotherapy to allow for specific action against the tumor and reduced toxicity. As of 2014, Phase I, II, and III trials were underway for antibody treatments that bind to this antigen.
Immune checkpoint blockade
A ligand-receptor interaction that has been investigated as a target for cancer treatment is the interaction between the transmembrane programmed cell death 1 protein (PD-1; also known as CD279) and its ligand, PD-1 ligand 1 (PD-L1). In normal physiology PD-L1 on the surface of a cell binds to PD1 on the surface of an immune cell, which inhibits the activity of the immune cell. It appears that upregulation of PD-L1 on the cancer cell surface may allow them to evade the host immune system by inhibiting T cells that might otherwise attack the tumor cell. Antibodies that bind to either PD-1 or PD-L1 and therefore block the interaction may allow the T-cells to attack the tumor. Initial clinical trial results with an IgG4 PD1 antibody called Nivolumab were published in 2010.
EGF receptor antibodies
Development of an anti-EGFR antibody, Matuzumab, was discontinued in 2008.
Polysaccharides
Certain compounds found in mushrooms, primarily polysaccharide compounds, can up-regulate the immune system and may have anti-cancer properties. For example, Beta-glucans, such as lentinan have been shown in laboratory studies to stimulate macrophage, NK cells, T cells, and immune system cytokines, and have been investigated in clinical trials as immunologic adjuvant therapies.
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.
Public awareness
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.
