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.
- 1 History
- 2 Cell-Based immunotherapy
- 3 Monoclonal antibody therapy
- 3.1 Types of monoclonal antibodies
- 3.2 Mechanisms of cell death
- 3.3 Approved antibodies
- 4 Cytokine therapy
- 5 New and future immunotherapies
- 6 Natural products
- 7 Public awareness
- 8 See also
- 9 External links
- 10 References
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.
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.
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.
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 (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.
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.
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.
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.
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 (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 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 (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 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 (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.
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.
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 (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 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 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.
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.
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.
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 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.
New and future immunotherapies
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.
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. Phase I, II, and III trials are underway for antibody treatments that bind to this antigen.
Immune checkpoint blockade
A ligand-receptor interaction that is currently being investigated as a target for cancer treatment is the programmed cell death 1 (PD-1; also known as CD279) and 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.
EGF receptor antibodies
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.
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.
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. 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. Polysaccharide-K, isolated from Trametes versicolor, is another polysaccharide that has anti-cancer properties.
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. In Australia, a pharmaceutical based on a mixture of several mycological extracts including lentinan and Polysaccharide-K is sold commercially as MC-S.
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. In light of these developments, in 2013 the Cancer Research Institute, a nonprofit organization dedicated to cancer immunotherapy, proclaimed June Cancer Immunotherapy Awareness Month. 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.
- Cancer Research Institute - What is Cancer Immunotherapy
- Autologous Immune Enhancement therapy for Cancer
- Association for Immunotherapy of Cancer
- Society for Immunotherapy of Cancer
- Cancer Immunotherapy Consortium
- Cancer Immunotherapy Explained
- Immunotherapy Information
- Strebhardt, K; Ullrich, A (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.
- Waldmann, TA (March 2003). "Immunotherapy: past, present and future.". Nature Medicine 9 (3): 269–77. doi:10.1038/nm0303-269. PMID 12612576.
- 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.
- Restifo, NP; Dudley, ME; Rosenberg, SA (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.
- Palucka, K; Banchereau, J (Jul 25, 2013). "Dendritic-cell-based therapeutic cancer vaccines.". Immunity 39 (1): 38–48. doi:10.1016/j.immuni.2013.07.004. PMID 23890062.
- Gardner, TA; Elzey, BD; Hahn, NM (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.
- 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.
- 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.
- Shore, ND; Mantz, CA; Dosoretz, DE; Fernandez, E; Myslicki, FA; McCoy, C; Finkelstein, SE; Fishman, MN (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.
- Scott, AM; Wolchok, JD; Old, LJ (Mar 22, 2012). "Antibody therapy of cancer.". Nature reviews. Cancer 12 (4): 278–87. doi:10.1038/nrc3236. PMID 22437872.
- Harding, FA; Stickler, MM; Razo, J; DuBridge, RB (May–Jun 2010). "The immunogenicity of humanized and fully human antibodies: residual immunogenicity resides in the CDR regions". MAbs 2 (3): 256–65. PMID 20400861.
- Weiner, LM; Surana, R; Wang, S (May 2010). "Monoclonal antibodies: versatile platforms for cancer immunotherapy.". Nature reviews. Immunology 10 (5): 317–27. doi:10.1038/nri2744. PMID 20414205.
- Seidel, UJ; Schlegel, P; Lang, P (2013). "Natural killer cell mediated antibody-dependent cellular cytotoxicity in tumor immunotherapy with therapeutic antibodies.". Frontiers in immunology 4: 76. doi:10.3389/fimmu.2013.00076. PMID 23543707.
- Gelderman, KA; Tomlinson, S; Ross, GD; Gorter, A (March 2004). "Complement function in mAb-mediated cancer immunotherapy.". Trends in immunology 25 (3): 158–64. doi:10.1016/j.it.2004.01.008. PMID 15036044.
- Sharkey, RM; Goldenberg, DM (March 2011). "Cancer radioimmunotherapy.". Immunotherapy 3 (3): 349–70. doi:10.2217/imt.10.114. PMID 21395378.
- Waldmann, Thomas A. (2003). "Immunotherapy: past, present and future". Nature Medicine 9 (3): 269–277. doi:10.1038/nm0303-269. PMID 12612576.
- Demko, S; Summers, J; Keegan, P; Pazdur, R (February 2008). "FDA drug approval summary: alemtuzumab as single-agent treatment for B-cell chronic lymphocytic leukemia.". The oncologist 13 (2): 167–74. doi:10.1634/theoncologist.2007-0218. PMID 18305062.
- Cohen, MH; Gootenberg, J; Keegan, P; Pazdur, R (March 2007). "FDA drug approval summary: bevacizumab plus FOLFOX4 as second-line treatment of colorectal cancer.". The oncologist 12 (3): 356–61. doi:10.1634/theoncologist.12-3-356. PMID 17405901.
- Cohen, MH; Gootenberg, J; Keegan, P; Pazdur, R (June 2007). "FDA drug approval summary: bevacizumab (Avastin) plus Carboplatin and Paclitaxel as first-line treatment of advanced/metastatic recurrent nonsquamous non-small cell lung cancer.". The oncologist 12 (6): 713–8. doi:10.1634/theoncologist.12-6-713. PMID 17602060.
- Summers, J; Cohen, MH; Keegan, P; Pazdur, R (2010). "FDA drug approval summary: bevacizumab plus interferon for advanced renal cell carcinoma.". The oncologist 15 (1): 104–11. doi:10.1634/theoncologist.2009-0250. PMID 20061402.
- Cohen, MH; Shen, YL; Keegan, P; Pazdur, R (November 2009). "FDA drug approval summary: bevacizumab (Avastin) as treatment of recurrent glioblastoma multiforme.". The oncologist 14 (11): 1131–8. doi:10.1634/theoncologist.2009-0121. PMID 19897538.
- de Claro, RA; McGinn, K; Kwitkowski, V; Bullock, J; Khandelwal, A; Habtemariam, B; Ouyang, Y; Saber, H; Lee, K; Koti, K; Rothmann, M; Shapiro, M; Borrego, F; Clouse, K; Chen, XH; Brown, J; Akinsanya, L; Kane, R; Kaminskas, E; Farrell, A; Pazdur, R (Nov 1, 2012). "U.S. Food and Drug Administration approval summary: brentuximab vedotin for the treatment of relapsed Hodgkin lymphoma or relapsed systemic anaplastic large-cell lymphoma.". Clinical cancer research : an official journal of the American Association for Cancer Research 18 (21): 5845–9. doi:10.1158/1078-0432.CCR-12-1803. PMID 22962441.
- Pazdur, Richard. "FDA approval for Cetuximab". Retrieved 7 November 2013.
- Cohen, MH; Chen, H; Shord, S; Fuchs, C; He, K; Zhao, H; Sickafuse, S; Keegan, P; Pazdur, R (2013). "Approval summary: Cetuximab in combination with cisplatin or carboplatin and 5-fluorouracil for the first-line treatment of patients with recurrent locoregional or metastatic squamous cell head and neck cancer.". The oncologist 18 (4): 460–6. doi:10.1634/theoncologist.2012-0458. PMID 23576486.
- Bross, PF; Beitz, J; Chen, G; Chen, XH; Duffy, E; Kieffer, L; Roy, S; Sridhara, R; Rahman, A; Williams, G; Pazdur, R (June 2001). "Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia.". Clinical cancer research : an official journal of the American Association for Cancer Research 7 (6): 1490–6. PMID 11410481.
- "FDA - Ibritumomab Tiuxetan". Retrieved 7 November 2013.
- Pazdur, Richard. "FDA approval for Ipilimumab". Retrieved 7 November 2013.
- Lemery, SJ; Zhang, J; Rothmann, MD; Yang, J; Earp, J; Zhao, H; McDougal, A; Pilaro, A; Chiang, R; Gootenberg, JE; Keegan, P; Pazdur, R (Sep 1, 2010). "U.S. Food and Drug Administration approval: ofatumumab for the treatment of patients with chronic lymphocytic leukemia refractory to fludarabine and alemtuzumab.". Clinical cancer research : an official journal of the American Association for Cancer Research 16 (17): 4331–8. doi:10.1158/1078-0432.CCR-10-0570. PMID 20601446.
- Giusti, RM; Cohen, MH; Keegan, P; Pazdur, R (March 2009). "FDA review of a panitumumab (Vectibix) clinical trial for first-line treatment of metastatic colorectal cancer.". The oncologist 14 (3): 284–90. doi:10.1634/theoncologist.2008-0254. PMID 19282350.
- James, JS; Dubs, G (Dec 5, 1997). "FDA approves new kind of lymphoma treatment. Food and Drug Administration.". AIDS treatment news (284): 2–3. PMID 11364912.
- Casak, SJ; Lemery, SJ; Shen, YL; Rothmann, MD; Khandelwal, A; Zhao, H; Davis, G; Jarral, V; Keegan, P; Pazdur, R (2011). "U.S. Food and drug administration approval: rituximab in combination with fludarabine and cyclophosphamide for the treatment of patients with chronic lymphocytic leukemia.". The oncologist 16 (1): 97–104. doi:10.1634/theoncologist.2010-0306. PMID 21212432.
- Pazdur, Richard. "FDA Approval for Tositumomab and Iodine I 131 Tositumomab". Retrieved 7 November 2013.
- "FDA Expands Use of Herceptin for Early Stage Breast Cancer After Primary Therapy". Retrieved 7 November 2013.
- Byrd JC, Stilgenbauer S, Flinn IW. Chronic Lymphocytic Leukemia. Hematology (Am Soc Hematol Educ Program) 2004: 163-183. Date retrieved: 26/01/2006.
- Domagała, A; Kurpisz, M (Mar–Apr 2001). "CD52 antigen--a review.". Medical science monitor : international medical journal of experimental and clinical research 7 (2): 325–31. PMID 11257744.
- Dearden, C (Jul 19, 2012). "How I treat prolymphocytic leukemia.". Blood 120 (3): 538–51. doi:10.1182/blood-2012-01-380139. PMID 22649104.
- Kirkwood, JM; Butterfield, LH; Tarhini, AA; Zarour, H; Kalinski, P; Ferrone, S (Sep–Oct 2012). "Immunotherapy of cancer in 2012.". CA: a cancer journal for clinicians 62 (5): 309–35. doi:10.3322/caac.20132. PMID 22576456.
- Lenz, HJ (April 2005). "Antiangiogenic agents in cancer therapy.". Oncology (Williston Park, N.Y.) 19 (4 Suppl 3): 17–25. PMID 15934499.
- Gerber, HP; Ferrara, N (Feb 1, 2005). "Pharmacology and pharmacodynamics of bevacizumab as monotherapy or in combination with cytotoxic therapy in preclinical studies.". Cancer Research 65 (3): 671–80. PMID 15705858.
- Sun, W (Oct 11, 2012). "Angiogenesis in metastatic colorectal cancer and the benefits of targeted therapy.". Journal of hematology & oncology 5: 63. doi:10.1186/1756-8722-5-63. PMID 23057939.
- Mukherji, SK (February 2010). "Bevacizumab (Avastin).". AJNR. American journal of neuroradiology 31 (2): 235–6. doi:10.3174/ajnr.A1987. PMID 20037132.
- Cheng, YD; Yang, H; Chen, GQ; Zhang, ZC (Nov 1, 2013). "Molecularly targeted drugs for metastatic colorectal cancer.". Drug design, development and therapy 7: 1315–1322. doi:10.2147/DDDT.S52485. PMID 24204124.
- Younes, A; Yasothan, U; Kirkpatrick, P (Jan 3, 2012). "Brentuximab vedotin.". Nature reviews. Drug discovery 11 (1): 19–20. doi:10.1038/nrd3629. PMID 22212672.
- Garnock-Jones, KP (Mar 2013). "Brentuximab vedotin: a review of its use in patients with hodgkin lymphoma and systemic anaplastic large cell lymphoma following previous treatment failure.". Drugs 73 (4): 371–81. doi:10.1007/s40265-013-0031-5. PMID 23494187.
- Bou-Assaly, W; Mukherji, S (April 2010). "Cetuximab (erbitux).". AJNR. American journal of neuroradiology 31 (4): 626–7. doi:10.3174/ajnr.A2054. PMID 20167650.
- Ricart, AD (Oct 15, 2011). "Antibody-drug conjugates of calicheamicin derivative: gemtuzumab ozogamicin and inotuzumab ozogamicin.". Clinical cancer research : an official journal of the American Association for Cancer Research 17 (20): 6417–27. doi:10.1158/1078-0432.CCR-11-0486. PMID 22003069.
- Food and Drug Administration. "Mylotarg (gemtuzumab ozogamicin): Market Withdrawal". Retrieved 23 November 2013.
- Ravandi, F; Estey, EH; Appelbaum, FR; Lo-Coco, F; Schiffer, CA; Larson, RA; Burnett, AK; Kantarjian, HM (Nov 10, 2012). "Gemtuzumab ozogamicin: time to resurrect?". Journal of clinical oncology : official journal of the American Society of Clinical Oncology 30 (32): 3921–3. doi:10.1200/JCO.2012.43.0132. PMID 22987091.
- Tennvall, J; Fischer, M; Bischof Delaloye, A; Bombardieri, E; Bodei, L; Giammarile, F; Lassmann, M; Oyen, W; Brans, B; Therapy Committee,, EANM; Oncology Committee,, EANM; Dosimetry Committee,, EANM (April 2007). "EANM procedure guideline for radio-immunotherapy for B-cell lymphoma with 90Y-radiolabelled ibritumomab tiuxetan (Zevalin).". European journal of nuclear medicine and molecular imaging 34 (4): 616–22. doi:10.1007/s00259-007-0372-y. PMID 17323056.
- Maloney, DG (May 24, 2012). "Anti-CD20 antibody therapy for B-cell lymphomas.". The New England Journal of Medicine 366 (21): 2008–16. doi:10.1056/NEJMct1114348. PMID 22621628.
- Sondak, VK; Smalley, KS; Kudchadkar, R; Grippon, S; Kirkpatrick, P (Jun 2011). "Ipilimumab.". Nature reviews. Drug discovery 10 (6): 411–2. doi:10.1038/nrd3463. PMID 21629286.
- Lipson, EJ; Drake, CG (Nov 15, 2011). "Ipilimumab: an anti-CTLA-4 antibody for metastatic melanoma.". Clinical cancer research : an official journal of the American Association for Cancer Research 17 (22): 6958–62. doi:10.1158/1078-0432.CCR-11-1595. PMID 21900389.
- Thumar, JR; Kluger, HM (Dec 2010). "Ipilimumab: a promising immunotherapy for melanoma.". Oncology (Williston Park, N.Y.) 24 (14): 1280–8. PMID 21294471.
- Chambers, CA; Kuhns, MS; Egen, JG; Allison, JP (2001). "CTLA-4-mediated inhibition in regulation of T cell responses: mechanisms and manipulation in tumor immunotherapy.". Annual review of immunology 19: 565–94. doi:10.1146/annurev.immunol.19.1.565. PMID 11244047.
- Castillo, J; Perez, K (2010). "The role of ofatumumab in the treatment of chronic lymphocytic leukemia resistant to previous therapies.". Journal of blood medicine 1: 1–8. PMID 22282677.
- Zhang, B (Jul–Aug 2009). "Ofatumumab.". mAbs 1 (4): 326–31. PMID 20068404.
- Keating, GM (May 28, 2010). "Panitumumab: a review of its use in metastatic colorectal cancer.". Drugs 70 (8): 1059–78. PMID 20481659.
- Saltz, L; Easley, C; Kirkpatrick, P (Dec 2006). "Panitumumab.". Nature reviews. Drug discovery 5 (12): 987–8. PMID 17201026.
- Keating, GM (Jul 30, 2010). "Rituximab: a review of its use in chronic lymphocytic leukaemia, low-grade or follicular lymphoma and diffuse large B-cell lymphoma.". Drugs 70 (11): 1445–76. PMID 20614951.
- Plosker, GL; Figgitt, DP (2003). "Rituximab: a review of its use in non-Hodgkin's lymphoma and chronic lymphocytic leukaemia.". Drugs 63 (8): 803–43. PMID 12662126.
- Cerny, T; Borisch, B; Introna, M; Johnson, P; Rose, AL (Nov 2002). "Mechanism of action of rituximab.". Anti-cancer drugs. 13 Suppl 2: S3–10. PMID 12710585.
- Janeway, Charles; Paul Travers, Mark Walport, and Mark Shlomchik (2001). Immunobiology; Fifth Edition. New York and London: Garland Science. ISBN 0-8153-4101-6.
- Weiner, GJ (Apr 2010). "Rituximab: mechanism of action.". Seminars in hematology 47 (2): 115–23. PMID 20350658.
- Rao, AV, Akabani, G, Rizzieri, DA. (2005). "Radioimmunotherapy for Non-Hodgkin's Lymphoma". Clin Med Res 3 (3): 157–165. doi:10.3121/cmr.3.3.157. PMC 1237157. PMID 16160070.
- Kaminski, MS, Tuck, M, Estes, J, Kolstad, A, Ross, CW, Zasadny, K, Regan, D, Kison, P et al. (2005). "131I-tositumomab therapy as initial treatment for follicular lymphoma". N Engl J Med 352 (5): 441–449. doi:10.1056/NEJMoa041511. PMID 15689582.
- Garnock-Jones, KP; Keating, GM; Scott, LJ (2010). "Trastuzumab: A review of its use as adjuvant treatment in human epidermal growth factor receptor 2 (HER2)-positive early breast cancer.". Drugs 70 (2): 215–39. PMID 20108993.
- Slamon, DJ, Godolphin, W, Jones, LA, Holt, JA, Wong, SG, Keith, DE, Levin, WJ, Stuart, SG et al. (1989). "Studies of the HER-2/neu proto oncogene in human breast and ovarian cancer". Science 244 (4905): 707–712. doi:10.1126/science.2470152. PMID 2470152.
- Shaaban, AM; Purdie, CA; Bartlett, JM; Stein, RC; Lane, S; Francis, A; Thompson, AM; Pinder, SE; Translational Subgroup of the NCRI Breast Clinical Studies, Group (Feb 2014). "HER2 testing for breast carcinoma: recommendations for rapid diagnostic pathways in clinical practice.". Journal of clinical pathology 67 (2): 161–7. PMID 24062360.
- van de Vijver, M (2002). "Emerging technologies for HER2 testing.". Oncology. 63 Suppl 1: 33–8. PMID 12422053.
- Dranoff, G (Jan 2004). "Cytokines in cancer pathogenesis and cancer therapy.". Nature reviews. Cancer 4 (1): 11–22. PMID 14708024.
- Dunn, GP; Koebel, CM; Schreiber, RD (November 2006). "Interferons, immunity and cancer immunoediting.". Nature reviews. Immunology 6 (11): 836–48. doi:10.1038/nri1961. PMID 17063185.
- Lasfar, A; Abushahba, W; Balan, M; Cohen-Solal, KA (2011). "Interferon lambda: a new sword in cancer immunotherapy.". Clinical & developmental immunology 2011: 349575. doi:10.1155/2011/349575. PMID 22190970.
- Coventry, BJ; Ashdown, ML (2012). "The 20th anniversary of interleukin-2 therapy: bimodal role explaining longstanding random induction of complete clinical responses.". Cancer management and research 4: 215–21. PMID 22904643.
- "Anti-CD47 antibody may offer new route to successful cancer vaccination - Office of Communications & Public Affairs - Stanford University School of Medicine". Med.stanford.edu. 2013-05-20. Retrieved 2013-08-25.
- Blaustein, Michael (2013-07-11). "New wonder drug matches and kills all kinds of cancer — human testing starts 2014". NYPOST.com. Retrieved 2013-08-25.
- Unanue, ER (Jul 2, 2013). "Perspectives on anti-CD47 antibody treatment for experimental cancer.". Proceedings of the National Academy of Sciences of the United States of America 110 (27): 10886–7. PMID 23784781.
- Ahmed, M; Cheung, NK (Jan 21, 2014). "Engineering anti-GD2 monoclonal antibodies for cancer immunotherapy.". FEBS letters 588 (2): 288–97. PMID 24295643.
- Pardoll, DM (Mar 22, 2012). "The blockade of immune checkpoints in cancer immunotherapy.". Nature reviews. Cancer 12 (4): 252–64. PMID 22437870.
- Patel, S; Goyal, A (Mar 2012). "Recent developments in mushrooms as anti-cancer therapeutics: a review.". 3 Biotech 2 (1): 1–15. PMID 22582152.
- Masuoka, J. (Apr 2004). "Surface glycans of Candida albicans and other pathogenic fungi: physiological roles, clinical uses, and experimental challenges" (Free full text). Clinical Microbiology Reviews 17 (2): 281–310. doi:10.1128/CMR.17.2.281-310.2004. ISSN 0893-8512. PMC 387410. PMID 15084502. (review)
- Fisher, M; Yang, LX (May–Jun 2002). "Anticancer effects and mechanisms of polysaccharide-K (PSK): implications of cancer immunotherapy.". Anticancer research 22 (3): 1737–54. PMID 12168863.
- "Coriolus Versicolor".
- Winslow, Ron (2013-05-15). "New Cancer Drugs Harness Power of Immune System - WSJ.com". Online.wsj.com. Retrieved 2013-08-25.
- "A workout a day may keep cancer away". CNN.com. Retrieved 2013-08-25.
- "News at CRI - CRI". Cancerresearch.org. 2013-05-07. Retrieved 2013-08-25.